Table of Content

08 August 2026, Volume 30 Issue 22 Previous Issue    Next Issue

For Selected:

Download Citations EndNote Reference Manager ProCite BibTeX RefWorks

Toggle Thumbnails

Select

U-shaped association between magnesium intake and all-cause and cancer mortality in patients with osteoarthritis Zhou Haidong, Lu Yaohong, Fan Shaoyong 2026, 30 (22):  5629-5638.  doi: 10.12307/2026.140 Abstract ( 52 )   PDF (3180KB) ( 27 )   Save BACKGROUND: Clarifying the relationship between dietary magnesium intake and mortality risk in patients with osteoarthritis can provide theoretical basis for optimizing dietary interventions, reducing all-cause mortality and cardiovascular disease mortality, and provide reference value for nutritional management in patients with osteoarthritis. OBJECTIVE: To assess the association between dietary magnesium intake and all-cause and etiological mortality in adults with osteoarthritis in the United States.  METHODS: We enrolled data of adults with osteoarthritis from the National Health and Nutrition Examination Survey (conducted by the National Center for Health Statistics under the U.S. Centers for Disease Control and Prevention, it aims to assess the health and nutritional status of the civilian population in the United States) between 2003 and 2020. The association between dietary magnesium intake and mortality in patients with osteoarthritis was evaluated by Cox proportional hazard model and two-stage Cox model. To assess whether the association between dietary magnesium intake and all-cause mortality was consistent across the population and to identify potential high-risk groups, subgroup analyses in terms of age, sex, body mass index, hypertension, diabetes mellitus, physical activity, smoking status, and drinking status were performed and tested for interactions. RESULTS AND CONCLUSION: (1) A total of 2 868 patients with osteoarthritis were included in this study. During the follow-up period, 699 all-cause deaths, 281 cardiovascular disease deaths and 143 cancer deaths were recorded. After multivariate adjustment, higher dietary magnesium intake was associated with a significantly lower risk of death from cardiovascular disease. Each 1-unit increase in dietary magnesium intake was associated with a 78% lower risk of death from cardiovascular disease (P=0.022 2). The results of quartile analysis of dietary magnesium intake were consistent with this. At the same time, dietary magnesium intake showed a U-shaped association with all-cause mortality and cancer mortality, with turning points at 0.38 g/d and 0.4 g/d, respectively. When magnesium intake was below the threshold, higher intake was significantly associated with lower all-cause mortality [hazard ratio (HR)=0.17, 95% confidence interval (CI)=0.06-0.50] and cancer mortality (HR=0.16, 95% CI=0.01-1.50). Above the threshold, however, magnesium intake was significantly associated with an increase in all-cause mortality (HR=2.94, 95% CI=0.55-15.84) and cancer mortality (HR=26.30, 95% CI=1.46-474.73). Subgroup analyses further verified the robustness of the results. (2) The results suggested that magnesium deficiency might play an adverse role in cardiovascular health. At the same time, there was a U-shaped relationship between dietary magnesium intake and all-cause mortality and cancer mortality, with either too low or too high magnesium intake associated with an increased risk of death. This finding provides new insights into the potential impacts of dietary magnesium intake on cardiovascular disease, cancer, and all-cause mortality, a scientific basis for nutritional interventions in patients with osteoarthritis, and theoretical support for the prevention and management of cardiovascular disease and cancer in China, especially in the context of the high prevalence of cardiovascular disease, where a rational magnesium intake can help to reduce the associated mortality. Figures and Tables | References | Related Articles | Metrics

Select

Transverse tibial bone transfer accelerates healing of foot ulcers in a rabbit model of type 2 diabetes mellitus: involvement and regulation of circular RNA Sun Zuyan, Huang Wenliang, Xu Lin, Li Haojie, Xie Tongliang, Yang Zhihang, Deng Jiang 2026, 30 (22):  5639-5649.  doi: 10.12307/2026.170 Abstract ( 44 )   PDF (11553KB) ( 7 )   Save BACKGROUND: Transverse tibial bone transfer is an emerging surgical technique that enhances local blood circulation and promotes angiogenesis, thereby accelerating the healing of diabetic foot ulcers. Although this technique has demonstrated positive clinical outcomes, its specific molecular mechanisms remain unclear. Recently, the role of circular RNA in angiogenesis and wound healing has gained increasing recognition. Circular RNA may influence the healing process by regulating the expression of related genes; however, its involvement in the treatment of diabetic foot ulcers through transverse tibial bone transfer has yet to be explored. OBJECTIVE: To investigate the therapeutic effects of transverse tibial bone transfer on diabetic foot ulcers in a rabbit model and the mechanism of action.  METHODS: Eighteen 3-month-old male New Zealand rabbits, weighing 2.8–3.6 kg, were included in this study. After being fed a high-sugar, high-fat diet for 1 month, type II diabetic rabbit models were induced by intravenous injection of alloxan monohydrate. After successful modeling, the right femoral artery at the mid-upper segment was ligated, and the full-thickness skin of the ipsilateral dorsum of the foot was excised to simulate the pathological characteristics of diabetic foot ulcers. The successfully modeled rabbits were then randomly divided into four groups (n = 4 rabbits per group): blank group (no additional treatment), dressing group (routine disinfection with povidone-iodine after modeling), sham surgery group (installing a transverse tibial bone transfer scaffold but without bone transfer procedure), surgery group (installing a transverse tibial bone transfer scaffold plus bone transfer procedure). At 7 and 14 days after surgery, the healing of the foot dorsum ulcers was observed in each group. At 7, 14, and 21 days after surgery, serum levels of vascular endothelial growth factor A and CD31 were measured via enzyme-linked immunosorbent assay. At 14 days after surgery, ulcer tissue samples from each group were collected for histopathological analysis (hematoxylin and eosin staining), CD31 immunofluorescence staining, and Western blot assay to assess vascular endothelial growth factor A and CD31 protein expression levels. At 7, 14, and 21 days after surgery, venous blood samples were collected from the surgery group for whole-genome sequencing, and the differential expression of circular RNA was analyzed. RESULTS AND CONCLUSION: At 14 and 21 days after surgery, the surgery group exhibited significantly better diabetic foot ulcer recovery compared with the other three groups, demonstrating superior epidermal regeneration, collagen deposition, and angiogenesis. At 14 and 21 days after surgery, the surgery group showed markedly higher serum levels of vascular endothelial growth factor A and CD31 than the other groups (P < 0.01). Gene sequencing analysis revealed the most pronounced changes in circular RNA expression on day 21, particularly the progressive downregulation of circular RNA PDS5B over time. This suggests a potential link between circular RNA PDS5B and angiogenesis and tissue repair mechanisms. All findings indicate that transverse tibial bone transfer effectively enhances diabetic foot ulcer healing in rabbits. The differential expression of circular RNAs, especially the significant decrease in circular RNA PDS5B, suggests that transverse tibial bone transfer may accelerate wound repair and angiogenesis by activating relevant molecular pathways. Figures and Tables | References | Related Articles | Metrics

Select

Cobalt chloride-induced hypoxic environment accelerates knee cartilage degeneration in New Zealand rabbits Xu Peng, Jiang Wei, Yu You, Lei Zhengliang, Tian Yang, Zhang Jie, Liu Luchang 2026, 30 (22):  5650-5658.  doi: 10.12307/2026.161 Abstract ( 44 )   PDF (3512KB) ( 12 )   Save BACKGROUND: Cobalt chloride solution is commonly used to induce osteoarthritis cell models in vitro. However, its ability to construct animal models of osteoarthritis by intra-articular injection remains unknown. OBJECTIVE: To investigate the effect of intra-articular injection of different concentrations of cobalt chloride solution on cartilage degeneration in the knee joint. METHODS: Thirty-six healthy adult male New Zealand rabbits were randomly divided into four groups: low, medium and high dose cobalt chloride groups and control group. The right hind knee was intra-articularly injected with 100, 200, and 300 μmol/(L·kg) of cobalt chloride, while the left hind knee served as the control knee and was injected with an equal amount of normal saline. At 4, 8 and 12 weeks after operation, four rats were killed respectively. The cartilage on the surface of the femur was exposed for gross morphological observation, and then the cartilage tissues were taken for hematoxylin-eosin staining, safranine O-fast green staining, the Osteoarthritis Research Society International scoring, and immunohistochemical staining of interleukin 1 and tumor necrosis factor α, to determine cartilage degeneration in various aspects. RESULTS AND CONCLUSION: (1) Gross observation: At the same postoperative time point, with the increase of cobalt chloride solution concentration, cartilage degeneration tended to aggravate progressively. High doses of cobalt chloride even involved the deeper layers of cartilage and subchondral bone. At the same concentration of cobalt chloride solution, with the prolongation of the modeling time, the cartilage degeneration developed progressively. (2) Hematoxylin-eosin staining, safranine O-fast green staining, and the Osteoarthritis Research Society International score: At the same postoperative time point, as the cobalt chloride solution concentration increased, the cartilage surface became rough, the cartilage surface layer became thinner, and the destruction was aggravated, with a progressive increase in the International Osteoarthritis Research Association score (P < 0.05). At the same concentration of cobalt chloride solution, with the prolongation of the modeling time, the chondrocyte arrangement tended to be disordered, polarity was lost, and the destruction of the superficial cartilage and subchondral bone was progressively aggravated, and the International Society for the Study of Osteoarthritis (ISSOA) score was gradually increased (P < 0.05). (3) Immunohistochemistry: At the same postoperative time point, with the increase of cobalt chloride solution concentration, cartilage degeneration was aggravated, intracellular brown granules were increased, and the positive expression of interleukin 1 and tumor necrosis factor α was increased (P < 0.01). At the same concentration of cobalt chloride solution, with the prolongation of the modeling time, cartilage destruction and fissures were increased, and the positive expression of interleukin 1 and tumor necrosis factor α was increased (P < 0.01). As a result, a model of osteoarthritis induced in New Zealand rabbits by intra-articular injection of cobalt chloride solution was successfully established, the stability and reliability of the animal model was preliminarily verified, and it also proved that cartilage degeneration develops progressively with the increase of the modeling concentration and the prolongation of the modeling time. Figures and Tables | References | Related Articles | Metrics

