HIF-2α induction in de novo lipogenesis in metabolic dysfunction-associated steatohepatitis is dependent on IL-21 signaling

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) has reached epidemic proportions globally. Understanding the molecular mechanisms that underlie these conditions offers significant potential for identifying new therapeutic targets. In this study, interleukin-21 receptor-deficient mice were used to investigate the role of IL-21 signaling in obesity-induced MASLD and MASH. Findings reveal that IL21R^+/+ mice exposed to a high-fat diet develop MASLD/MASH, with hepatic activation of IL-21 signaling driving de novo lipogenesis through Janus kinase 1-STAT5-dependent induction of hypoxia-induced transcription factor 2α (HIF-2α). HIF-2α elevation stimulates genes involved in de novo lipogenesis, contributing to increased hepatic lipid accumulation and MASLD progression. Elevated levels of TGF-β1 and increased collagen deposition indicate hepatic stellate cell activation, facilitating the development of liver fibrosis. Moreover, upregulation of HIF-2α enhances expression of the amino acid transporter solute carrier family 7 member 5, leading to mammalian target of rapamycin complex 1-mediated inhibition of autophagy. In contrast, il21r^-/- mice exhibited diminished Janus kinase 1-STAT5 signaling and were protected from MASLD/MASH. Liver from individuals afflicted with fatty liver disease or nodular cirrhosis show increased IL-21R protein that co-localized with CD4, implicating activated T cells as a potential source of IL-21 for receptor activation. Collectively, these results indicate that targeting IL-21 receptor signaling may represent a promising strategy for reducing MASLD/MASH.