XBP1s-Regulated GFPT1 via Facilitating O-GlcNAcylation of FASN S509 Is Involved in Arsenic-Induced MASLD through Promoting Fatty Acid Synthesis in Hepatocytes

Arsenic in groundwater and agricultural systems poses a challenge to food safety and public health. Although environmental arsenic exposure is a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), its molecular mechanism remains unclear. Chronic arsenic exposure induced hepatic steatosis and upregulated fatty acid synthase (FASN) in mice. Mechanistically, arsenic triggered splicing of X-box binding protein 1 (XBP1) into its active form, XBP1s, which promoted the transcription of glutamine-fructose-6-phosphate aminotransferase 1 (GFPT1). This increased flux of the hexosamine biosynthetic pathway (HBP) elevated UDP-GlcNAc and O-GlcNAcylation. Mass spectrometry identified Ser509 as an O-GlcNAcylated site on FASN, and its mutation abolished arsenic-induced lipid accumulation. O-GlcNAcylation at Ser509 stabilized FASN by inhibiting ubiquitin-mediated degradation and promoting fatty acid synthesis. This study identifies the XBP1s-GFPT1 axis and O-GlcNAcylation of FASN S509 as essential in arsenic-induced MASLD.