由于肥胖流行，导致代谢功能障碍相关脂肪性肝炎 (MASH)，从而导致 HCC，全球 HCC 发病率不断增加。然而，人们对 MASH-HCC 的分子途径知之甚少。我们之前曾报道，缺氧相关因子 HAF (SART1 /-) 单倍体不足的雄性小鼠自发发展为 MASH-HCC。然而，导致与 HAF 丢失相关的 HCC 的细胞类型尚不清楚。我们生成了 SART1 floxed 小鼠，将其与肝细胞（Alb-Cre；hepS-/-）或骨髓细胞（Alb-Cre；hepS-/-）内表达 Cre 重组酶的小鼠杂交（ LysM-Cre、macS-/-)。 HepS-/- 小鼠（雄性和雌性）发生的 HCC 与严重的炎症和脂质失调相关，这表明 HAF 主要在肝细胞内预防 HCC。 HAF 缺陷肝细胞显示 P-p65 和 P-p50 以及 NF-κB 通路的许多成分均减少，体外使用 HAF siRNA 重现了这一点。 HAF 消耗也会引发细胞凋亡，表明 HAF 通过抑制肝细胞凋亡来预防 HCC。我们发现 HAF 通过调节 TRADD 和 RIPK1 的转录来调节 NF-κB 活性。喂食高脂饮食 (HFD) 的小鼠在 26 周后表现出肝脏内 HAF、P-p65 和 TRADD 的显着抑制，但在 40 周后表现出这些蛋白质的显着上调，这表明 HAF-NF-κB 轴的失调到 MASH 的进展。在人类中，与正常肝脏相比，单纯性脂肪变性肝脏中的 HAF 显着减少，但 HCC 中的 HCC 显着增加。HAF 是 NF-κB 通路的新型转录调节因子，是 MASH 和 MASH-HCC 进展过程中细胞命运的关键决定因素。版权所有 © 2024 作者。由 Wolters Kluwer Health, Inc. 出版

HCC incidence is increasing worldwide due to the obesity epidemic, which drives metabolic dysfunction-associated steatohepatitis (MASH) that can lead to HCC. However, the molecular pathways driving MASH-HCC are poorly understood. We have previously reported that male mice with haploinsufficiency of hypoxia-associated factor, HAF (SART1+/-) spontaneously develop MASH-HCC. However, the cell type(s) responsible for HCC associated with HAF loss are unclear.We generated SART1-floxed mice, which were crossed with mice expressing Cre-recombinase within hepatocytes (Alb-Cre; hepS-/-) or myeloid cells (LysM-Cre, macS-/-). HepS-/- mice (both male and female) developed HCC associated with profound inflammatory and lipid dysregulation suggesting that HAF protects against HCC primarily within hepatocytes. HAF-deficient hepatocytes showed decreased P-p65 and P-p50 and in many components of the NF-κB pathway, which was recapitulated using HAF siRNA in vitro. HAF depletion also triggered apoptosis, suggesting that HAF protects against HCC by suppressing hepatocyte apoptosis. We show that HAF regulates NF-κB activity by regulating transcription of TRADD and RIPK1. Mice fed a high-fat diet (HFD) showed marked suppression of HAF, P-p65 and TRADD within their livers after 26 weeks, but showed profound upregulation of these proteins after 40 weeks, implicating deregulation of the HAF-NF-κB axis in the progression to MASH. In humans, HAF was significantly decreased in livers with simple steatosis but significantly increased in HCC compared with normal liver.HAF is novel transcriptional regulator of the NF-κB pathway and is a key determinant of cell fate during progression to MASH and MASH-HCC.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.