Select

Articular cartilage lesions at different stages of steroid-induced osteonecrosis of the femoral head: characteristics and mechanisms of crescent sign formation Wan Ziyi, Jiang Mengyu, Zhou Yuehui, Xue Yuxuan, Wei Yangwenxiang, Zhou Chi 2026, 30 (22):  5659-5670.  doi: 10.12307/2026.132 Abstract ( 62 )   PDF (5273KB) ( 25 )   Save BACKGROUND: The crescent sign is a significant radiological feature in the progression of steroid-induced osteonecrosis of the femoral head (SIONFH), indicating the separation and defect of articular cartilage and subchondral bone. The appearance of the crescent sign is associated with the mid-to-late stages of the disease and poor prognosis. However, studies on the specific pathological characteristics and progression patterns of articular cartilage in SIONFH are limited. OBJECTIVE: To observe the pathological features of articular cartilage in SIONFH specimens at different stages, explore the underlying pathological mechanisms, and elucidate the formation mechanism of the crescent sign, providing a theoretical basis for optimizing hip-preserving strategies. METHODS: Femoral head specimens from SIONFH patients who underwent total hip replacement surgery at the First Affiliated Hospital of Guangzhou University of Chinese Medicine from 2021 to 2024 were selected. According to the ARCO staging system, the specimens were divided into mild, moderate, and severe collapse groups, with fresh femoral neck fracture specimens as the control group. All specimens were coronally sectioned, and the necrotic cartilage surface was obtained for histological staining (hematoxylin-eosin, Safranin O-fast green) and pathological assessment. Immunohistochemical staining was used to detect bone and cartilage-related protein expression, while Western blotting was employed to measure the expression levels of relevant proteins. An apoptosis kit was used to detect the level of apoptosis in articular cartilage. RESULTS AND CONCLUSION: (1) Gross observation revealed that the control group had smooth cartilage surfaces without wrinkling or proliferation, and no separation defects between articular cartilage and subchondral bone, which was strong but pliable in texture. In contrast, SIONFH specimens exhibited significant wrinkling of the cartilage surface, with separation defects between articular cartilage and subchondral bone, which felt relaxed upon palpation. (2) Pathological observation of the femoral head showed that in the control group, chondrocytes were orderly arranged, the cartilage matrix was uniformly stained, the tidemark was intact and continuous, and the calcified cartilage layer was clearly connected to the subchondral bone with orderly trabecular arrangement. In SIONFH specimens, chondrocytes were disordered, with increased empty lacunae, varying degrees of matrix staining loss, duplication and loss of the tidemark, numerous cavities and sclerosis in the calcified cartilage layer, and invasion of granulation tissue into these cavities. Separation defects were observed between calcified cartilage and subchondral bone, with abundant granulation tissue in the subchondral bone trabecular spaces. (3) Immunohistochemical analysis revealed increased positive staining for Runt-related transcription factor 2, matrix metalloproteinase 13, matrix metalloproteinase 3, type I collagen alpha 2 chain in the calcified cartilage layer and deep cartilage of SIONFH specimens. Increased positive staining for vascular endothelial growth factor A, hypoxia-inducible factor 1α, interleukin 1β, tumor necrosis factor α was observed in the subchondral bone trabecular spaces and granulation and scar tissues of deep cartilage. (4) Western blot results showed decreased expression of type II collagen α1 chain and SOX9 proteins, and increased expression of Runt-related transcription factor 2, matrix metalloproteinase 13, hypoxia-inducible factor 1α, and vascular endothelial growth factor A in SIONFH specimens. (5) Caspase 3/7 activity was significantly higher in SIONFH specimens than the control group and was positively correlated with the degree of collapse. In conclusion, articular cartilage lesions in SIONFH patients are primarily concentrated in the deep and calcified cartilage areas surrounding the necrotic zone. Subchondral bone tissue necrosis leads to changes in the local microenvironment and elastic modulus, causing sclerosis of the calcified cartilage. As the femoral head continues to bear weight, stress concentration in the sclerotic area around the necrotic zone leads to brittle fractures, initiating the crescent sign. Fracture of bone and cartilage disrupts the subchondral cortical bone barrier, and invasion of granulation tissues into the subchondral bone trabecular spaces directly stimulates calcified and deep cartilage, resulting in terminal differentiation and apoptosis of chondrocytes, matrix degradation, and cavity formation. This leads to a decline in the repair capacity of articular cartilage. The affected cartilage cannot properly integrate with the subchondral bone, further exacerbating joint cartilage wear. As the disease progresses, extensive separation defects between bone and cartilage occur, manifesting as the crescent sign on imaging. Figures and Tables | References | Related Articles | Metrics

Select

Potential mechanism by which iroquois homeobox 3 regulates the browning of perivascular adipose tissue in vascular injury Hu Xiaoyong, Song Qianhua, Yang Zhaoying, Tang Rui, Li Hongjian 2026, 30 (22):  5671-5681.  doi: 10.12307/2026.169 Abstract ( 44 )   PDF (15946KB) ( 15 )   Save BACKGROUND: Vascular injury-related diseases have garnered significant attention in the medical field, and the browning of perivascular adipose tissue is closely linked to these diseases. However, the regulatory mechanisms of specific genes involved in this process remain unclear.  OBJECTIVE: To investigate the potential mechanism by which iroquois homeobox 3 regulates the browning of perivascular adipose tissue in vascular injury. METHODS: The perivascular adipose tissue-related single-cell sequencing data matrix GSE275779 was analyzed to investigate the expression levels and functions of iroquois homeobox 3 in various cell subpopulations. In conjunction with adipocyte-related microarray and sequencing data GSE44059, GSE7032, GSE185518, and GSE168387, differentially expressed genes were identified, and the expression level of iroquois homeobox 3 during the differentiation of browning adipocytes was validated. The downstream target genes of iroquois homeobox 3 were screened using the msigdb database and the ChIP-seq database GTRD. By disrupting iroquois homeobox 3 and overexpressing retinol saturase in adipocyte precursor cells, the mRNA and protein expression levels of adipocyte browning-related genes were detected using quantitative polymerase chain reaction and western blot analysis. RESULTS AND CONCLUSION: Bioinformatics analysis results showed that adipocyte characteristic factors PR domain containing 16, cell death-inducing DFFA-like effector A, and uncoupling protein 1 were significantly downregulated in diabetic perivascular adipose tissue, and these genes were all involved in fat browning. Combined with high-throughput sequencing data analysis, iroquois homeobox 3 was found to be highly expressed in brown adipose tissue and to play a role in the differentiation process of brown adipocytes. Retinol saturase was identified as a downstream target gene of iroquois homeobox 3, and its expression levels differed during the differentiation of brown adipocytes. In mature brown adipocytes, knocking down iroquois homeobox 3 resulted in a decrease in the expression of retinol saturase and adipocyte browning-related markers (uncoupling protein 1, peroxisome proliferator-activated receptor gamma coactivator 1 alpha, PR domain containing 16). In the retinol saturase rescue experiment, overexpressing retinol saturase substantially upregulated the protein levels of adipocyte browning-related markers, but did not affect the expression of iroquois homeobox 3. This study preliminarily reveals the potential mechanism by which iroquois homeobox 3 regulates the browning of perivascular adipose tissue in vascular injury.  Figures and Tables | References | Related Articles | Metrics

