{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T14:44:30Z","timestamp":1787669070953,"version":"build-2736575974"},"reference-count":226,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2014Next Generation EU","award":["533-03-23-0006"],"award-info":[{"award-number":["533-03-23-0006"]}]},{"award":["533-03-23-0006"],"award-info":[{"award-number":["533-03-23-0006"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Insulin resistance (IR) is traditionally viewed within the context of type 2 diabetes. However, it increasingly appears to represent a broader systemic metabolic risk state with potential relevance for carcinogenesis. Chronic hyperinsulinemia can activate insulin-like growth factor-1-dependent pathways, including phosphoinositide 3-kinase\/protein kinase B\/mechanistic target of rapamycin and mitogen-activated protein kinase signaling, promoting cellular proliferation while limiting apoptosis. At the same time, IR is closely linked to oxidative stress, chronic low-grade inflammation, and epigenetic alterations, together shaping a tumor-promoting microenvironment. Epidemiological studies report consistent associations between IR and increased cancer risk, particularly for endometrial, liver, and colorectal cancers. Yet causality remains uncertain and likely varies by tumor type. Notably, metabolic dysfunction may also occur in individuals with normal body mass index (BMI), underscoring the limitations of BMI-based risk assessment. Unlike previous reviews that primarily focused on individual mechanisms or epidemiological associations, this review examines IR as a systemic metabolic risk state by integrating molecular, epidemiological, biomarker-based, and prevention-oriented perspectives. Particular emphasis is placed on strategies for earlier risk identification using integrated biomarker approaches, including fasting glucose, homeostatic model assessment of insulin resistance, triglyceride-to-high-density lipoprotein ratio, high-sensitivity C-reactive protein, and insulin-like growth factor-1. Emerging tools such as continuous glucose monitoring and hepatokine profiling may further refine risk detection. Sustained lifestyle modification\u2014diet, physical activity, sleep, and stress regulation\u2014remains central to prevention. Pharmacological therapies, including glucagon-like peptide-1 receptor agonists and dual incretin agents, offer additional metabolic benefits, although their long-term impact on cancer risk is still unclear. Therefore, IR is best understood not as an isolated risk factor, but as a systemic metabolic risk state that may influence cancer development, with implications for prevention and early risk stratification.<\/jats:p>","DOI":"10.3390\/ijms27125495","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T05:52:37Z","timestamp":1781761957000},"page":"5495","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Insulin Resistance as a Systemic Metabolic Risk State for Cancer: Mechanisms, Biomarkers, and Prevention"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2734-7955","authenticated-orcid":false,"given":"Marijana","family":"Matek Sari\u0107","sequence":"first","affiliation":[{"name":"Department of Health Studies, University of Zadar, Splitska 1, 23000 Zadar, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3371-1151","authenticated-orcid":false,"given":"Nata\u0161a","family":"Lisica \u0160iki\u0107","sequence":"additional","affiliation":[{"name":"Department of Health Studies, University of Zadar, Splitska 1, 23000 Zadar, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4435-8472","authenticated-orcid":false,"given":"Tamara","family":"Sori\u0107","sequence":"additional","affiliation":[{"name":"Psychiatric Hospital Ugljan, Oto\u010dkih dragovoljaca 42, 23275 Ugljan, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Sari\u0107","sequence":"additional","affiliation":[{"name":"School of Medicine, Catholic University of Croatia, Ilica 242, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrija","family":"Ivani\u0161in","sequence":"additional","affiliation":[{"name":"Independent Researcher, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivona","family":"Brodi\u0107","sequence":"additional","affiliation":[{"name":"Independent Researcher, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9837-7185","authenticated-orcid":false,"given":"Mirta","family":"Mili\u0107","sequence":"additional","affiliation":[{"name":"Division of Toxicology, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chiefari, E., Mirabelli, M., La Vignera, S., Tanyola\u00e7, S., Foti, D.P., Aversa, A., and Brunetti, A. 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