{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T01:25:34Z","timestamp":1787189134296,"version":"build-2736575974"},"reference-count":23,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Nephrology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>To investigate whether miR\u2010145\u20105p regulates high\u2010glucose\u2010induced ferroptosis and injury in renal tubular epithelial cells through the KLF4\/SIRT3\/GPX4 signaling axis. Ferroptosis, a regulated form of iron\u2010dependent cell death, has been increasingly implicated in DKD pathogenesis. The present investigation was designed to explore the functional significance and underlying molecular mechanisms of the miR\u2010145\u20105p\/KLF4\/SIRT3\/GPX4 signalling cascade in ferroptotic cell death of renal tubular epithelial cells during DKD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A high\u2010glucose\u2010stimulated in\u00a0vitro DKD model was constructed using human renal tubular epithelial cells (HK\u20102) exposed to 25.0\u2009mmol\/L glucose. Gene and protein expression profiles were characterised through RT\u2010qPCR, Western blotting and immunofluorescence staining. Cellular viability, apoptotic rates and ferroptosis\u2010associated biomarkers were quantified using CCK\u20108 assay, flow cytometric analysis, ELISA and JC\u20101 mitochondrial probe, respectively. Molecular binding interactions were confirmed through dual luciferase reporter assays and co\u2010immunoprecipitation experiments. Intracellular reduced glutathione (GSH) content and GPX4 enzymatic activity were additionally measured to evaluate the functional status of the antioxidant arm of ferroptosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>High glucose exposure triggered time\u2010dependent cellular damage and ferroptotic responses in HK\u20102 cells, characterised by elevated miR\u2010145\u20105p levels alongside diminished KLF4, SIRT3 and GPX4 expression. Forced expression of miR\u2010145\u20105p aggravated cellular damage and ferroptotic phenotypes, whilst its functional suppression conferred cytoprotection. Mechanistic analyses demonstrated that miR\u2010145\u20105p directly engages the 3\u2032\u2010UTR of KLF4 to repress its expression. Restoring KLF4 expression attenuated high\u2010glucose\u2010mediated cellular injury and enhanced SIRT3 and GPX4 levels. Co\u2010immunoprecipitation assays verified a physical protein\u2013protein association between KLF4 and SIRT3. Functionally, HG stimulation reduced intracellular GSH content and GPX4 enzymatic activity. These changes were aggravated by miR\u2010145\u20105p overexpression but were partially reversed by miR\u2010145\u20105p inhibition or KLF4 overexpression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In the context of hyperglycemia, miR\u2010145\u20105p facilitates ferroptotic cell death in renal tubular epithelial cells through KLF4 suppression, consequently attenuating the SIRT3\/GPX4 signalling cascade and worsening DKD\u2010related cellular injury. This regulatory axis may constitute a promising molecular intervention target for DKD treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nep.70237","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T07:44:12Z","timestamp":1784879052000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>miR<\/scp>\n                    \u2010145\u20105p Targets\n                    <scp>KLF4<\/scp>\n                    to Regulate the\n                    <scp>SIRT3<\/scp>\n                    \/\n                    <scp>GPX4<\/scp>\n                    Axis, Mediating Ferroptosis and Exacerbating Tubular Epithelial Cell Injury in Diabetic Nephropathy"],"prefix":"10.1111","volume":"31","author":[{"given":"Hongjin","family":"Tan","sequence":"first","affiliation":[{"name":"Xianning Central Hospital (The First Affiliated Hospital of Hubei University of Science and Technology)  Xianning Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuopeng","family":"Lu","sequence":"additional","affiliation":[{"name":"People's Hospital of Tongcheng County  Xianning Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meirong","family":"Xu","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Hubei University of Science and Technology  Xianning Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7538-6843","authenticated-orcid":false,"given":"Ganlin","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, Xianning Medical College Hubei University of Science and Technology  Xianning Hubei China"},{"name":"National Demonstration Center for Experimental (General Practice) Education, Xianning Medical College Hubei University of Science and Technology  Xianning Hubei 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