Select

Gushukang Granule-containing drug serum improves dexamethasone-induced atrophy of C2C12 myotubes via regulating mitochondrial homeostasis Wei Wei, Liu Hongfei, Qi Xiaonan, Liu Yantong, Wang Deyu, Yu Zhitong, Qiao Chunlin, Wang Shixuan, Teng Hai 2026, 30 (22):  5682-5693.  doi: 10.12307/2026.141 Abstract ( 62 )   PDF (4343KB) ( 9 )   Save BACKGROUND: Gushukang Granule is a Chinese herbal compound preparation, which is commonly used clinically for the treatment of osteoporosis and other bone-related diseases. However, its role in the regulation of muscle metabolism is not clear. OBJECTIVE: To investigate the inhibitory effect of Gushukang Granule-containing serum on dexamethasone-induced C2C12 muscle atrophy. METHODS: (1) In vivo experiment: Thirty-six 3-month-old female Sprague-Dawley rats were randomly divided into model group, blank group and Gushukang group, with 12 rats in each group. The rats in the model group were given 2.5 mg/kg dexamethasone by intragastric administration, once a day, for 1 week, followed by 3 weeks of normal feeding. The rats in the Gushukang group were given 0.48 g/kg Gushukang Granule suspension by intragastric administration after modeling, once a day, for 3 weeks. The rats in the blank group were given the same amount of distilled water by intragastric administration without modeling, once a day for 4 weeks. Two hours after the last administration, the left femur and gastrocnemius specimens of rats were taken and stained with hematoxylin-eosin to observe the morphological changes. At the same time, RNA was extracted from the right gastrocnemius and femur tissues, and the mRNA expression levels of mitochondrial function, autophagy and inflammatory genes were detected by real-time fluorescent quantitative PCR. (2) In vitro experiment: C2C12 cells were cultured and induced with 2% equine serum to differentiate into myotube cells. The differentiated myotube cells were divided into control group, model group and Gushukang Granule-containing serum group. The muscle atrophy model was constructed by incubation with 4 µmol/L dexamethasone for 48 hours, in which the Gushukang group was treated with dexamethasone for 24 hours followed by cultured with 10% Gushukang drug-containing serum for another 24 hours. Cell counting kit-8 was used to detect cell viability, flow cytometry was used to detect reactive oxygen species, and ultrastructural changes were observed by transmission electron microscopy. The expression levels of mitochondrial function related proteins, autophagy related proteins and antioxidant related proteins were detected by western blot. RESULTS AND CONCLUSION: (1) Hematoxylin-eosin staining showed that compared with the model group, the muscle fiber structure recovered well in the Gushukang group. Real-time fluorescence quantitative PCR further verified the upregulatory effect of Gushukang Granule-containing serum on mitochondrial function and autophagy related genes, supporting its multi-target mechanism to alleviate muscle atrophy. (2) The results of flow cytometry and cell counting kit-8 showed that the reactive oxygen species level in C2C12 cells was significantly increased after dexamethasone treatment (P < 0.05), and the cell viability was significantly decreased (P < 0.05). Under the transmission electron microscopy, dexamethasone induced ultrastructure disorder, the number of organelles decreased significantly, and mitochondrial atrophy and fuzzy state appeared, accompanied by a large number of autophagosomes and cytoplasmic vacuoles. Western blot results showed that the expressions of mitochondrial function-related proteins (translocase of outer mitochondrial membrane 20 and heat shock protein 60) were significantly decreased after dexamethasone treatment, the autophagy related proteins (LC3 and Beclin-1) were abnormally expressed (P < 0.05), and the expression of silent information regulator 1 was significantly decreased (P < 0.05). It is suggested that dexamethasone can destroy mitochondrial homeostasis and inhibit autophagy. After treatment with drug-containing serum of Gushukang Granules, reactive oxygen species level was significantly decreased (P < 0.05), and cell viability was significantly increased (P < 0.05). Under the transmission electron microscopy, the ultrastructure of the cells was improved and the morphology of mitochondria was relatively restored, but not completely repaired. Western blot results further showed that the expressions of translocase of outer mitochondrial membrane 20, heat shock protein 60 and silent information regulator 1 were significantly up-regulated (P < 0.05), and the expressions of LC3 and Beclin-1 returned to normal levels (P < 0.05). These findings indicate that the drug-containing serum of Gushukang Granules plays a positive role in improving mitochondrial function, reducing oxidative stress and regulating autophagy. Figures and Tables | References | Related Articles | Metrics

Select

Biomarkers for diabetic foot ulcers: single-cell transcriptomics bioinformatics analysis and experimental validation Yang Wenyan, Wang Huayu, Yang Like, Pang Xue, Wang Yutao 2026, 30 (22):  5694-5706.  doi: 10.12307/2026.171 Abstract ( 87 )   PDF (28288KB) ( 14 )   Save BACKGROUND: Factors such as infection, limb ischemia, and histiocyte activation are involved in diabetic foot ulcers, but the key cell subpopulations influencing diabetic foot ulcer healing remain unclear, and specific biomarkers for diabetic foot ulcers have yet to be identified. Gene Expression Omnibus (GEO) is a publicly accessible database managed by the National Center for Biotechnology Information (NCBI) that stores high-throughput gene expression data, allowing users to freely submit, share, query, and analyze data. By conducting secondary analysis on published data, research costs can be minimized and new research avenues and methods can be discovered. OBJECTIVE: To screen for biomarkers for diabetic foot ulcers using single-cell transcriptomics and conventional transcriptomics bioinformatics analysis, high-dimensional weighted gene co-expression network analysis, and weighted gene co-expression network analysis. METHODS: The single-cell transcriptomics dataset GSE165816 from the gene expression database was downloaded, including unhealed ulcer tissue samples from diabetic foot ulcer patients and foot skin samples from diabetic patients. After data quality control, dimensionality reduction, differential analysis, cell type annotation, and pseudotime analysis, cell types throughout the entire course of diabetic foot ulcers were identified, differentially expressed genes were obtained, and high-dimensional weighted gene co-expression network analysis was used to identify gene modules highly associated with diabetic foot ulcers. The conventional transcriptomics datasets GSE68183 and GSE80178, including unhealed ulcer tissue samples from diabetic foot ulcer patients and foot skin samples from diabetic patients, were downloaded to screen for differentially expressed genes. Weighted gene co-expression network analysis was used to screen for gene modules associated with diabetic foot ulcers. The differentially expressed genes from single-cell transcriptomics, conventional transcriptomics samples, weighted gene co-expression network analysis, and high-dimensional weighted gene co-expression network analysis were integrated to screen for biomarkers of diabetic foot ulcers. The GSE134431 dataset was downloaded as a validation conventional transcriptomics dataset to compare the expression levels of diabetic foot ulcer biomarkers in single-cell transcriptomics and validation conventional transcriptomics datasets. Wound tissues were obtained from diabetic and diabetic foot ulcer rat models to detect biomarker expression levels using immunohistochemistry and Western blot assays. RESULTS AND CONCLUSION: Single-cell transcriptomics data analysis revealed that epithelial cell differentiation ran through the entire pathological process of diabetic foot ulcers. A total of 146 differentially expressed genes were identified, including 59 upregulated genes and 87 downregulated genes. High-dimensional weighted gene co-expression network analysis identified 19 gene modules associated with diabetic foot ulcers, containing 476 core genes. Conventional transcriptomics data analysis identified 913 differentially expressed genes, including 343 upregulated genes and 570 downregulated genes; weighted gene co-expression network analysis identified 19 gene modules associated with diabetic foot ulcers, containing 887 genes. Two biomarkers for diabetic foot ulcers were identified: S100A14 and SFN. The expression levels of these two genes were higher in diabetic foot ulcer samples from single-cell transcriptomics and conventional transcriptomics validation datasets compared with diabetic patients' foot skin samples. Animal experiments showed that the expression levels of S100A14 and SFN in wound tissue from diabetic foot ulcer rats were higher than those in back skin tissue from diabetic rats. These findings suggest that epithelial cells play a crucial role in the pathological process of diabetic foot ulcers, with S100A14 and SFN highly expressed in these ulcers, indicating that they could be potential targets for the treatment of diabetic foot ulcer. Figures and Tables | References | Related Articles | Metrics

Select

Mechanism by which the paraventricular nucleus of the hypothalamus is involved in chronic pain and anxiety in mice with lumbar disc herniation Shi Gaolong, Ge Caijun, Chen Jianpeng, Wang Yuanbin, Fan Zelin, Yan Jun, Wang Qianliang 2026, 30 (22):  5707-5715.  doi: 10.12307/2026.137 Abstract ( 39 )   PDF (2471KB) ( 8 )   Save BACKGROUND: Patients with lumbar disc herniation (LDH) often experience comorbid anxiety due to chronic pain and functional limitations, significantly affecting their quality of life. However, the mechanisms underlying the pain-anxiety comorbidity remain unclear. OBJECTIVE: To investigate the neural regulatory mechanisms of the paraventricular nucleus in the hypothalamus in a mouse model of lumbar disc herniation with chronic pain-anxiety comorbidity. METHODS: A total of 100 C57BL/6 mice were randomly divided into a normal group (24 mice) and a model group (76 mice). The lumbar disc herniation model was established in the model group using a needle puncture method. Seventy-two successfully modeled mice were randomly divided into the model group, oxytocin group, and oxytocin+Vasotocin group, with 24 mice in each group. Mice in the oxytocin group received a 200 nL injection of oxytocin (0.5 μg/μL) into the paraventricular nucleus of the hypothalamus. Mice in the oxytocin+Vasotocin group received a 200 nL injection of oxytocin into the paraventricular nucleus and a 20 μL intraperitoneal injection of Vasotocin (an oxytocin antagonist, 0.15 μg/μL). Anxiety-like behavioral changes were evaluated via the elevated plus maze and open field tests on day 20 after modeling. Mechanical paw withdrawal threshold and thermal paw withdrawal latency experiments were conducted for all groups before modeling and 21 days after modeling. On day 21 post-modeling, immunofluorescence staining was used to observe c-FOS expression in the paraventricular nucleus of the hypothalamus; q-PCR was employed to detect mRNA expression levels of inflammatory factors prostaglandin E2, tumor necrosis factor-α, and interleukin-1β; and western blot analysis was used to assess the protein expression levels of oxytocin receptors and p-ERK1/2.  RESULTS AND CONCLUSION: (1) Compared with the normal group, the model group exhibited significantly reduced mechanical pain thresholds and thermal pain thresholds (P < 0.05), significantly decreased open arm duration and entries in the elevated plus maze (P < 0.05), and significantly reduced time spent and entries in the open area of the open field test (P < 0.05). Compared with the normal group, the mRNA expression levels of inflammatory factors prostaglandin E2, tumor necrosis factor-α, and interleukin-1β in the dorsal root ganglion tissue were significantly elevated (P < 0.05), c-FOS expression in the paraventricular nucleus of the hypothalamus was significantly increased (P < 0.05), the expression of oxytocin receptor protein in the paraventricular nucleus of the hypothalamus was significantly decreased, and p-ERK1/2 protein expression was significantly increased in the model group (P < 0.05). (2) Compared with the model group, the oxytocin group showed significantly increased mechanical pain thresholds and thermal pain thresholds (P < 0.05), significantly increased open arm duration and entries in the elevated plus maze (P < 0.05), and significantly increased time spent and entries in the open area of the open field test (P < 0.05). Compared with the model group, the mRNA expression levels of inflammatory factors prostaglandin E2, tumor necrosis factor-α, and interleukin-1β in the dorsal root ganglion tissue were significantly reduced (P < 0.05), c-FOS expression in the paraventricular nucleus of the hypothalamus was significantly decreased (P < 0.05), the expression of oxytocin receptor protein in the paraventricular nucleus of the hypothalamus was significantly increased, and p-ERK1/2 protein expression was significantly decreased in the oxytocin group (P < 0.05). (3) Compared with the oxytocin group, the oxytocin+Vasotocin group exhibited significantly reduced mechanical pain thresholds and thermal pain thresholds (P < 0.05), significantly decreased open arm duration and entries in the elevated plus maze (P < 0.05), and significantly reduced time spent and entries in the open area of the open field test (P < 0.05). Compared with the oxytocin group, the mRNA expression levels of inflammatory factors prostaglandin E2, tumor necrosis factor-α, and interleukin-1β in the dorsal root ganglion tissue were significantly increased (P < 0.05), c-FOS expression in the paraventricular nucleus of the hypothalamus was significantly elevated (P < 0.01), the expression of oxytocin receptor protein in the paraventricular nucleus of the hypothalamus was significantly decreased, and p-ERK1/2 protein expression was significantly increased in the oxytocin+Vasotocin group (P < 0.05). In conclusion, oxytocin can significantly alleviate chronic pain and anxiety-like behaviors in mice with lumbar disc herniation, and suppress inflammation in the dorsal root ganglion. Its mechanism may be related to the activation of the ERK signaling pathway in the paraventricular nucleus of the hypothalamus and the downregulation of inflammatory factor expression. Figures and Tables | References | Related Articles | Metrics

