Obesity is a complex chronic condition characterized by an excess of body fat that manifests in various clinical pathophenotypes, each affecting liver health differently. One significant cause of chronic liver diseases among those living with obesity is metabolic dysfunction-associated steatotic liver disease (MASLD), which is linked to one or more cardiometabolic risk factors in individuals who do not engage in harmful alcohol consumption. Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and is increasingly being associated with MASLD through intricate immunological, cellular, proinflammatory, molecular, and genetic mechanisms. In this review, we examine the molecular changes and altered functions of hepatocytes related to lipid accumulation, oxidative stress, inflammatory responses, and the regulation of signaling pathways such as mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and nuclear factor kappa B (NF-κB). We also explore how these processes impact cell proliferation, apoptosis, autophagy, migration, the immunological environment, angiogenesis, and cell differentiation. Finally, we discuss the challenges posed by MASLD-HCC and how these may be effectively managed by promoting effective risk stratification, early diagnosis, and innovative treatment schedules for this numerically growing category of patients.
Weiskirchen et al. (2026) studied this question.