Jingkai Di, Zijian Guo, Tingting Chen, Jinsong He, Yingda Qin, Feida Wang, Chuan Xiang
BACKGROUND: This study explores the links between palmitoylation-related genes and the progression of osteoarthritis (OA) and its downstream regulatory mechanism. METHODS: By integrating palmitoylation-related gene eQTL data with OA GWAS data, Mendelian randomization (MR) and the summary data-based MR (SMR) analyses were used to identify causal links. Key genes were validated by RNA-seq differential expression analysis, and Western blot and qRT-PCR confirmed genes expression and their impacts in chondrocytes. CCK-8 and EdU assays detected effects on chondrocyte proliferation, while transwell assays explored roles in migration. Mediation analysis identified downstream mechanisms. RESULTS: MR analysis showed ZDHHC14 exerted a significant protective effect against OA (OR = 0.927, 95% CI: 0.898-0.956, P < 0.001). RNA-seq, WB, and qPCR confirmed ZDHHC14 was significantly downregulated in OA. After ZDHHC14 knockdown, the expression of ACAN, COL2A1 and SOX9 decreased, and the expression of ADAMTS5 and MMP13 increased. Functional experiments demonstrated ZDHHC14 knockdown impaired chondrocyte proliferation and migration. Mediation analysis revealed ZDHHC14 reduced OA risk by regulating sphingomyelin and 3-hydroxybutyroylglycine levels. CONCLUSION: This study is the first to reveal that ZDHHC14 inhibits OA progression by regulating metabolic homeostasis, providing crucial theoretical support and new directions for OA treatment strategies targeting palmitoylation.