Select

Prostaglandin E1 pretreatment inhibits ferroptosis in endothelial cells in a rat model of spinal cord ischemia-reperfusion injury Huang Yushan, Wang Rongrong, Li Xiangmiao, Bai Jinzhu 2026, 30 (22):  5716-5727.  doi: 10.12307/2026.160 Abstract ( 36 )   PDF (2029KB) ( 11 )   Save BACKGROUND: Ferroptosis is an important pathological mechanism in spinal cord ischemia-reperfusion injury. Although studies have confirmed that prostaglandin E1 attenuates cerebral microvascular endothelial cell injury in the hippocampus induced by chronic cerebral hypoperfusion, its effect on ferroptosis of endothelial cells after spinal cord ischemia-reperfusion injury remains poorly studied. OBJECTIVE: To investigate whether prostaglandin E1 pretreatment attenuates spinal cord ischemia-reperfusion injury by inhibiting ferroptosis in endothelial cells and to elucidate possible mechanisms. METHODS: (1) Cell experiment: Rat spinal cord microvascular endothelial cells were divided into four groups. Control group was cultured in normoxia (20% O2) with complete medium. Model group was cultured in a hypoxic incubator (95% N2 and 5% CO2) with glucose-free and serum-free medium for 3 hours (oxygen-glucose deprivation), and then in normoxia (20% O2) with complete medium for 12 hours (reoxygenation), to establish an oxygen-glucose deprivation/reoxygenation model to simulate spinal cord ischemia-reperfusion injury. Pretreatment group was subjected to oxygen-glucose deprivation for 3 hours and incubation for 2 hours, followed by treatment with prostaglandin E1 for 2 hours and reoxygenation for 12 hours. Inhibitor group was subjected to oxygen-glucose deprivation for 3 hours, followed by addition of nuclear factor erythroid 2-related factor 2 inhibitor ML385 for 2 hours, then incubated with prostaglandin E1 for 2 hours, and reoxygenated for 12 hours. At the end of treatment, intracellular malondialdehyde, glutathione and Fe2+ concentration were detected, cell viability was measured by cell counting kit-8 assay, immunofluorescence staining with western blot assay were detected the expressions of acyl-coenzyme A synthase long-chain family member 4, and glutathione peroxidase 4, the intracellular reactive oxygen species level was detected by flow cytometry, and Western blot was detected the protein expressions of nuclear factor erythroid 2-related factor 2, and heme oxygenase 1.  (2)Animal experiment: 45 rats were randomly divided into three groups. Sham group (n = 15) only opened the abdomen to expose the abdominal aorta but did not block it. Model group (n = 15) clamped the abdominal aorta for 30 minutes and then injected normal saline via the tail vein, followed by the restoration of arterial blood flow to establish a model of spinal cord ischemia-reperfusion injury. Pretreatment group (n = 15) clamped the abdominal aorta for 30 minutes and then injected with prostaglandin E1 via the tail veinord, followed by restoration of arterial blood flow. Twenty-four hours after restoration of arterial blood flow, motor function and neuronal damage in rats were assessed by Basso-Beattie-Bresnahan score, inclined plane test and Nissl staining. The blood-spinal cord barrier integrity and microvessel density were assessed by spinal cord water content measurement, zonula occludens-1 (ZO-1) immunofluorescence staining and CD34 immunohistochemical staining. The ferroptosis in spinal cord tissue was assessed by immunofluorescence staining, Prussian blue staining, Western blot and biochemical assays.  RESULTS AND CONCLUSION: (1) Cell experiment: Oxygen-glucose deprivation/reoxygenation decreased the viability of rat spinal cord microvascular endothelial cells, induced cellular ferroptosis, and down-regulated the protein expressions of nuclear factor erythroid 2-related factor 2, and heme oxygenase 1, and the above effects of oxygen-glucose deprivation/reoxygenation on rat spinal cord microvascular endothelial cells were suppressed by pretreatment with prostaglandin E1. The effects of prostaglandin E1 pretreatment were partially reversed by ML385. (2) Animal experiment: Prostaglandin E1 pretreatment attenuated motor function deficits, neuronal damage, and blood-spinal cord barrier damage, improved microvessel density, and inhibited ferroptosis in spinal cord tissues in rats caused by spinal cord ischemia-reperfusion injury. Overall, prostaglandin E1 pretreatment protects against spinal cord ischemia-reperfusion injury by inhibiting ferroptosis in endothelial cells through activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signaling pathway. Figures and Tables | References | Related Articles | Metrics

Select

Establishing a diagnostic model for recurrent spontaneous abortion based on the levels of autophagy-related genes in the endometrium Tang Cen, Hu Wanqin 2026, 30 (22):  5728-5738.  doi: 10.12307/2026.175 Abstract ( 48 )   PDF (7055KB) ( 11 )   Save BACKGROUND: The etiology of recurrent spontaneous abortion is complex. With the development of genetics and other fields, it has been found that the abnormal expression of autophagy-related genes may lead to the imbalance of cell homeostasis, thus triggers pathological processes, such as apoptosis, inflammatory response and immunosuppressive response, and affects the endometrial microenvironment, trophoblastic function and immune cell function, thereby leading to recurrent spontaneous abortion. By using the recurrent spontaneous abortion samples in the Gene Expression Omnibus database, the expression changes and regulatory mechanisms of autophagy-related genes were analyzed, which is helpful to reveal the mechanism of recurrent spontaneous abortion and develop new therapeutic strategies. However, the specific mechanism of autophagy-related genes in recurrent spontaneous abortion and their interaction with other biological processes still need to be further studied. OBJECTIVE: To establish a risk score prognostic model for patients with recurrent spontaneous abortion based on autophagy-related genes. METHODS: Endometrial gene expression matrix of patients with recurrent abortion was obtained from the Gene Expression Omnibus database, autophagy-related genes were obtained from the Human Autophagy Database (HADb), and 30 differentially co-expressed autophagy-related genes were identified. The biological functions of autophagy-related genes were analyzed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and DisGeNET enrichment. LASSO and logistic regression analyses were used to identify 16 autophagy-related genes as potential biomarkers. A Nomogram model was subsequently established for the target gene, and the prediction accuracy of the model was evaluated by using the receiver operating characteristic curve. The optimal machine model was selected by comparing the performance of six machine learning models, including random forest model, support vector machine model and generalized linear model. Nomogram, calibration curve and decision curve were used to analyze the machine model to verify the validity of the prediction. RESULTS AND CONCLUSION: (1) GO analysis showed that the functions of autophagy-related genes in patients with recurrent abortion were mainly involved in autophagy regulation, cellular catabolism, and the formation of mitochondria or other organelle membranes. (2) KEGG analysis showed that autophagy-related genes were enriched in autophagy regulation, phosphatidylinositol 3-kinase/protein kinase B signaling pathway, human papillomavirus infection and neurodegeneration pathway in patients with recurrent abortion. (3) Gene set enrichment analysis showed that autophagy-related genes in patients with recurrent abortion were involved in the biological processes of copper detoxification and proton transmembrane transport, the cellular components of sarcoplasmic reticulum, and the molecular function of regulating nucleoside diphosphate phosphatase activity. (4) A predictive risk model was constructed, and 16 specific autophagy related genes were found to be predictive targets for recurrent abortion. (5) The best neural network model was selected according to the detection efficiency of the machine model, and five most important gene variables related to recurrent abortion autophagy (MAP2K7, CALCOCO2, SAR1A, TUSC1 and STK11) were identified. (6) Using the European population analysis of recurrent abortion samples in the GEO database, gene expression patterns, differentially expressed genes and signaling pathways in recurrent abortion samples can be analyzed from the level of genetic single nucleotide polymorphisms. The predictive model and machine learning model based on good predictive efficiency can identify new therapeutic targets and potential biomarkers related to autophagy in patients with recurrent abortion, which has certain guiding significance for clinical work and mechanism research. Figures and Tables | References | Related Articles | Metrics

