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In obesity-related kidney disease (OKD), ectopic lipid accumulation in renal proximal tubule cells impairs autophagic flux, exacerbating kidney injury. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, such as dapagliflozin, induce a fasting-like metabolic state and increase circulating \u03b2-hydroxybutyrate (\u03b2-HB) levels. However, the role of \u03b2-HB in modulating autophagic flux in OKD remains unclear. To investigate the potential involvement of \u03b2-HB in the renoprotective effects of dapagliflozin, diet-induced obesity (DIO) mice were used. Twelve DIO mice maintained on a high-fat diet (HFD) were randomly assigned to receive dapagliflozin or the \u03b2-HB precursor 1,3-butanediol (n\u00a0=\u00a06 per group). For each treatment, six DIO mice on HFD served as experimental models and were compared with six age-matched mice fed a standard chow diet as controls. Our study showed that dapagliflozin treatment significantly increased plasma \u03b2-HB levels and improved metabolic profiles in DIO mice. Exogenous ketone supplementation elicited similar metabolic and renoprotective effects. Both interventions enhanced autophagic flux in proximal tubule cells and attenuated structural damage in glomeruli and tubules. The renoprotective effects of dapagliflozin were associated with improved autophagic flux, suggesting that elevated \u03b2-HB levels may contribute to these benefits. The data suggest that dapagliflozin improves autophagic flux in OKD, potentially mediated by increased plasma \u03b2-HB levels. These findings provide insight into the metabolic mechanisms underlying SGLT-2 inhibitor-mediated renoprotection and highlight \u03b2-HB as a possible therapeutic target in OKD.<\/jats:p>","DOI":"10.1042\/bcj20240504","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T09:32:26Z","timestamp":1774344746000},"page":"479-491","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dapagliflozin regulates autophagy in nephropathy associated with non-diabetic obesity via elevated plasma \u03b2-hydroxybutyrate levels"],"prefix":"10.1042","volume":"483","author":[{"given":"Yan","family":"Kong","sequence":"first","affiliation":[{"name":"1NHC Key Laboratory of Hormones and Development, Tianjin \u00adKey Laborato\u00adry of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyue","family":"Peng","sequence":"additional","affiliation":[{"name":"2Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenying","family":"Fan","sequence":"additional","affiliation":[{"name":"3Jinjiang Municipal Hospital (Shanghai Sixth People\u2019s Hospital Fujian), Jinjiang 362200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"1NHC Key Laboratory of Hormones and Development, Tianjin \u00adKey Laborato\u00adry of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijie","family":"Wu","sequence":"additional","affiliation":[{"name":"1NHC Key Laboratory of Hormones and Development, Tianjin \u00adKey Laborato\u00adry of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaoyan","family":"Zheng","sequence":"additional","affiliation":[{"name":"1NHC Key Laboratory of Hormones and Development, Tianjin \u00adKey Laborato\u00adry of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1945-8877","authenticated-orcid":false,"given":"Chunyan","family":"Shan","sequence":"additional","affiliation":[{"name":"1NHC Key Laboratory of Hormones and Development, Tianjin \u00adKey Laborato\u00adry of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"2026032405321955000_B1","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1016\/S0140-6736(09)62004-3","article-title":"Early recognition and prevention of chronic kidney disease","volume":"375","author":"James","year":"2010","journal-title":"Lancet"},{"key":"2026032405321955000_B2","doi-asserted-by":"publisher","first-page":"1095211","DOI":"10.3389\/fendo.2022.1095211","article-title":"Obesity-related kidney disease: Beyond hypertension and insulin-resistance","volume":"13","author":"Arabi","year":"2022","journal-title":"Front. 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