Impact of PNPLA3 Genotype on Hepatic Steatosis Response to Pemafibrate in MASLD With Dyslipidemia

AIM: Pemafibrate, a selective peroxisome proliferator-activated receptor-α modulator (SPPARMα), improves liver enzymes in metabolic dysfunction-associated steatotic liver disease (MASLD). Whether treatment response is influenced by PNPLA3 genotype remains unclear. METHODS: We retrospectively analyzed 93 Japanese patients with MASLD and dyslipidemia treated with pemafibrate for 48 weeks. Changes in controlled attenuation parameter (CAP), liver stiffness measurement (LSM), and FibroScan-AST (FAST) score were compared according to PNPLA3 genotype. RESULTS: Overall, ALT, AST, GGT, and lipid parameters decreased significantly, and FAST improved, whereas CAP showed no overall change. Stratified analysis revealed CAP decreased in PNPLA3 CC and CG but not in GG, with greater reduction in CC compared to CG or GG. Among patients with weight loss, the reduction in CAP did not differ significantly between genotypes. LSM changes were not genotype dependent. CONCLUSIONS: Pemafibrate reduced hepatic steatosis preferentially in PNPLA3 CC carriers, whereas PNPLA3 G-allele carriers showed attenuated CAP improvement without weight loss. PNPLA3 polymorphism may influence steatosis-lowering efficacy of pemafibrate, underscoring the need for genotype-informed therapeutic strategies.