Select

Effects of high-intensity interval training combined with estrogen therapy on skeletal muscle stem cells, myonuclear domain and ribosome function in ovariectomized rats Sun Yuan, Shu Jun, Ren Shuang, Wang Chenyu 2026, 30 (22):  5739-5748.  doi: 10.12307/2026.155 Abstract ( 57 )   PDF (3969KB) ( 19 )   Save BACKGROUND: Estrogen deficiency can lead to a decrease in skeletal muscle mass and muscle strength in postmenopausal women, thereby affecting their quality of life. Muscle mass is maintained by satellite cells, which are regulated by estrogen. Regular exercise, especially high impact exercise (such as resistance training and high-intensity interval training), can induce muscle hypertrophy, but the role and mechanism of estrogen are still unclear.  OBJECTIVE: To explore the effects of high-intensity interval training combined with estrogen therapy on skeletal muscle hypertrophy in ovariectomized rats and reveal its possible mechanism.  METHODS: Sixty 8-week-old female Sprague-Dawley rats were divided into five groups using a random number table method: sham operation, model sedentary group, model exercise group, model hormone group, or model combined group. Bilateral ovariectomy was used to establish an estrogen deficiency model. Twelve weeks after operation, the model exercise and model combined group performed high-intensity interval training for 8 weeks (3 times/week), and hormone treatment groups received abdominal subcutaneous injection of 17β-estradiol (once a day for 8 weeks). Seventy-two hours after the last training, the grip force of the forelimb was measured by an electronic grip force meter. The gastrocnemius muscle was separated, and the gastrocnemius mass index was calculated based on the ratio of muscle mass/body mass. The cell cross-sectional area was obtained by hematoxylin-eosin staining. The muscle fiber types were classified by immunofluorescence staining and myonuclear number, myonuclear domain size and number of activated satellite cells were obtained. The total protein concentration in the gastrocnemius muscle was determined by BCA method, and the total RNA in the gastrocnemius muscle was extracted by Trizol method. The expression of ribosomal protein S6 protein was detected by western blot, and the expression of ribosomal RNA (rRNA) was determined by real-time fluorescence quantitative PCR.  RESULTS AND CONCLUSION: (1) Compared with the sham operation group, the body mass and proportion of myosin heavy chain type I muscle fiber increased (P < 0.05), and the uterine mass index, gastrocnemius mass index, grip force, cell cross-sectional area, myosin heavy chain type IIa proportion, satellite cell and myonuclear number, myonuclear domain size, total protein and RNA contents in the gastrocnemius muscle, and the expression of ribosomal protein S6, 18S rRNA and 28S rRNA decreased (P < 0.05) in the model sedentary group. (2) Compared with the model sedentary group, body mass and myosin heavy chain type IIb proportion decreased (P < 0.05), and the uterine mass index, gastrocnemius mass index, grip force, cell cross-sectional area, myosin heavy chain type IIa proportion, satellite cell number, myonuclear domain size, total protein and RNA contents in the gastrocnemius muscle, and ribosomal protein S6 and 28S rRNA expression levels increased (P < 0.05) in the model exercise group. (3) Compared with the model exercise and model hormone groups, the gastrocnemius mass index, grip force, cell cross-sectional area, satellite cell number, myonuclear domain size, total protein and RNA contents in the gastrocnemius muscle, and ribosomal protein S6 and 28S rRNA expression levels increased (P < 0.05) in the model combined group. In conclusion, estrogen can enhance the skeletal muscle hypertrophy response induced by high-intensity interval training in ovariectomized rats, and the mechanism may be related to activation of satellite cell, increased myonuclear domain and ribosome biogenesis, and improved ribosome function.  Figures and Tables | References | Related Articles | Metrics

Select

Effects of protein kinase C on the expression of myocardial SarcKATP channels in model rats during exercise preconditioning Wang Kai, Zhou Yuehui 2026, 30 (22):  5749-5755.  doi: 10.12307/2026.091 Abstract ( 44 )   PDF (1224KB) ( 10 )   Save BACKGROUND: Exercise preconditioning produces early and late myocardial protective effects, in which protein kinase C and myocardial ATP-sensitive potassium channels (SarcKATP) are mediators and effectors, respectively. Protein kinase C regulates the expression of myocardial SarcKATP channels. OBJECTIVE: To compare the effects of protein kinase C on the expression of myocardial SarcKATP channel subunits, inward recirculating potassium channel 6.2 (Kir6.2) and sulfonylurea receptor 2A (SUR2A), in exercise preconditioning. METHODS: Forty-eight Sprague-Dawley rats were randomly divided into five groups: control group (no intervention), early exercise preconditioning group, protein kinase C inhibitor (pre-exercise intraperitoneal injection) + early exercise preconditioning group, late exercise preconditioning group, and protein kinase C inhibitor + late exercise preconditioning group. After preconditioning, the distribution and expression changes of Kir6.2 and SUR2A mRNAs in the rat myocardium were observed and detected using real-time fluorescent quantitative PCR. The distribution and expression changes of Kir6.2 and SUR2A proteins were observed and detected using western blot. RESULTS AND CONCLUSION: (1) Compared with the control group, the mRNA expression of Kir6.2 and SUR2A showed no significant difference in the early and late exercise preconditioning groups. Compared with the early exercise preconditioning group, the protein kinase C inhibitor + early exercise preconditioning group showed a decrease in Kir6.2 mRNA expression and an increase in Kir6.2 protein expression, while both SUR2A mRNA and protein levels decreased. (2) Compared with the late exercise preconditioning group, the protein kinase C inhibitor + late exercise preconditioning group showed reduced Kir6.2 expression at mRNA and protein levels; meanwhile, SUR2A mRNA expression reduced and SUR2A expression increased. For the same subunit of myocardial Kir6.2 or SUR2A, protein kinase C exerts coordinated and complementary regulatory effects on its expression regulation in early and late exercise preconditioning, and as for different subunits of Kir6.2 and SUR2A, protein kinase C also has coordinated and complementary effects on their expression regulation in early and late exercise preconditioning. Figures and Tables | References | Related Articles | Metrics

Select

Effects of piRNA CFAPIR in doxorubicin-induced ferroptosis models of rat and human cardiomyocytes Tao Xiangyu, Wang Shuang, Li Yuhan, Cao Jimin, Sun Teng 2026, 30 (22):  5756-5769.  doi: 10.12307/2026.133 Abstract ( 64 )   PDF (2896KB) ( 10 )   Save BACKGROUND: Ferroptosis plays a critical role in doxorubicin-induced cardiomyopathy; however, its specific regulatory mechanisms require further elucidation. Piwi-interacting RNA 413 (piRNA413) regulates ferroptosis in doxorubicin-induced cardiomyocytes, designated as cardiac ferroptosis-associated piRNA (CFAPIR). However, the specific regulatory mechanism needs to be further elucidated. OBJECTIVE: To investigate the role and regulatory mechanism of piRNA CFAPIR in doxorubicin-induced cardiomyocyte ferroptosis and cardiomyopathy. METHODS: (1) Intraperitoneal injection of doxorubicin was used to induce cardiomyopathy in mice. The myocardium was in situ injected with CFAPIR knocking down lentivirus. The body mass and survival rate of mice were monitored and recorded; cardiac function, heart volume and mass, inflammation, and fibrosis were evaluated. (2) Doxorubicin was used to induce ferroptosis in AC16 cardiomyocytes. CFAPIR inhibitor was transfected into cardiomyocytes. Cell injury and ferroptosis were assessed by measuring ferroptosis markers, intracellular iron level, malondialdehyde content, and reduced glutathione level, along with evaluating mitochondrial dysfunction. Additionally, the effect of CFAPIR on ABCB8 expression levels was analyzed. RESULTS AND CONCLUSION: (1) The level of CFAPIR was significantly up-regulated in both doxorubicin-induced cardiomyopathy animal model (P < 0.000 1) and the cardiomyocyte ferroptosis model (P < 0.01). (2) At the animal level, CFAPIR knockdown markedly attenuated doxorubicin-induced cardiotoxicity, including the prevention of body mass loss (P < 0.05), improvement in survival rate, preservation of cardiac function (P < 0.01), reduction of cardiac atrophy (P < 0.05), inhibition of elevated lactate dehydrogenase activity (P < 0.05), and mitigation of cardiac fibrosis (P < 0.000 1). (3) At the cellular level, CFAPIR knockdown significantly improved doxorubicin-induced ferroptosis in cardiomyocytes, as evidenced by enhanced cell viability (P < 0.05), reduced lactate dehydrogenase activity (P < 0.01), upregulation of ferroptosis markers xCT (P < 0.01) and glutathione peroxidase 4 (P < 0.001), downregulation of prostaglandin-endoperoxide synthase 2 mRNA expression (P < 0.05), alleviation of iron overload (P < 0.05), decreased malondialdehyde levels (P < 0.05), restoration of reduced glutathione content (P < 0.01), reduced reactive oxygen species accumulation (P < 0.01), and improvement in mitochondrial membrane potential (P < 0.05). (4) CFAPIR knockdown significantly mitigated the doxorubicin-induced downregulation of the iron transport protein ABCB8 (P < 0.05). In conclusion, CFAPIR expression is markedly elevated in both the animal model of doxorubicin-induced cardiomyopathy and the cardiomyocyte ferroptosis model. CFAPIR knockdown significantly alleviates doxorubicin-induced cardiotoxicity and cardiomyocyte ferroptosis, potentially by targeting the mitochondrial iron transport protein ABCB8. Figures and Tables | References | Related Articles | Metrics

