Browsing by Subject "UCHL1"

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    UCHL1 enhances TSC1 transcription by stabilizing FOXO1 through deubiquitination in knee osteoarthritis
    (2026) Jiawei Lu; Chonghao Gu; Zikang Xie; Zhongyu Xia; Bingqing Guo; Tao Jiang; Yu Wang; Biología Celular e Histología; Universidad de Murcia, Departamento de Biologia Celular e Histiologia
    Ferroptosis has been shown to play a significant role in the pathophysiological progression of knee osteoarthritis (KOA). In this study, we sought to investigate the biological role of Ubiquitin C-terminal hydrolase 1 (UCHL1) in KOA and elucidate its underlying molecular mechanisms. An in vitro KOA cell model was established by stimulating C28/I2 chondrocytes with IL-1β, and UCHL1 expression was decreased in IL-1β-treated chondrocytes. Notably, overexpression of UCHL1 significantly alleviated IL-1β induced ferroptosis and extracellular matrix (ECM) degradation. Mechanistically, UCHL1 facilitated the deubiquitination and stabilization of FOXO1. Knockdown of FOXO1 partially reversed the inhibitory effects of UCHL1 on ferroptosis and ECM degradation. Furthermore, FOXO1 was found to bind to the Tuberous Sclerosis Complex 1 (TSC1) promoter, enhancing TSC1 transcription. Intriguingly, knockdown of FOXO1 counteracted the inhibitory effects of UCHL1 overexpression on ferroptosis and ECM degradation, while these effects were rescued by TSC1 overe xpression. In vivo experiments demonstrated that UCHL1 alleviated cartilage damage in KOA rats by inhibiting ferroptosis and ECM degradation through the FOXO1/TSC1 axis. These findings demonstrate the pivotal role of UCHL1 in regulating ferroptosis and maintaining ECM homeostasis, offering novel insights into the molecular mechanisms driving KOA progression.