{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T23:59:27Z","timestamp":1790899167898,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82200906"],"award-info":[{"award-number":["82200906"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170720"],"award-info":[{"award-number":["82170720"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Diabetic kidney disease (DKD) is a leading cause of end\u2010stage renal disease, with podocyte injury driving disease progression. Mitochondrial dysfunction and ferroptosis contribute to podocyte loss, yet the underlying molecular mechanisms remain incompletely understood. The anti\u2010aging protein Klotho protects podocytes, but how Klotho deficiency links to mitochondrial dysfunction and ferroptosis is unclear. Here, we identify SPARC, a matricellular protein upregulated in podocytes, as a key mediator linking Klotho deficiency to mitochondrial injury and ferroptosis. In human DKD biopsies and genetically modified mice, including Klotho\u2010deficient, Klotho\u2010overexpressing, and SPARC knockout mice, reduced Klotho expression correlated with ferroptosis markers (GPX4, SLC7A11, P53, 4\u2010HNE, and ACSL4) and mitochondrial abnormalities. Mechanistically, Klotho deficiency activated PKC\u03b1, leading to ubiquitination\u2010mediated degradation of the transcription factor CUX1. Loss of CUX1 derepressed SPARC, which activated TGF\u03b2\u2010RII\/Smad signaling, leading to mitochondrial dysfunction and ferroptosis. In vitro, SPARC knockdown or CUX1 overexpression preserved mitochondrial structure and ferroptosis defenses under high glucose, whereas SPARC overexpression alone induced ferroptosis even in normoglycemic conditions. These findings establish a Klotho\/PKC\u03b1\/CUX1\/SPARC\/TGF\u03b2\u2010RII axis as a critical regulator of podocyte mitochondrial dysfunction and ferroptosis. Beyond DKD, SPARC knockout also protected podocytes in ischemia\u2010reperfusion injury\u00a0and unilateral ureteral obstruction models, suggesting that SPARC may have broader implications in kidney injury and the progression toward chronic kidney disease.<\/jats:p>","DOI":"10.1002\/advs.77202","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T07:53:05Z","timestamp":1787989985000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["SPARC Drives Podocyte Mitochondrial Damage and Ferroptosis in Diabetic Kidney Disease Following Klotho Deficiency"],"prefix":"10.1002","author":[{"given":"Qing","family":"Yang","sequence":"first","affiliation":[{"name":"National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases Ministry of Education Key Laboratory of Child Development and Disorders Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases Children's Hospital of Chongqing Medical University  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Jiang","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases Ministry of Education Key Laboratory of Child Development and Disorders Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases Children's Hospital of Chongqing Medical University  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Xiong","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases Ministry of Education Key Laboratory of Child Development and Disorders Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases Children's Hospital of Chongqing Medical University  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xindi","family":"Zhou","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases Ministry of Education Key Laboratory of Child Development and Disorders Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases Children's Hospital of Chongqing Medical University  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinqin","family":"Tan","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases Ministry of Education Key Laboratory of Child Development and Disorders Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases Children's Hospital of Chongqing Medical University  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Xiao","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases Ministry of Education Key Laboratory of Child Development and Disorders Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases Children's Hospital of Chongqing Medical University  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Qiu","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases Ministry of Education Key Laboratory of Child Development and Disorders Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases Children's Hospital of Chongqing Medical University  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Gan","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases Ministry of Education Key Laboratory of Child Development and Disorders Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases Children's Hospital of Chongqing Medical University  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6242-7152","authenticated-orcid":false,"given":"Yaxi","family":"Chen","sequence":"additional","affiliation":[{"name":"Centre For Lipid Research &amp; Chongqing Key Laboratory of Metabolism on Lipid and Glucose the Second Affiliated Hospital of Chongqing Medical University  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiping","family":"Yang","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases Ministry of Education Key Laboratory of Child Development and Disorders Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases Children's Hospital of Chongqing Medical University  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9231-8869","authenticated-orcid":false,"given":"Wei","family":"Jiang","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases Ministry of Education Key Laboratory of Child Development and Disorders Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases Children's Hospital of Chongqing Medical University  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2481-7168","authenticated-orcid":false,"given":"Qiu","family":"Li","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases Ministry of Education Key Laboratory of Child Development and Disorders Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases Children's Hospital of Chongqing Medical University  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41574-025-01171-3","article-title":"Mechanisms of Diabetic Kidney Disease and Established and Emerging Treatments","volume":"22","author":"Martinez Leon V.","year":"2025","journal-title":"Nature Reviews Endocrinology"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.01.012"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2210639"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"i438","DOI":"10.1136\/bmj.i438","article-title":"Diabetes Mellitus as a Compelling Indication for Use of renin Angiotensin System Blockers: Systematic Review and Meta\u2010analysis of Randomized Trials","volume":"352","author":"Bangalore S.","year":"2016","journal-title":"Bmj"},{"issue":"2","key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"248","DOI":"10.2337\/dbi18-0007","article-title":"Sodium\u2010glucose Cotransporter 2 Inhibition and Diabetic Kidney Disease","volume":"68","author":"Alicic R. 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