Proteomic profiling of MST3-deficient hepatocytes revealed coordinated activation of mitochondrial and lysosomal pathways, consistent with enhanced fatty acid degradation and catabolic clearance.<h4>Conclusions</h4>Our findings in the selected mouse model of MASH-HCC suggest that MST3 is dispensable for hepatocarcinogenesis, yet its antagonism dampens diet-induced metabolic dysfunction and effectively attenuates MASH severity, challenging the prevailing assumption that targeting MASH driver genes alone is sufficient to prevent HCC development in the context of obesity. The gene discussed is STK24; the disease is obesity disorder.