UCHL5 stabilizes ALK5 to promote autophagy dependent ferroptosis in osteoarthritis
TL;DR
The findings identify the UCHL5/ALK5 pathway as a regulator of autophagy-dependent ferroptosis in OA, offering a potential therapeutic target for OA treatment.
Abstract
Ferroptosis is recognized as a key driver in the pathological progression of osteoarthritis (OA), but its regulatory mechanisms remain incompletely understood. To address this gap, we focused on the deubiquitinating enzyme UCHL5, which is implicated in OA progression, to elucidate its function in modulating ferroptosis within the OA context. Through in vitro experiments involving UCHL5 knockdown and overexpression in chondrocytes, and in vivo studies using UCHL5 knockout mice, we demonstrate that UCHL5 promotes OA pathogenesis by activating autophagy-dependent ferroptosis. Genetic suppression of UCHL5 significantly inhibited ferroptosis, enhanced chondrocyte survival, and facilitated functional recovery in OA models. Mechanistically, UCHL5 deubiquitinates and stabilizes ALK5 by specifically cleaving Lys48-linked polyubiquitin chains via its C185 catalytic residue. This UCHL5-ALK5 axis activates autophagy, promotes ferroptosis, and accelerates cartilage matrix degradation. Our findings identify the UCHL5/ALK5 pathway as a regulator of autophagy-dependent ferroptosis in OA, offering a potential therapeutic target for OA treatment.