Select

Forkhead box transcription factor O3 affects bone metabolism and participates in the pathological processes of various bone-related diseases Han Jie, Hu Tianfa, Wu Yachao, Nong Bin, Yu Kailong 2026, 30 (22):  5770-5781.  doi: 10.12307/2026.182 Abstract ( 34 )   PDF (7628KB) ( 4 )   Save BACKGROUND: Bone metabolism disorders can cause the occurrence of bone-related diseases, and forkhead box transcription factor O3 (FoxO3a) can affect the processes of proliferation, differentiation and apoptosis of bone tissue cells by regulating oxidative stress and autophagy levels, and thereby regulate the bone metabolism. OBJECTIVE: To systematically analyze the relevant research literature on the regulation of bone metabolism by FoxO3a and its mechanism of action in bone diseases and to provide a reference for subsequent studies targeting FoxO3a in the treatment of bone diseases. METHODS: Literature searches were conducted using the following strategies: CNKI (China National Knowledge Infrastructure): SU=FoxO3a OR SU=Foxo3 OR SU=Forkhead box O3 OR SU=AND SU=Forkhead box transcription factor O3) AND SU=bone; WanFang Medical Database: Subject:("FoxO3a") OR Subject:("Foxo3") OR Subject:("Forkhead box O3") OR Subject:("Forkhead box transcription factor O3") AND Subject:("bone"); PubMed: ((FoxO3a) OR (Foxo3) OR (Forkhead box O3))AND ((bone) OR (Skeleton)). Outdated, repetitive, low-quality, and irrelevant studies were excluded, and 56 articles were ultimately included for review. RESULTS AND CONCLUSION: (1) FoxO3a and bone marrow mesenchymal stem cells: FoxO3a can promote the formation of osteogenic lineages and also facilitate early osteogenic differentiation by activating autophagy. Meanwhile, FoxO3a exhibits antioxidant properties in bone marrow mesenchymal stem cells, protecting the cells from aging induced by oxidative stress. (2) FoxO3a and osteoblasts: FoxO3a can inhibit osteogenesis in osteoblasts by interfering with the Wnt/β-catenin pathway, and at the same time activate antioxidant enzymes to protect mature osteoblasts. FoxO3a can promote the proliferation and differentiation of osteoblast progenitor cells and facilitate osteogenic differentiation by activating autophagy. (3) FoxO3a and osteoclasts: The expression of FoxO3a can resist oxidative stress and activate the autophagy process to inhibit osteoclast generation. (4) FoxO3a and bone cells: FoxO3a can protect bone cells through antioxidant effects and also reduce bone loss by inhibiting the p16 and p53 signaling pathways and increasing aging-related secretory phenotypes. (5) FoxO3a and chondrocytes: FoxO3a plays a protective role for chondrocytes in osteoarthritis, inhibits the decomposition or apoptosis of chondrocytes, promotes the synthesis of extracellular matrix in chondrocytes, and can inhibit chondrocyte hypertrophy. However, the high co-expression of FoxO3a and Runt-related transcription factor 1 in chondrocytes promotes the early cartilage formation and terminal hypertrophy of chondroprogenitor cells. (6) FoxO3a affects bone metabolism by participating in processes such as oxidative stress resistance and regulating autophagy, and is involved in the pathological processes of various bone-related diseases. Figures and Tables | References | Related Articles | Metrics

Select

Virtual reality therapy on neuropathic pain following spinal cord injury Du Xinyu, Zhao Donglin, Zhang Shuyang, Li Shihao, Xing Zheng, Chu Xiaolei, Li Qi 2026, 30 (22):  5782-5791.  doi: 10.12307/2026.236 Abstract ( 65 )   PDF (2650KB) ( 13 )   Save BACKGROUND: Virtual reality has demonstrated unique advantages as a novel non-pharmacological intervention in the treatment of neuropathic pain following spinal cord injury. OBJECTIVE: To systematically review the pathogenesis of neuropathic pain following spinal cord injury, summarize the specific application modes and mechanisms of virtual reality therapy for this condition, and explore key factors influencing treatment efficacy, thereby providing novel therapeutic options for patients with neuropathic pain following spinal cord injury. METHODS: A literature search was conducted in the CNKI, PubMed, Web of Science, and Cochrane Library databases up to June 2025. The Chinese and English search terms included “spinal cord injury, central sensitization, cerebral cortex, noninvasive therapy, neuropathic pain, virtual reality.” A total of 1 352 articles were retrieved, and 73 articles that met the inclusion criteria were ultimately included in the analysis. RESULTS AND CONCLUSION: The development of neuropathic pain following spinal cord injury involves complex mechanisms in both the spinal cord and brain, closely associated with central sensitization at the spinal level and abnormal plasticity changes in the brain. Virtual reality, as a novel intervention approach, can be used alone or in combination with other intervention methods, showing unique therapeutic value for the multidimensional pathogenesis of neuropathic pain after spinal cord injury. Standalone virtual reality applications primarily involve virtual walking interventions aimed at restoring abnormal changes in brain plasticity. Combined virtual reality applications demonstrate certain efficacy in both inhibiting central sensitization and regulating brain plasticity. Although virtual reality interventions show considerable potential for treating neuropathic pain following spinal cord injury, current research and applications have certain limitations. Future efforts should focus on addressing these issues to fully realize the therapeutic value of virtual reality in managing neuropathic pain following spinal cord injury. Figures and Tables | References | Related Articles | Metrics

Select

Strategies for the application of miRNA-targeted therapy in the treatment of osteoporosis Wu Lingjie, Zheng Kaiyuan, Wang Guangrong, Yin Chong 2026, 30 (22):  5792-5803.  doi: 10.12307/2026.180 Abstract ( 86 )   PDF (2488KB) ( 100 )   Save BACKGROUND: Studies have shown that miRNAs, as important post-transcriptional regulators of genes, play a key role in the onset and progression of osteoporosis. Through in-depth research on the biology of miRNA regulation of osteoporosis, its potential healing mechanisms have been revealed, and this field has become a hot focus of current research. OBJECTIVE: To explore the regulatory role of miRNAs in the development of osteoporosis and their molecular mechanisms, and to provide an overview of the key difficulties encountered in the therapeutic strategies for osteoporosis targeting miRNAs and their solutions. METHODS: We searched PubMed, Web of Science and CNKI databases for relevant literature published up to March 2025. The search terms were “miRNA, osteoporosis, angiogenesis, osteogenesis, gene therapy, drug delivery” in English and “miRNA, osteoporosis, gene therapy, ribonucleic acid drugs, delivery carrier” in Chinese. After reading the titles and abstracts for preliminary screening, we excluded the literature with poor relevance, old information, or repetitive views and lack of authority, and finally included 138 papers for review. RESULTS AND CONCLUSION: (1) miRNAs are highly efficient non-coding RNAs with a wide range of applications that can precisely regulate cellular activities, and they show significant therapeutic potential in regulating osteoblast function and bone angiogenesis, which are potentially valuable in the treatment of osteoporosis. (2) Although miRNA-based targeted therapeutics have entered the preclinical research stage in other disease areas, they still face the challenges of insufficient in vivo stability of nucleic acids and off-target effects during clinical translation. (3) In response to the challenges faced by miRNA therapeutics, researchers have proposed a variety of strategies, including precise positioning of the target genes of miRNAs to reduce off-target effects; chemical modification to improve the stability of nucleic acid drugs in vivo; reducing the cost of nucleic acid production to advance the research; and optimizing the delivery pathways of nucleic acid drugs by using viral vectors, exosomes, and various types of biomaterials. (4) Advances in technology continue to drive innovation in improving the performance of nucleic acid drug carriers, ultimately achieving precise and efficient drug delivery and targeted therapeutic effects. Figures and Tables | References | Related Articles | Metrics

Select

Postbiotic targeting muscle aging: mechanistic insights and application prospects of urolithin A Yang Zijiang, Guo Chenggen, Deng Ziao, Xue Xinxuan 2026, 30 (22):  5804-5813.  doi: 10.12307/2026.201 Abstract ( 103 )   PDF (2779KB) ( 29 )   Save BACKGROUND: Urolithin A is a natural active compound produced by the metabolism of dietary polyphenols, which has multiple biological effects such as promoting mitochondrial function, antioxidation and anti-inflammation. In recent years, the development of urolithin A in delaying aging-related diseases has received extensive attention. However, the specific mechanism of its action in improving muscle aging remains unclear and further systematic research is still needed. OBJECTIVE: To systematically explore the mechanism of action of urolithin A in muscle aging, providing a theoretical basis for its potential application value in delaying muscle aging. METHODS: The Web of Science, PubMed, China National Knowledge Infrastructure (CNKI) and WanFang Database were retrieved from January 2000 to April 2025. The search terms were "urolithin A, muscle aging, mitochondrial function, mitophagy, inflammation, oxidative stress, muscle function, skeletal muscle" in English and Chinese. According to the inclusion and exclusion criteria, 80 literatures were finally selected for review. RESULTS AND CONCLUSION: (1) Urolithin A is a metabolite generated by the conversion of dietary polyphenolic compounds ellagic acid and ellagic acid under the action of intestinal microorganisms, and is widely present in pomegranates, berries and nuts. It has a unique α-benzocoumarin structure, with a small molecular weight, strong lipophilicity and easy absorption. The production of urolithin A depends on an individual’s intestinal microbiota and can be classified into different metabolic types. Moreover, this ability weakens with age, reflecting changes in intestinal function and physiological state. (2) Muscle aging is a process jointly driven by mitochondrial dysfunction, chronic inflammation and neuromuscular functional degeneration. With the increase of age, mitochondrial energy metabolism declines, and the accumulation of reactive oxygen species aggravates cell damage. Chronic low-grade inflammation accelerates protein breakdown, inhibits synthesis, and weakens the muscle repair ability. Neuromuscular junction degeneration and signal transduction disorders lead to muscle denervation and atrophy. These factors interact with each other, contributing to a continuous decline in muscle mass and function. (3) Urolithin A synergistically improves muscle aging through a multi-target mechanism. Its main functions include: activating the PTEN-induced kinase 1/Parkin signaling pathway, eliminating damaged mitochondria, and enhancing metabolic functions such as the tricarboxylic acid cycle, fatty acid oxidation and oxidative phosphorylation; inhibiting the nuclear factor-κB and protein kinase B/mitogen-activated protein kinase signaling pathways, up-regulating anti-inflammatory factors such as interleukin-10 and transforming growth factor-β1, and down-regulating pro-inflammatory factors such as interleukin-1β and tumor necrosis factor-α to achieve inflammatory regulation; enhancing the activities of antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase, inhibiting the generation of reactive oxygen species and alleviating oxidative stress. (4) Urolithin A promotes the proliferation and differentiation of muscle stem cells, activates anabolic pathways, enhances protein synthesis, boosts muscle strength, and simultaneously regulates molecular mechanisms related to endurance and fatigue resistance, thereby enhancing muscle endurance and comprehensively improving muscle performance. (5) Urolithin A shows broad prospects in delaying muscle aging and promoting muscle health, but existing studies are limited by small sample sizes, short cycles and individual differences. In the future, there is an urgent need to carry out large-scale and long-term clinical research to clarify the dose-effect, explore individualized and combined intervention strategies, and focus on the application potential of urolithin A as a sports nutrition supplement in enhancing physical fitness and promoting healthy aging. Figures and Tables | References | Related Articles | Metrics

