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Although autophagy dysfunction is a documented contributor to IDD, the precise pathobiological role of chaperone\u2010mediated autophagy (CMA) remains poorly understood. Here, we demonstrate that CMA activity is downregulated in nucleus pulposus cells (NPCs) from IDD patients and IL\u20101\u03b2\u2010induced rat intervertebral disc cell models, causing cytoplasmic accumulation of a novel CMA substrate, Midnolin (MIDN). Accumulated MIDN bypasses the ubiquitin\u2010proteasome system and directly binds to Tuberous Sclerosis Complex 2 (TSC2), mediating its degradation. TSC2 loss relieves mechanistic target of rapamycin complex 1 (mTORC1) inhibition, resulting in mTORC1 hyperactivation, which drives cellular senescence, senescence\u2010associated secretory phenotype (SASP), and extracellular matrix (ECM) degradation in NPCs. In vitro and in a rat caudal needle puncture model, MIDN knockdown (shRNA), CMA activation (LAMP2A overexpression), or mTORC1 inhibition (Rapamycin) significantly attenuated IL\u20101\u03b2 or MIDN overexpression\u2010induced senescence and disc degeneration. Our findings reveal an \u201cImpaired CMA\u2013MIDN accumulation\u2013TSC2 degradation\u2013mTORC1 activation\u201d axis central to IDD pathogenesis, offering potential therapeutic targets.<\/jats:p>","DOI":"10.1002\/advs.77428","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T15:41:51Z","timestamp":1787845311000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impaired Chaperone\u2010Mediated Autophagy Accelerates Intervertebral Disc Degeneration by Inducing MIDN Accumulation to Target TSC2 for Proteasomal Degradation"],"prefix":"10.1002","author":[{"given":"Xianglong","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Orthopedics Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 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