Biological mechanism of mitophagy in idiopathic pulmonary fibrosis

doi:10.12307/2025.672

Chinese Journal of Tissue Engineering Research ›› 2025, Vol. 29 ›› Issue (31): 6708-6716.doi: 10.12307/2025.672

Biological mechanism of mitophagy in idiopathic pulmonary fibrosis

Xie Yizi1, 2, 3, 4, Lin Xueying1, 2, 4, Zhang Xinxin1, 2, 3, 4, Huang Xiufang1, 2, 3, 4, Zhan Shaofeng2, 4, Jiang Yong5, Cai Yan6

1The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China; 2The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China; 3Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China; 4Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou 510000, Guangdong Province, China; 5Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen 518104, Guangdong Province, China; 6Guangdong Provincial Hospital of Chinese Medicine, Zhuhai, Zhuhai 519015, Guangdong Province, China

Received:2024-06-21 Accepted:2024-08-12 Online:2025-11-08 Published:2025-02-25
Contact: Cai Yan, Master, Chief physician, Guangdong Provincial Hospital of Chinese Medicine, Zhuhai, Zhuhai 519015, Guangdong Province, China
About author:Xie Yizi, Doctoral candidate, The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China; The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China; Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou 510000, Guangdong Province, China
Supported by:
Cultivation and Construction Project of Respiratory Disease Regional Diagnosis and Treatment Center of Guangdong Provincial Hospital of Chinese Medicine, Zhuhai (to CY); Science and Technology Research Special Project of Guangdong Provincial Hospital of Chinese Medicine, No. YN2023MS09 (to CY); Excellent Clinical Talent Training Project of The Second Guangdong Provincial Hospital of Chinese Medicine, No. (2024)88 (to CY); Sanming Project of Medicine in Shenzhen, No. SZZYSM202206013; Guangdong Provincial Key Department (Traditional Chinese and Western Medicine Collaborative Department) Construction Project (to JY); National Traditional Chinese Medicine Advantage Specialty Construction Project (Department of Pulmonary Disease, The First Affiliated Hospital of Guangzhou University of Chinese Medicine) (to ZSF)

Abstract

Abstract: BACKGROUND: Mitophagy is closely associated with the development of idiopathic pulmonary fibrosis, but its mechanism remains unclear.
OBJECTIVE: To investigate the biological mechanism of mitophagy in idiopathic pulmonary fibrosis and provide ideas for the risk prediction of idiopathic pulmonary fibrosis and subtype differentiation.
METHODS: The mitophagy-related genes in idiopathic pulmonary fibrosis were obtained through GEO and Reactome Pathway databases. The mitophagy-related characteristic genes in idiopathic pulmonary fibrosis were screened based on intergroup differences and random forest model. GO functional enrichment analysis and KEGG, Reactome with WIKI pathway enrichment analyses were performed by g:Profiler database. Mitophagy subtypes in idiopathic pulmonary fibrosis were distinguished by consensus clustering method and immune infiltration analysis was performed. The mitophagy-related key gene was screened. Finally, the predictive value of mitophagy-related key gene for the risk of idiopathic pulmonary fibrosis was quantified by alignment diagram and the correlation between mitophagy-related key gene and clinical characteristics of idiopathic pulmonary fibrosis was explored.
RESULTS AND CONCLUSION: (1) A total of 13 genes related to mitophagy in idiopathic pulmonary fibrosis were identified and 5 characteristic genes were screened, containing PINK1, RPS27A, SRC, HIF1A, and CDH6. (2) GO analysis was mainly involved in ubiquitin protein ligase binding, and cellular response to hypoxia. Pathway enrichment analysis was mainly involved in PINK1-PRKN mediated mitophagy, NOTCH signaling pathway, signaling by EGFR and angiogenesis. (3) HIF1A had significant expression differences between subtypes, which might serve as a key gene for the differentiation of mitophagy subtypes of idiopathic pulmonary fibrosis. (4) Immune infiltration analysis suggested that myeloid-derived suppressor cell, neutrophil and type 1 T helper cell might have infiltration differences between subtypes, while HIF1A was positively correlated with multiple immune cells. (5) Alignment diagram suggested that the risk of idiopathic pulmonary fibrosis might be predicted by the expression level of HIF1A. (6) Clinical characteristics analysis indicated patients with high expression of HIF1A might have poorer lung function and more severe fibrosis. It is concluded that PINK1, RPS27A, SRC, HIF1A, and CDH6 may influence the development of idiopathic pulmonary fibrosis through mitophagy, in which HIF1A may serve as a key gene for risk prediction with clinical subtype differentiation and HIF1A is strongly associated with the lung function of patients.

Key words: ">idiopathic pulmonary fibrosis, mitophagy, mitophagy-related key gene, subtype analysis, enrichment analysis, immune infiltration analysis, lung function, bioinformatic

CLC Number:

Xie Yizi, Lin Xueying, Zhang Xinxin, Huang Xiufang, Zhan Shaofeng, Jiang Yong, Cai Yan. Biological mechanism of mitophagy in idiopathic pulmonary fibrosis[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(31): 6708-6716.

Figures/Tables 4

2.5 免疫浸润分析在特发性肺纤维化亚型之间，骨髓来源抑制性细胞、中性粒细胞、1型辅助性T细胞存在浸润差异，且差异有显著性意义(P < 0.05)，见图7A。分析5个线粒体自噬特征基因与免疫细胞之间的相关性，发现HIF1A与免疫细胞存在较强的正相关性，见图7B。在基因亚型之间，活化的CD4+ T细胞、嗜酸性粒细胞、骨髓来源抑制性细胞、肥大细胞、中性粒细胞与1型辅助性T细胞存在浸润差异，且差异有显著性意义(P < 0.05)，见图7C。由此可见，特发性肺纤维化亚型与基因亚型之间的免疫浸润差异存在一定的相似性，再一次提示亚型分析的可信度。此外，骨髓来源抑制性细胞、中性粒细胞与1型辅助性T细胞在亚型B、基因亚型B中均呈上调状态，提示免疫状态较为活跃。 2.6 列线图模型构建通过特发性肺纤维化亚型分析及单样本基因集富集分析，筛选出特发性肺纤维化的线粒体自噬关键基因HIF1A，构建列线图模型。根据患者HIF1A的表达水平可预测特发性肺纤维化的发病风险，见图8A。以Bootstrap法对列线图进行内部验证，对原始数据进行重复抽样1 000次，结果显示平均绝对误差为0.052。实际曲线和理想曲线拟合度一般，见图8B。临床决策曲线提示，当风险阈值为0.65-0.99时，其临床获益率良好，见图8C。临床影响曲线提示，当高风险阈值 > 0.7时，模型判定为特发性肺纤维化的高风险人群与实际发生特发性肺纤维化的人群高度重叠，见图8D。因此，检测HIF1A的表达水平可能预测临床特发性肺纤维化发生风险。 2.7 线粒体自噬关键基因与特发性肺纤维化临床特征关系的探索 HIF1A高表达组的用力肺活量显著低于HIF1A低表达组(P < 0.05)，HIF1A高表达组的一氧化碳弥散量也低于HIF1A低表达组，但差异无显著性意义(P > 0.05)，见图9。这提示HIF1A高表达的患者肺功能更差，纤维化程度更严重。 "

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Biological mechanism of mitophagy in idiopathic pulmonary fibrosis

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