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Calcium oxalate (CaOx) crystals disrupt lipid metabolism and damage RTECs, thereby promoting nephrolithiasis. We found that SIRT5, a highly expressed desuccinylase in RTECs, was markedly reduced in kidneys from patients with CaOx stones and in mouse models. Multi\u2010omics analyses integrating succinylomics, lipidomics, and proteomics showed that SIRT5 maintains lipid metabolic homeostasis by desuccinylating key fatty acid oxidation (FAO) enzymes. SIRT5 deficiency impaired FAO, causing polyunsaturated fatty acid (PUFA) accumulation, phospholipid remodeling, and ferroptosis. Oxidative membrane damage subsequently increased crystal adhesion, establishing a vicious cycle of crystal deposition and tubular injury. Acetyl\u2010CoA acyltransferase 2 (ACAA2) was identified as a functional SIRT5 substrate. The K13R mutation reduced ACAA2 succinylation and preserved its activity, whereas K13E impaired the protective effect of SIRT5 overexpression against CaOx\u2010induced injury. Collectively, our findings define a SIRT5\u2010ACAA2 axis linking impaired FAO to lipid peroxidation, ferroptosis, and crystal adhesion, highlighting this pathway as a potential therapeutic target for CaOx nephrolithiasis.<\/jats:p>","DOI":"10.1002\/advs.77703","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SIRT5\u2010Mediated Desuccinylation of ACAA2 Protects Against Calcium Oxalate\u2010Induced Kidney Injury by Regulating Fatty Acid Oxidation to Suppress Mitochondrial Oxidative Injury and Ferroptosis"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3505-1905","authenticated-orcid":false,"given":"Qinhong","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Urology Renmin Hospital of Wuhan University Wuhan University  Wuhan China"},{"name":"Hubei 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