Select

Role of fibrosis in tissue injury repair Li Feihong, Wang Linrong, Cheng Leping 2026, 30 (22):  5814-5831.  doi: 10.12307/2026.179 Abstract ( 79 )   PDF (2482KB) ( 24 )   Save BACKGROUND: Fibrosis results from dysregulated tissue healing, characterized by abnormal proliferation of fibroblasts and excessive deposition of extracellular matrix at fibrotic sites. Fibrosis can occur in nearly all organs, including the skin, liver, kidneys, heart, and lungs.   OBJECTIVE: To summarize fibrosis-related diseases, including skin fibrosis, liver fibrosis, renal fibrosis, and cardiac fibrosis, with a focus on elucidating key aberrant cells, dysregulated signaling pathways, and therapeutic approaches. METHODS: The PubMed and CNKI databases were searched using keywords: “fibrosis, fibroblasts, fibrotic organs, extracellular matrix, tissue repair, and inflammatory response" in Chinese and English, respectively. Literature was screened based on inclusion and exclusion criteria, and 200 articles were ultimately selected for review.  RESULTS AND CONCLUSION: Key abnormal cells in fibrosis include immune cells (macrophages, neutrophils, lymphocytes), fibroblasts, epithelial cells, and endothelial cells. Fibroblasts play a central role in fibrotic progression. Major dysregulated signaling pathways in fibrosis include transforming growth factor-β signaling pathway, Wnt/β-catenin signaling pathway, Notch signaling pathway, Toll-like receptor 4/MyD88/nuclear factor-κB signaling pathway, and Hippo/Yes-associated protein signaling pathway. Abnormal activation or inactivation of these pathways regulates fibrogenesis. Epigenetic modifications (DNA methylation, histone modifications, and non-coding RNA regulation) modulate fibrotic progression. Anti-fibrotic therapy can be administered through three main approaches: drug, cell, and gene therapies. These strategies can target relevant signaling pathways to inhibit the sustained activation of fibroblasts. Fibrosis can also be alleviated by modulating extracellular matrix deposition, thereby improving tissue and organ function. Figures and Tables | References | Related Articles | Metrics

Select

The role of exercise-regulated mitophagy in cardiovascular diseases Ji Long, Gong Guopan, Kong Xiangkui, Jin Pan, Chen Ziyang, Pu Rui 2026, 30 (22):  5832-5843.  doi: 10.12307/2026.228 Abstract ( 59 )   PDF (1915KB) ( 22 )   Save BACKGROUND: Mitophagy plays a crucial regulatory role in the occurrence and development of cardiovascular diseases. Exercise intervention can mediate mitophagy to improve cardiovascular function, which provides new insights for the clinical prevention and treatment of cardiovascular diseases. OBJECTIVE: To summarize the regulatory role of mitophagy in cardiovascular diseases, the influence of exercise on mitophagy, and the mechanism by which exercise-mediated mitophagy improves cardiovascular diseases. METHODS: PubMed and CNKI databases were searched for relevant literature using the search terms of “mitophagy, mitochondrial function, cardiovascular disease, aerobic exercise, resistance training, combined aerobic resistance exercise, high-intensity interval training” in Chinese and English, respectively. Based on the inclusion and exclusion criteria, totally 88 documents were finally included for summary and analysis. RESULTS AND CONCLUSION: (1) Mitophagy plays a crucial role in the regulation of cardiovascular diseases such as heart failure, myocardial hypertrophy, atherosclerosis, and myocardial ischemia-reperfusion injury. Moreover, mitophagy imbalance or disorder can exacerbate the pathological process of cardiovascular diseases. (2) Various exercise modalities can activate mitophagy by regulating the expression of mitophagy-related factors. Among them, aerobic exercise promotes autophagosomes formation, thereby enhancing the regulatory capacity of mitophagy; resistance training modulates mitochondrial biogenesis; combined aerobic and resistance exercise further influences mitophagy by facilitating lysosomal biogenesis; high-intensity interval training enhances mitophagic function through the regulation of mitochondrial dynamics-related protein expression. (3) Exercise plays a pivotal role in the prevention and treatment of cardiovascular diseases through the regulation of mitophagy, which attenuates myocardial fibrosis, inhibits cardiomyocyte apoptosis, modulates myocardial oxidative stress, and improves endothelial cell function. These findings provide a novel perspective on how exercise promotes overall health and contributes to the prevention and treatment of cardiovascular diseases. Figures and Tables | References | Related Articles | Metrics

Select

Transcription factor EB improves Alzheimer’s disease via the autophagy-lysosome pathway Hu Yalin, Huang Fengqin, Yang Boyin, Luo Xingmei 2026, 30 (22):  5844-5858.  doi: 10.12307/2026.193 Abstract ( 155 )   PDF (2160KB) ( 12 )   Save BACKGROUND: Studies have confirmed that transcription factor EB and its dependent autophagy-lysosome pathway play a role in the development of various neurodegenerative diseases, including Alzheimer’s disease. OBJECTIVE: To summarize the role of transcription factor EB-mediated autophagy-lysosome pathway in Alzheimer’s disease. METHODS: Electronic databases including PubMed, Web of Science, Cochrane Library, CNKI, WanFang Medical Network, and VIP were searched. The search period was from database inception to January 2025. The search terms were “Alzheimer Disease, AD, Transcription Factor EB, TFEB, Autophagy-lysosome Pathway, Autophagy, Lysosomes, Amyloid beta, Aβ, Tau, Tau protein” in English as well as “Alzheimer’s disease, transcription factor EB, autophagic lysosomes, autophagy, lysosomes, β-amyloid, Tau” in Chinese. Additionally, the references of relevant reviews and grey literature were manually supplemented. A total of 100 articles were finally included for review.  RESULTS AND CONCLUSION: Amyloid-β deposition and Tau protein phosphorylation are the key pathological features of Alzheimer’s disease. Abnormalities in the autophagy-lysosome pathway promote the formation of neurotoxic protein aggregates such as amyloid-β and Tau, leading to the clinical manifestations of Alzheimer’s disease characterized by cognitive dysfunction and behavioral abnormalities. Transcription factor EB is a key regulator of the autophagy-lysosome pathway, controlling the transcription of many autophagy-related genes and lysosomal biogenesis. After entering the nucleus, transcription factor EB upregulates the expression of autophagy-lysosome pathway-related genes, significantly increasing the clearance rate of amyloid-β and Tau and significantly reducing neuronal toxicity. Therefore, increasing attention focuses on improving the pathology and behavioral deficits of Alzheimer’s disease by targeting transcription factor EB to affect the biological activity of autophagic lysosomes. For example, activating transcription factor EB through drug intervention and non-drug intervention can reduce β-amyloid deposition and Tau protein phosphorylation, thereby improving cognitive impairment in Alzheimer’s disease. Figures and Tables | References | Related Articles | Metrics

Select

Visualization analysis of dynamic evolution of hot topics in the field of physical activity and neural plasticity Deng Qing , Zhang Yeting , Mou Xiangqian , Wang Qingjun 2026, 30 (22):  5859-5866.  doi: 10.12307/2026.186 Abstract ( 64 )   PDF (1737KB) ( 36 )   Save BACKGROUND: In recent years, numerous studies have shown that physical activity significantly promotes neural plasticity, contributing to improvements in cognitive abilities and neurological health. However, the current state and dynamic evolution of the research field on "physical activity and neural plasticity" have not been systematically organized and analyzed. This lack of comprehensive understanding may hinder accurate predictions regarding the future development trends in this area. OBJECTIVE: Using bibliometric methods, we analyzed the dynamic evolution trajectory of research topics in the field of physical activity and neural plasticity, organized the development trends and the evolution of the knowledge framework in this area, and provided directional references for subsequent research. METHODS: Relevant literature was retrieved from the Web of Science Core Collection database (www.webofscience.com) using the following search strategy: TS=(("physical activity" OR exercise OR "motor activity" OR "physical exercise" OR "aerobic exercise" OR "physical training") AND ("neuroplasticity" OR "brain plasticity" OR "neural plasticity" OR "cognitive plasticity" OR "brain adaptability")). A total of 2 098 eligible articles were screened and included. Co-word analysis and visualization analysis were performed using SciMAT software. Keyword maps, strategic coordinate maps, and topic evolution path maps were created to reveal the dynamic evolution process of research topics in the field of physical activity and neural plasticity. RESULTS AND CONCLUSION: Research in the field of physical activity and neural plasticity exhibits a strong development trend. Studies are becoming more comprehensive, and there is substantial potential for future development. This field encompasses five main evolutionary directions: "physical activity," "adult mice," "stem cells," "individual differences," and "randomized controlled trials," which have resulted in 15 sub-evolutionary pathways. Topics such as "the elderly," "animal models," and "diseases" are expected to become key areas of focus for future research. Therefore, it is recommended that future studies use randomized controlled trials and optimized experimental designs for animal models to investigate the long-term effects of physical activity on neural plasticity and cognitive function, along with the underlying mechanisms involved. Furthermore, there should be a focus on the clinical validation of multimodal interventions in specific populations. Figures and Tables | References | Related Articles | Metrics

