Publication: UCHL1 enhances TSC1 transcription by stabilizing FOXO1 through deubiquitination in knee osteoarthritis
Authors
Jiawei Lu ; Chonghao Gu ; Zikang Xie ; Zhongyu Xia ; Bingqing Guo ; Tao Jiang ; Yu Wang
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Publisher
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Universidad de Murcia, Departamento de Biologia Celular e Histiologia
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DOI
https://doi.org/10.14670/HH-18-995
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info:eu-repo/semantics/article
Description
Abstract
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.
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