Our results demonstrate that nuciferine possesses potent function on attenuating or inhibiting lipid accumulation and inflammation and regulates the expression of PASK and its relevant target genes involved in lipid metabolism and inflammation in OA-induced HepG2 cells, indicating that nuciferine and PASK have a potential inhibitory effect against NAFLD/NASH, and the PASK might play an important role in nuciferine-mediated regulation. Here, PASK is linked to metabolic dysfunction-associated steatohepatitis.