Abstract
Knee osteoarthritis (KOA) is a leading cause of chronic pain and disability. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a systemic metabolic disorder that influences extra-hepatic conditions. Although cross-sectional studies link MAFLD to KOA, prospective evidence remains limited. This study aimed to investigate the longitudinal association between MAFLD, and KOA and assess the mediating role of inflammation. This study included 303,604 participants from the UK Biobank without baseline osteoarthritis. MAFLD was defined using the fatty liver index alongside metabolic criteria, fibrosis severity was assessed using the Fibrosis-4 score, and MAFLD subtypes were categorized. Incident KOA was identified through linked health records. Cox proportional hazard regression model was used to estimate hazard ratios (HR) and 95% confidence interval (CI) for the association. Mediation analysis evaluated the potential role of high-sensitivity C-reactive protein (hs-CRP). Over a median follow-up of 13.67 years, 17,137 KOA cases occurred. MAFLD was associated with an 18% higher risk of KOA (HR 1.18, 95% CI 1.13-1.24), with risk increasing by fibrosis severity (P for trend < 0.001). Among subtypes, MAFLD-overweight/obesity showed a significant association with KOA (HR 1.19, 95% CI 1.14-1.25), while MAFLD-diabetes (HR 1.05, 95% CI 0.96-1.16) and MAFLD-lean (HR 1.23, 95% CI 0.93-1.62) did not reach statistical significance. Additionally, hs-CRP explained 8.94% of the association between MAFLD and KOA. MAFLD was independently associated with higher KOA risk; inflammation partially mediates this association. These findings suggest MAFLD as a systemic metabolic condition affecting musculoskeletal health, supporting integrated management strategies.