UCHL1 alleviates nucleus pulposus cell senescence by promoting chaperone-mediated autophagy antagonizing autophagy-dependent ferroptosis through deubiquitination of HSPA8

作者：Zhouwei Wu, Yang Shu, Zhichen Jiang, Yuxuan Zhu, Haibo Liang, Yifeng Shi, Sunlong Li, Shuhao Zhang, Yining Xu, Chenglong Hong, Juntao Ying, Chenggui Wang, Xiangyang Wang · 发表于：Autophagy · 年份：2025 · DOI：10.1080/15548627.2025.2544287 · 被引用次数：14 · 研究领域：Circular RNAs in diseases、Epigenetics and DNA Methylation、Ferroptosis and cancer prognosis

Chaperone-mediated autophagy (CMA), a lysosome-dependent protein degradation pathway, plays a pivotal yet poorly understood role in cellular senescence-related degenerative diseases. Our study sheds light on a novel mechanism whereby UCHL1 plays a crucial role in mitigating nucleus pulposus cell (NPC) senescence and intervertebral disc degeneration (IVDD) by activating CMA to counteract autophagy-dependent ferroptosis. Through sequencing analysis of human samples, we identified UCHL1 as a potential factor influencing disc degeneration. Further research revealed that UCHL1 activates CMA by stabilizing HSPA8 through deubiquitination. HSPA8, in turn, recognizes and promotes the degradation of HPCAL1 via the CMA pathway by binding to its “KFERQ” motif, ultimately alleviating NPC senescence. Importantly, we demonstrated that engineered exosomes delivering UCHL1-overexpressing plasmids effectively alleviated NPC senescence and significantly mitigated the progression of IVDD. This finding underscores the significance of CMA-regulated ferroptosis in IVDD through UCHL1 modulation and as a promising target for improving chronic pain and IVDD progression.Abbreviations: AAV: adeno-associated virus; AB: Alcian Blue; ACSL4: acyl-CoA synthetase long chain family member 4; ALP: autophagy-lysosome pathway; Baf-A1: bafilomycin A1; CHX: cycloheximide; CMA: chaperone-mediated autophagy; Co-IP: co-immunoprecipitation; DUBs: deubiquitinating enzymes; eMI: endosomal microautophagy; Evs: extracellul...