Beyond Insulin Resistance: Exploring the Centrality of the Gut–Liver Axis in Mediating Immunometabolic Dysregulation Driving Hepatocellular Carcinoma in MASLD and Diabetes

Hepatocellular carcinoma (HCC) represents a major global health challenge and the third leading cause of cancer-related mortality worldwide. Its epidemiological burden is rapidly increasing, largely driven by the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), which is now recognized as the most common chronic liver disease globally. Notably, MASLD frequently coexists with type 2 diabetes mellitus (T2DM), sharing several features, including the interplay of common genetic, metabolic, and environmental factors, thus contributing to a complex multifactorial pathogenesis. Relevantly, patients affected by both conditions represent a subgroup at particularly high risk of liver disease progression and hepatocarcinogenesis. In this population, metabolic and inflammatory disturbances act synergistically to create a pro-tumorigenic hepatic environment where insulin resistance (IR) plays a crucial role, by driving hepatic lipotoxicity, mitochondrial dysfunction, and inflammatory signaling with oxidative stress, thereby establishing a permissive environment for worsening steatosis and malignant transformation. Increasing evidence supports the concept of MASLD as a multisystem disorder reflecting the systemic nature of metabolic dysfunction. Within this framework, beyond IR, extrahepatic factors have also emerged as important contributors to steatosis progression, worsening of T2DM, and modulation of HCC risk. In particular, the gut-liver axis has gained recognition as a key regulator of hepatic homeostasis, integrating signals from the intestinal microbiota, immune responses, and metabolic pathways. Dysregulation of this crosstalk promotes systemic inflammation and metabolic imbalance, exacerbating IR and fostering a pro-oncogenic hepatic environment. This review examines the interconnected metabolic and immune mechanisms linking IR and gut-liver axis dysfunction to HCC development in patients with MASLD and T2DM, highlighting their implications for risk stratification and precision-based therapeutic strategies.