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IR, a central feature of the metabolic syndrome, promotes hepatic lipid accumulation, inflammation and mitochondrial dysfunction, fostering the transition from steatosis to advanced liver injury and hepatocellular carcinoma (HCC). This review summarizes current evidence on the molecular mechanisms linking MASLD, IR and HCC, highlighting the role of insulin resistance in liver carcinogenesis and disease progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A comprehensive literature search was conducted to identify experimental, clinical and epidemiological studies addressing the interplay between MASLD, IR and HCC. Key molecular pathways and risk profiles were synthesised and compared across etiologies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>IR contributes to hepatic lipid deposition, oxidative stress and chronic inflammation through activation of PI3K\/Akt and mTOR signalling. The coexistence of MASLD and IR enhances pro\u2010inflammatory and pro\u2010fibrotic pathways, accelerating the evolution to HCC. Patients with MASLD\u2010associated HCC exhibit distinct metabolic and molecular characteristics compared with those with viral or alcohol\u2010related HCC. Novel biomarkers and advanced imaging modalities show promise for identifying high\u2010risk individuals at earlier disease stages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Although substantial progress has been made in understanding the MASLD\u2013IR\u2013HCC axis, critical gaps remain regarding genetic, environmental and metabolic determinants. A multidisciplinary approach integrating metabolic, molecular and oncologic research is essential for improving early detection, risk stratification and the development of targeted therapies against metabolic liver cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/eci.70132","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:00:01Z","timestamp":1760112001000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Metabolic dysfunction\u2010associated steatotic liver disease, insulin resistance and hepatocellular carcinoma: A deadly triad"],"prefix":"10.1111","volume":"56","author":[{"given":"Alfredo","family":"Caturano","sequence":"first","affiliation":[{"name":"Department of Human Sciences and Promotion of the Quality of Life San Raffaele Roma University  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enes","family":"Erul","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Ankara University Faculty of Medicine  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Nilo","sequence":"additional","affiliation":[{"name":"Data Collection G\u2010STeP Research Core Facility, Fondazione Policlinico Universitario A. 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