E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction‐Associated Steatohepatitis

• DOI: 10.1002/advs.202410880
• Publication Date: 2024-10-28T11:39:55Z
• Authors: Zheng Liu; Hao Wang; Yuan Liang; Mu Liu; Qiyuan Huang; Mingming Wang; Jinren Zhou; Qingfa Bu; Haoming Zhou; Ling Lu
• Keywords: Steatohepatitis

Abstract Macrophages are essential for the development of steatosis, hepatic inflammation, and fibrosis in metabolic dysfunction‐associated steatohepatitis(MASH). However, roles macrophage E2F2 progression MASH have not been elucidated. This study reveals that expression is dramatically downregulated livers from mice humans, this adversely correlated with severity disease. Myeloid‐specific depletion aggravates intrahepatic stellate cell activation, hepatocyte lipid accumulation during progression. Mechanistically, can inhibit SLC7A5 transcription directly. deficiency upregulates to mediate amino acids flux, resulting enhanced glycolysis, impaired mitochondrial function, increased macrophages proinflammatory response a Leu‐mTORC1‐dependent manner. Moreover, bioinformatics analysis CUT &Tag assay identify direct binding Nrf2 promoter promote its nuclear translocation. Genetic or pharmacological activation effectively activates attenuate Finally, patients treated CDK4/6 inhibitors demonstrate reduced activity but PBMCs. These findings indicated suppresses by reprogramming acid metabolism via SLC7A5‐ Leu‐mTORC1 signaling pathway. Activating holds promise as therapeutic strategy MASH.