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We identified CRISPLD2 (cysteine\u2010rich secretory protein LCCL domain\u2010containing 2) as a critical regulator of nucleus pulposus cells (NPCs) homeostasis during IVDD. Single\u2010cell transcriptomic analysis (scRNA\u2010seq) revealed degenerative NPCs subsets enriched in iron metabolism and lipid peroxidation. CRISPLD2 knockdown in NPCs led to disrupted redox balance, elevated lipid peroxides, and excessive iron accumulation, promoting oxidative stress\u2010induced ferroptosis and disc degeneration. Mechanistically, we identified a CRISPLD2\u2010miR\u2010548I\u2010IL17A axis that governs ferroptotic cell death in IVDD, where CRISPLD2 deficiency was associated with reduced miR\u2010548I expression, accompanied by subsequent upregulation of IL17A, thereby amplifying inflammatory and oxidative stress responses. In vivo, CRISPLD2 knockdown induced spontaneous IVDD and increased pain sensitivity, while restoration of CRISPLD2 or inhibition of IL17A alleviated ferroptosis and improved NPCs survival. Adeno\u2010associated virus (AAV)\u2010mediated overexpression of CRISPLD2 successfully alleviated IVDD in lumbar spine instability and needle\u2010puncture models, reducing oxidative stress\u2010induced ferroptosis and restoring disc integrity. These findings highlight the critical role of CRISPLD2 in regulating oxidative stress\u2010induced ferroptosis in IVDD and suggest that targeting the CRISPLD2\u2010miR\u2010548I\u2010IL17A axis may provide a novel therapeutic strategy for preventing disc degeneration and alleviating discogenic pain.<\/jats:p>","DOI":"10.1002\/advs.202516477","type":"journal-article","created":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T04:43:07Z","timestamp":1768020187000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["CRISPLD2 Attenuates Intervertebral Disc Degeneration by Suppressing Oxidative Stress\u2010Induced Ferroptosis through the miR\u2010548I\u2010IL17A Axis"],"prefix":"10.1002","volume":"13","author":[{"given":"Yangyang","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Orthopedics &amp; Spine Surgery Laboratory of Spinal and Spinal Cord Injury Regeneration and Repair The First Affiliated Hospital of Anhui Medical University  Hefei P. 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