Chinese Journal of Tissue Engineering Research ›› 2026, Vol. 30 ›› Issue (29): 7715-7723.doi: 10.12307/2026.265

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Zinc finger DHHC-type containing 2 emerges as a novel therapeutic target in osteoarthritis pathogenesis: genome-wide data analysis in European populations

Wei Bingqi1, 2, Zhang Xinyue1, 2, Ren Xingyue1, 2, Sun Jiahui1, 2, Chen Liu1, 2, Li Yijing1, 2, Qi Yifan1, 2, Wang Shangzeng1, 2   

  1. 1School of Orthopedics, Henan University of Chinese Medicine, Zhengzhou 450002, Henan Province, China; 2Department of Orthopaedics, Henan Provincial Hospital of Traditional Chinese Medicine (The Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou 450002, Henan Province, China
  • Received:2025-07-28 Revised:2025-12-13 Online:2026-10-18 Published:2026-03-07
  • Contact: Wang Shangzeng, Chief physician, Doctoral supervisor, School of Orthopedics, Henan University of Chinese Medicine, Zhengzhou 450002, Henan Province, China; Department of Orthopaedics, Henan Provincial Hospital of Traditional Chinese Medicine (The Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou 450002, Henan Province, China
  • About author:Wei Bingqi, MS candidate, School of Orthopedics, Henan University of Chinese Medicine, Zhengzhou 450002, Henan Province, China; Department of Orthopaedics, Henan Provincial Hospital of Traditional Chinese Medicine (The Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou 450002, Henan Province, China
  • Supported by:
    National Natural Science Foundation of China, No. 82374490 (to WSZ); Natural Science Foundation of Henan Province, No. 222300420486 (to WSZ); University Science and Technology Innovation Team of Henan Province, No. 24IRTSTHN040 (to WSZ); the Scientific Research Project of Traditional Chinese Medicine in Henan Province, Nos. 2023ZYZD06, 2021ZY2010 and 2019ZY2035 (all to WSZ); the Science and Technology Benefit People Plan Project of Zhengzhou, No. 2023KJHM0009 (to WSZ); Key Research and Development Projects in Henan Province, No. 241111311700 (to WSZ); the Henan Provincial Young and Middle-Aged Health Science & Technology Innovation Leading Talents Program, No. LJRC2024020 (to WSZ); Henan Provincial College Students’ Innovation and Entrepreneurship Training Program, No. 202410471006 (to QYF)

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Abstract: BACKGROUND: Studies have suggested that palmitoylation-mediated regulation offers distinct advantages in osteoarthritis. Therefore, it is essential to utilize whole-genome data to explore novel key drug-targetable tissue-constructing hubs of palmitoylation regulation in osteoarthritis from a genetic perspective.
OBJECTIVE: To explore novel key drug targets involved in palmitoylation-mediated regulation of osteoarthritis pathogenesis through Mendelian randomization analysis, thereby providing valuable insights for developing targeted therapeutic strategies against osteoarthritis.
METHODS: We identified 31 palmitylation-related genes from three independent studies and cross-referenced them with 15 695 druggable genes from the eQTLGen Consortium database (which is published by the University of Groningen in the Netherlands, and aims to enhance the understanding of diseases at the plasma proteome genetic level and includes multiple druggable gene targets), yielding 22 potential drug targets for palmitylation regulation. Using Mendelian randomization, sensitivity analysis, and colocalization analysis, we further investigated these targets to identify novel candidates for palmitylation-mediated osteoarthritis [osteoarthritis genome-wide association study (GWAS) data sourced from the GWAS Catalog, National Human Genome Research Institute, USA, which integrates data extracted from published GWAS studies and contains genetic association data for various diseases]. GeneMANIA and STRING interaction network analyses were performed to explore the potential interacting proteins of these novel drug targets. After further validation with osteoarthritis-associated genes (also sourced from the GWAS Catalog database), the interacting proteins of the palmitoylation-mediated novel drug targets for osteoarthritis were confirmed.
RESULTS AND CONCLUSION: (1) Thirty-one palmitylation-related genes were paired to obtain 22 potential drug targets, zinc finger DHHC-type containing 2 was identified as a novel therapeutic target for palmitylation-mediated osteoarthritis, following Mendelian randomization, sensitivity analysis, and colocalization analysis. GeneMANIA and STRING network analyses further revealed seven potential interacting proteins, among which zinc finger DHHC-type containing 3 exhibited a particularly strong functional association with zinc finger DHHC-type containing 2. These findings suggest that zinc finger DHHC-type containing 2 serves as a key druggable target in palmitylation-mediated osteoarthritis pathogenesis, while zinc finger DHHC-type containing 3 may act as a synergistic interactor. This provides a foundation for developing effective and safe therapeutic strategies for patients with osteoarthritis by targeting this regulatory axis. (2) The use of international databases and European population data provides valuable insights to enhance biomedical and clinical researches in China. These comprehensive resources, characterized by large sample sizes and robust datasets, not only enable the identification of novel regulatory targets but also serve as crucial reference benchmarks for osteoarthritis studies in the Chinese population. Such cross-population analytical approaches empower Chinese researchers to systematically pinpoint druggable genetic targets and develop personalized, precision therapeutic strategies for osteoarthritis through the modulation of palmitylation pathways. 

Key words: osteoarthritis, palmitoylation, protein modification, Mendelian randomization, drug targets, causal relationship, co-location analysis, gene verification 

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