Targeting PNPLA3 I148M variant in MASLD: Cell-type specific mechanisms and precision therapy opportunities

The PNPLA3 I148M variant is the primary genetic risk factor for metabolic dysfunction-associated steatotic liver disease, representing the most promising target for interventions in this increasingly prevalent disease. In this review, we describe the lipotoxicity effects of the mutant protein in both hepatocytes and hepatic stellate cells (HSCs), driven by its weak triglyceride-hydrolysing activity, altered lipid composition, and resistance to ubiquitin-proteasomal degradation. In the context of MASLD-associated oxidative stress, lipid retention and peroxidation lead to mitochondrial dysfunction, ER stress, and ferroptosis in hepatocytes, while promoting HSC activation and fibrogenesis, thus driving the pathological transition from benign steatosis to MASH. We also summarize mechanism-based therapeutic strategies aimed at supporting the development of personalised, targeted interventions for I148M carriers.