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-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.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: extracellular vesicles; Exo: exosome; GPX4: glutathione peroxidase 4; H&E: hematoxylin and eosin; HsNPCs: Human NPCs; IF: immunofluorescence; IHC: immunohistochemistry; IP-MS: immunoprecipitation mass spectrometry; IVDD: intervertebral disc degeneration; IVDs: intervertebral discs; LBP: low back pain; LDP: lumbar disc prolapse; MRI: magnetic resonance imaging; N/L: NH4Cl and leupeptin; NP: nucleus pulposus; NPCs: nucleus pulposus cells; PCA: principal component analysis; qRT-PCR: quantitative real-time PCR; RnBMSCs: rat bone marrow mesenchymal stem cells; RnNPCs: rat NPCs; ROS: reactive oxygen species; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; SD: Sprague-Dawley; SO: Safranin O-Fast Green; TBHP: tert-butyl hydroperoxide; UCHL1: ubiquitin C-terminal hydrolase L1; UPS: ubiquitin-proteasome system. UCHL1Abbreviations:
