Background: Obesity has emerged as a major global health burden, markedly increasing the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). These conditions are now recognized as key drivers of hepatocellular carcinoma (HCC), particularly in populations with rising obesity rates. Notably, liver cancer exhibits the strongest association with obesity among all cancer types, emphasizing the pivotal role of metabolic dysfunction in hepatic carcinogenesis. The growing incidence of MASH-related HCC, especially in Western countries, underscores the urgent public health challenge posed by obesity-linked liver diseases. Genetic susceptibility plays a critical role in determining MASLD and MASH outcomes. Among known variants, the PNPLA3 I148M allele is the most robustly associated with hepatic steatosis, inflammation, and fibrosis. However, interindividual differences in disease severity among carriers point to additional genetic modifiers. Our research highlights DNAJA3, particularly the rs3747579-TT variant, as a novel contributor to MASH and MASH-related HCC. DNAJA3 encodes a mitochondrial chaperone that preserves mitochondrial integrity and cellular homeostasis. Its deficiency disrupts mitochondrial biogenesis, shifts energy metabolism toward glycolysis, and promotes lipid accumulation and cholesterol synthesis. We further observed a positive global correlation between MASH-related HCC prevalence and the frequency of the DNAJA3 eQTL variant, reinforcing its pathogenic relevance. Interaction analyses of DNAJA3 and PNPLA3 variants indicate that the convergence of mitochondrial and lipid dysregulation amplifies liver cancer risk.