{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:25:50Z","timestamp":1792106750777,"version":"4.4.0"},"reference-count":146,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Metabolic syndrome and chronic kidney disease frequently coexist, acting synergistically to amplify the risk of adverse cardiovascular and renal outcomes. Large epidemiological studies now identify metabolic syndrome as an independent determinant of incident chronic kidney disease, accelerated estimated glomerular filtration rate decline and progression to end-stage kidney disease, even after adjustment for diabetes and hypertension. These observations have driven a conceptual shift away from haemodynamic and glomerular hyperfiltration-centric models towards an integrated paradigm of metabolic dysfunction\u2013associated kidney disease. This framework emphasises systemic insulin resistance, lipotoxicity, chronic low-grade inflammation and disrupted cellular energy homeostasis as central drivers of renal injury. Within the kidney, metabolic syndrome promotes renal microvascular rarefaction, endothelial glycocalyx disruption, podocyte injury and tubular\u2013interstitial inflammation. At the cellular and molecular level, key mechanisms include dysregulated adipokine and hepatokine signalling; ectopic lipid accumulation and renal lipotoxicity; mitochondrial dysfunction; endoplasmic reticulum stress; defective autophagy and mitophagy; oxidative stress and epigenetic remodelling. Importantly, several established therapies including renin\u2013angiotensin\u2013aldosterone system blockade, non-steroidal mineralocorticoid receptor antagonists and sodium\u2013glucose cotransporter-2 inhibitors appear to confer renoprotection through modulation of these metabolic and cellular stress pathways. In this focused narrative review, we summarise the recent advances in the molecular and cellular mechanisms linking metabolic syndrome to kidney dysfunction. We highlight the key knowledge gaps and outline potential future therapeutic opportunities at the metabolic\u2013renal interface.<\/jats:p>","DOI":"10.3389\/fendo.2026.1785937","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:13:20Z","timestamp":1776399200000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Metabolic syndrome and kidney dysfunction: emerging molecular and cellular mechanisms at the metabolic\u2013renal interface"],"prefix":"10.3389","volume":"17","author":[{"given":"William R.","family":"Marshall","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Sciences, University of Manchester","place":["Manchester, United Kingdom"]},{"name":"Donal O\u2019Donoghue Renal Research Centre, Northern Care Alliance NHS Foundation Trust","place":["Salford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren","family":"Green","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences, University of Manchester","place":["Manchester, United Kingdom"]},{"name":"Donal O\u2019Donoghue Renal Research Centre, Northern Care Alliance NHS Foundation Trust","place":["Salford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smeeta","family":"Sinha","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences, University of Manchester","place":["Manchester, United Kingdom"]},{"name":"Donal O\u2019Donoghue Renal Research Centre, Northern Care Alliance NHS Foundation Trust","place":["Salford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip A.","family":"Kalra","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences, University of Manchester","place":["Manchester, United 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