Metabolic dysfunction‐associated steatotic liver disease, insulin resistance and hepatocellular carcinoma: A deadly triad

Abstract Background Metabolic dysfunction‐associated steatotic liver disease (MASLD) has become a leading cause of chronic liver disease worldwide, driven by the increasing prevalence of obesity and insulin resistance (IR). 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. Methods 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. Results 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‐inflammatory and pro‐fibrotic pathways, accelerating the evolution to HCC. Patients with MASLD‐associated HCC exhibit distinct metabolic and molecular characteristics compared with those with viral or alcohol‐related HCC. Novel biomarkers and advanced imaging modalities show promise for identifying high‐risk individuals at earlier disease stages. Conclusions Although substantial progress has been made in understanding the MASLD–IR–HCC 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.