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Diagnosis of MAFLD requires evidence of hepatic steatosis combined with obesity, type 2 diabetes mellitus, or other metabolic dysregulation conditions, all of which significantly elevate the risk of chronic kidney disease (CKD). This review discusses the pathological mechanisms of lipid accumulation and insulin resistance in MAFLD and CKD, highlighting their mechanistic connections. Specifically, ectopic fat accumulation triggered by metabolic reprogramming, oxidative stress and inflammation induced by energy overload, modified lipids, uremic toxins, and senescence, as well as insulin resistance pathways activated by pro-inflammatory factors and lipotoxic products, collectively exacerbate simultaneous hepatic and renal injury. Moreover, interactions among hyperinsulinemia, the sympathetic nervous system, the renin\u2013angiotensin system (RAS), and altered adipokine and hepatokine profiles further amplify insulin resistance, ectopic lipid deposition, and systemic damage. Finally, the review explores potential therapeutic strategies targeting lipid metabolism, insulin sensitivity, and RAS activity, which offer promise for dual-organ protection and improved outcomes in both hepatic and renal systems.<\/jats:p>","DOI":"10.3390\/ijms26146962","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T09:33:53Z","timestamp":1753090433000},"page":"6962","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Lipid Accumulation and Insulin Resistance: Bridging Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Kidney Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Xinyi","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3565-8024","authenticated-orcid":false,"given":"Chun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20420188221145549","DOI":"10.1177\/20420188221145549","article-title":"MAFLD: A multisystem disease","volume":"14","author":"Pipitone","year":"2023","journal-title":"Ther. 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