急性肝衰竭（ALF）的发展取决于其局部引发物。炎症是一种高频关键因素，加速肝细胞死亡和肝衰竭。在受伤应激下，转录因子缺氧诱导因子-1α（HIF-1α）在巨噬细胞中的表达通过氧依赖和氧独立机制得到促进，从而促进细胞因子白细胞介素-1β（IL-1β）的表达和分泌。IL-1β通过与肝细胞上的受体（IL-1R）进行信号传导进一步诱导肝细胞凋亡或坏死。在巨噬细胞中HIF-1α基因敲除或在肝细胞中IL-1R基因敲除可以保护肝脏免受衰竭损伤。然而，巨噬细胞中HIF-1α抑制对ALF是否具有保护作用尚不清楚。本研究揭示了小分子HIF-1α抑制剂PX-478可以抑制骨髓源性巨噬细胞（BMDMs）中的IL-1β表达和分泌，但不影响肿瘤坏死因子α（TNFα）的表达。PX-478预处理通过降低肝脏炎症反应缓解了LPS/D-GalN诱导的ALF小鼠的肝损伤。此外，PX-478的预防性或治疗性应用与TNFα中和抗体的联合显著改善了LPS/D-GalN诱导的ALF。综上所述，我们的数据表明，PX-478的应用导致巨噬细胞中HIF-1α抑制和IL-1β分泌减少，这代表了一种有前景的治疗策略，用于炎症引起的ALF。 © 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

The development of acute liver failure (ALF) is dependent on its local inducer. Inflammation is a high-frequency and critical factor that accelerates hepatocyte death and liver failure. In response to injury stress, the expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) in macrophages is promoted by both oxygen-dependent and oxygen-independent mechanisms, thus promoting the expression and secretion of the cytokine interleukin-1β (IL-1β). IL-1β further induces hepatocyte apoptosis or necrosis by signaling through the receptor (IL-1R) on hepatocyte. HIF-1α knockout in macrophages or IL-1R knockout in hepatocytes protects against liver failure. However, whether HIF-1α inhibition in macrophages has a protective role in ALF is unclear. In this study, we revealed that the small molecule HIF-1α inhibitor PX-478 inhibits the expression and secretion of IL-1β, but not tumor necrosis factor α (TNFα), in bone marrow-derived macrophages (BMDMs). PX-478 pretreatment alleviates liver injury in LPS/D-GalN-induced ALF mice by decreasing the hepatic inflammatory response. In addition, preventive or therapeutic administration of PX-478 combined with TNFα neutralizing antibody markedly improved LPS/D-GalN-induced ALF. Taken together, our data suggest that PX-478 administration leads to HIF-1α inhibition and decreased IL-1β secretion in macrophages, which represents a promising therapeutic strategy for inflammation-induced ALF.© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.