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

  • J Agric Food Chem. 2026 Apr 15;74(14):11814-11831. doi: 10.1021/acs.jafc.6c00603.
Wenjie Li  1 ,  Bowen Fan  1 ,  Han Li  2 ,  Qiong Du  1 ,  Jiaheng Lin  1 ,  Yi Yang  1 ,  Xiaolin Ding  1 ,  Haoran Zhang  1 ,  Haibo Xia  1 ,  Binafsha Manzoor Syed  3 ,  Cheng Cheng  1 ,  Qizhan Liu  1
Affiliations
  • 1. Center for Global Health, China International Cooperation Center for Environment and Human Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
  • 2. Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, Guangdong, People's Republic of China.
  • 3. Medical Research Center, Liaquat University of Medical & Health Sciences, Jamshoro 76090, Sindh, Pakistan.
PMID: 41920731 DOI: 10.1021/acs.jafc.6c00603
Abstract

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.

Keywords
O-GlcNAcylation; X-box binding protein 1; arsenic; metabolic dysfunction-associated steatotic liver disease.
Products