Metabolic-dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a growing cause of chronic liver disease and hepatocellular carcinoma (HCC). It is linked to increasing obesity and metabolic syndrome rates in the Western world. MASLD-HCC can develop earlier in fibrosis stages compared to other liver diseases, complicating risk stratification and treatment decisions. Therapeutic responses, especially to immune checkpoint inhibitors, may vary by disease aetiology, highlighting the need for patient stratification. MASLD is characterized by hepatic steatosis with at least one cardiometabolic risk factor. It ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Obesity, type 2 diabetes, and metabolic syndrome are key risk factors for MASLD progression to MASH, cirrhosis, and mortality. The "multiple hit" hypothesis suggests that environmental factors contribute to lipid accumulation, insulin resistance, and gut microbiota changes, leading to liver damage and HCC. MASLD-HCC is associated with increased cardiovascular disease mortality, and its incidence is rising. HCC is the most common liver cancer, with MASLD being the leading cause in many regions. HCC risk factors include age, male gender, and advanced fibrosis/cirrhosis. Genetic polymorphisms, such as those related to PNPLA3, may contribute to disease progression. HCC pathogenesis in MASLD involves chronic inflammation, fibrosis, and genetic instability. Immune responses, including activated CD8+ T cells and NK cells, can promote tumorigenesis, while effective immune responses may prevent malignant transformation. Signalling pathways like Wnt/β-catenin, PI3K/Akt/mTOR, and Hedgehog are involved in HCC development. Treatment for MASLD-HCC is challenging, with limited options for early-stage disease. Lifestyle modifications, including diet and exercise, are key, but may not be sufficient. Pharmacological therapies, such as PPARγ agonists and GLP-1 receptor agonists, show promise. Statins and metformin also have potential in reducing HCC risk. HCC treatment options include surgical resection, liver transplantation, and systemic therapies like immune checkpoint inhibitors. However, MASLD-HCC patients often present at advanced stages, limiting curative options. Treatment responses may vary by aetiology, and further research is needed to develop targeted therapies and improve patient outcomes. Overall, MASLD-HCC remains a complex disease requiring tailored approaches for effective management.Metabolic-dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a growing cause of chronic liver disease and hepatocellular carcinoma (HCC). It is linked to increasing obesity and metabolic syndrome rates in the Western world. MASLD-HCC can develop earlier in fibrosis stages compared to other liver diseases, complicating risk stratification and treatment decisions. Therapeutic responses, especially to immune checkpoint inhibitors, may vary by disease aetiology, highlighting the need for patient stratification. MASLD is characterized by hepatic steatosis with at least one cardiometabolic risk factor. It ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Obesity, type 2 diabetes, and metabolic syndrome are key risk factors for MASLD progression to MASH, cirrhosis, and mortality. The "multiple hit" hypothesis suggests that environmental factors contribute to lipid accumulation, insulin resistance, and gut microbiota changes, leading to liver damage and HCC. MASLD-HCC is associated with increased cardiovascular disease mortality, and its incidence is rising. HCC is the most common liver cancer, with MASLD being the leading cause in many regions. HCC risk factors include age, male gender, and advanced fibrosis/cirrhosis. Genetic polymorphisms, such as those related to PNPLA3, may contribute to disease progression. HCC pathogenesis in MASLD involves chronic inflammation, fibrosis, and genetic instability. Immune responses, including activated CD8+ T cells and NK cells, can promote tumorigenesis, while effective immune responses may prevent malignant transformation. Signalling pathways like Wnt/β-catenin, PI3K/Akt/mTOR, and Hedgehog are involved in HCC development. Treatment for MASLD-HCC is challenging, with limited options for early-stage disease. Lifestyle modifications, including diet and exercise, are key, but may not be sufficient. Pharmacological therapies, such as PPARγ agonists and GLP-1 receptor agonists, show promise. Statins and metformin also have potential in reducing HCC risk. HCC treatment options include surgical resection, liver transplantation, and systemic therapies like immune checkpoint inhibitors. However, MASLD-HCC patients often present at advanced stages, limiting curative options. Treatment responses may vary by aetiology, and further research is needed to develop targeted therapies and improve patient outcomes. Overall, MASLD-HCC remains a complex disease requiring tailored approaches for effective management.