Hand osteoarthritis is a common heterogeneous joint disorder with unclear molecular mechanisms and no disease-modifying drugs. This study used single-cell RNA sequencing to compare cellular composition and gene expression in osteoarthritic and non-osteoarthritic cartilage. A novel inflammatory chondrocyte subpopulation was identified, along with alterations in fibrocartilage chondrocytes. Ferroptosis pathway enrichment and increased *FTH1* expression were observed in osteoarthritic cartilage. Mendelian randomization and population-based studies validated the association between high *FTH1* expression and increased hand osteoarthritis risk. High serum ferritin levels were also linked to a higher prevalence of hand osteoarthritis. These findings suggest inflammatory and fibrocartilage chondrocytes are key subpopulations, and ferroptosis is a crucial pathway in hand osteoarthritis.

Hui Li, Xiaofeng Jiang, Yongbing Xiao, Yuqing Zhang, Weiya Zhang, Michael Doherty, Jacquelyn Nestor, Changjun Li, Jing Ye, Tingting Sha, Houchen Lyu, Jie Wei, Chao Zeng, Guanghua Lei