Upadacitinib counteracts hepatic lipid deposition via the repression of JAK1/STAT3 signaling and AMPK/autophagy-mediated suppression of ER stress

Abstract

Upadacitinib (UPA) has been utilized to treat conditions such as rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis by modulating inflammation via the JAK pathway. However, its impact on hepatic lipogenesis remains insufficiently studied. This research evaluated protein expression through Western blotting, lipid accumulation with oil red O staining, autophagosomes in hepatocytes via MDC staining, and hepatic apoptosis via cell viability and caspase 3 activity assays. This study aimed to explore the effects of UPA on hepatic lipogenesis and the underlying molecular mechanisms in in vitro models of hepatic steatosis. These findings demonstrated that UPA reduced lipid deposition, apoptosis, and ER stress in palmitate-treated hepatocytes. UPA treatment inhibited phosphorylated JAK1 and STAT3 while promoting the expression of phosphorylated AMPK and autophagy markers. AMPK siRNA negated the effects of UPA on lipogenic lipid deposition, apoptosis, JAK1/STAT3 phosphorylation, and ER stress. These results reveal that UPAmitigates ER stress through the JAK1/STAT3/AMPK pathway, thereby reducing lipid deposition and apoptosis in hyperlipidemic hepatocytes, supporting its potential as a therapeutic strategy for treating hepatic steatosis in obese individuals.