Select

The relationship between inflammatory cytokines and frozen shoulder: a large-sample analysis of the European population based on the FinnGen GWAS database Yan Wei, Kong Lingjun, He Tianxiang, Zhu Qingguang, Xi Xiaobing, Fang Min 2026, 30 (22):  5867-5875.  doi: 10.12307/2026.135 Abstract ( 42 )   PDF (3353KB) ( 17 )   Save BACKGROUND: Frozen shoulder is a common disease in orthopedics, but there is no specific clinical indicator for diagnosis. There is a significant association between inflammatory cytokines and frozen shoulder, but the specific causal relationship is not yet clear. This study used summary statistical data from genome-wide association studies (GWAS) for Mendelian randomization analysis. GWAS data are based on large-sample genetic variation information, which can reduce environmental confounding factors and more reliably infer the causal relationship between inflammatory cytokines and frozen shoulder, filling the limitations of traditional observational studies that cannot determine causal relationships. OBJECTIVE: To explore the causal relationship between inflammatory cytokines and frozen shoulder using bidirectional two-sample Mendelian randomization method. METHODS: Using the summary statistical data of GWAS in the FinnGen database, the causal relationship between 41 inflammatory cytokines and frozen shoulder was analyzed. The FinnGen database is a collaborative initiative launched by the Finnish Institute for Health and Welfare (THL), the University of Helsinki, and other Finnish research institutions. It comprises 2 942 case samples and 167 641 controls of European ancestry, integrating genomic data, clinical phenotypes, and biochemical indicators from hundreds of thousands to millions of individuals. This resource supports genetic association studies for various diseases. This study was based on publicly accessible summary-level data and exempt from ethical review. Bidirectional Mendelian randomization analysis was performed using inverse variance weighting, weighted median, weighted model, simple model, MR-Egger regression, and sensitivity analysis (including MR-Egger, MR-PRESSO, Cochran’s Q test). RESULTS AND CONCLUSION: Monocyte chemotactic protein 3 has significant causal effects in both positive and negative directions. In positive analysis, monocyte chemoattractant protein 3 was positively correlated with frozen shoulder risk [odds ratio (OR)=1.176, 95% confidence interval (CI): 1.034-1.338, P=0.014]; in reverse analysis, frozen shoulder was negatively correlated with monocyte chemoattractant protein 3 levels (OR=0.782, 95% CI: 0.625-0.979, P=0.032). In addition, a significant association was found between tumor necrosis factor β and the risk of frozen shoulder (OR=1.126, 95% CI: 1.002-1.264, P=0.046); in reverse analysis, stromal cell-derived factor 1α also showed a significant association with the risk of frozen shoulder (OR=1.1, 95% CI: 1.011-1.196, P=0.028), indicating a reliable correlation between tumor necrosis factor β, stromal cell-derived factor 1α, and frozen shoulder. This bidirectional Mendelian randomization study revealed the complex interaction between monocyte chemoattractant protein 3 and frozen shoulder, suggesting that monocyte chemoattractant protein 3 may be a potential therapeutic target. In addition, tumor necrosis factor β has been shown to be associated with the risk of frozen shoulder and may be a potential risk factor for frozen shoulder. And frozen shoulder is also associated with elevated levels of stromal cell-derived factor 1α, which has the potential to become a diagnostic biomarker for frozen shoulder. However, further research is needed to elucidate the biological mechanisms behind these causal relationships. Furthermore, the analysis of international databases provides candidate molecules and causal inference paradigms for Chinese research, but precise translation needs to be achieved in combination with local data. Figures and Tables | References | Related Articles | Metrics

Select

Shared genetic basis and causal relationship between nutrition, nutritional status and inflammatory bowel disease Liao Guibin, Wu Yixuan, Tang Jing, Huang Jinke, Wang Jun, Yan Ziqi, Liu Shujun, Zhang Haiyan 2026, 30 (22):  5876-5885.  doi: 10.12307/2026.255 Abstract ( 44 )   PDF (1989KB) ( 44 )   Save BACKGROUND: Inflammatory bowel disease, encompassing ulcerative colitis and Crohn’s disease, is a chronic condition linked to malnutrition, sarcopenia, and disease severity, with limited research on their genetic associations.  OBJECTIVE: To systematically explore the common genetic basis and causal relationships between nutrition, nutritional status, and inflammatory bowel disease using advanced statistical genetics. METHODS: Single nucleotide polymorphism data for nutritional markers (minerals, vitamins, albumin, hemoglobin, and fatty acids) and sarcopenia traits (appendicular lean mass and grip strength) were obtained from the GWAS Catalog database (jointly established by the National Human Genome Research Institute and the European Bioinformatics Institute, which systematically curates published genome-wide association studies). Summary statistics for inflammatory bowel disease and its subtypes were retrieved from the FinnGen R10 release (a large-scale genomics project coordinated by the Finnish Institute for Health and Welfare). Advanced statistical genetics methods, including linkage disequilibrium score regression, cross-phenotype association analysis, and Mendelian randomization, were applied to infer the associations between nutritional markers, sarcopenia, and inflammatory bowel disease. RESULTS AND CONCLUSION: This study revealed notable genetic correlations: vitamin D with inflammatory bowel disease (rg=-0.080, P=0.029) and ulcerative colitis (rg=-0.087, P=0.027), appendicular lean mass with inflammatory bowel disease (rg=-0.100, P=0.000 2), ulcerative colitis (rg=-0.100, P=0.000 2), and small intestine Crohn’s disease (rg=-0.081, P=0.035), grip strength with small intestine Crohn’s disease (rg=-0.125, P=0.035). Furthermore, Mendelian randomization analysis demonstrated a positive causal link between magnesium levels and inflammatory bowel disease (OR=1.41, P=0.036), and small intestine Crohn’s disease (OR=1.78, P=0.035). Cross-phenotype association identified shared single nucleotide polymorphisms, particularly within the human leukocyte antigen region, influencing both nutritional status and inflammatory bowel disease. Our findings advanced the understanding of genetic connections between nutrition, sarcopenia, and inflammatory bowel disease, suggesting that targeted nutritional management may be key in mitigating disease progression. This research paves the way for more personalized treatment approaches, with potential implications for preventive strategies in inflammatory bowel disease care. Figures and Tables | References | Related Articles | Metrics

Select

Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for major depressive disorder Zhou Menghan, Liu Shuning, Jiang Tao, Sun Zhuangzhuang, Cao Lingling, Su Xin, Yu Cheng, Guo Junpeng 2026, 30 (22):  5886-5896.  doi: 10.12307/2026.212 Abstract ( 66 )   PDF (5345KB) ( 24 )   Save BACKGROUND: The occurrence of major depressive disorder is typically associated with genetic and environmental factors. Currently, the diagnosis of major depressive disorder mainly relies on clinical interviews and symptom assessments, lacking clear and reproducible biological markers. This can lead to misdiagnosis and missed diagnoses, delaying the timing of treatment. OBJECTIVE: To identify druggable genes that may act as potential therapeutic targets for major depressive disorder by conducting comprehensive genome-wide Mendelian randomization analysis. METHODS: By integrating expression quantitative trait locus (eQTL) data and protein quantitative trait locus (pQTL) data from pharmacologically actionable genes with genome-wide association study (GWAS) data on major depressive disorder (including 177 377 cases and 445 321 controls), Mendelian randomization analysis was conducted to identify druggable genes that have a causal relationship with major depressive disorder. Additionally, enrichment analysis, protein-protein interaction network construction, drug target identification, and molecular docking simulations were performed to further explore potential therapeutic strategies. RESULTS AND CONCLUSION: A total of 4 394 druggable genes were analyzed, and 21 druggable genes considerably associated with major depressive disorder were identified. Bayesian colocalization analysis indicated that BTN3A3 (butyrophilin subfamily 3 member A3), CISD1 (CDGSH iron sulfur domain 1), and PSMB4 (proteasome subunit beta type 4) had approximate Bayesian factor-based hypothesis 4 posterior probabilities (H4.abf) > 0.5, supporting the possibility of shared causal variations. Gene Ontology (GO) enrichment analysis revealed that these genes were mainly involved in several functional pathways related to major depression, including "antigen processing and presentation," "protein degradation and processing," "mitochondrial outer membrane," and "immune receptor activity." Protein-protein interaction network analysis showed a moderate degree of connectivity among the identified genes (21 nodes and 14 edges). Drug target identification highlighted gemcitabine (CID 60750), fucose (CID 17106), and isocorydine (CID 2826) as major candidate compounds, which were strongly associated with several key genes. Molecular docking analysis revealed stable drug-protein interactions, with isocorydine exhibiting the most stable binding energy with BTN3A3 (-52.74 kJ/mol). Furthermore, the combination of Mendelian randomization with genomics and structural biology analysis methods provides valuable decision-making support for target prioritization and drug repurposing, offering new ideas and directions for the efficient utilization of basic research resources and drug development for major depressive disorder. Figures and Tables | References | Related Articles | Metrics