Han Qing, Chen Yujun, Yuan Junbo, Zhang Li, Zheng Qifan, Jin Guanghui
Department of Basic Medical Sciences, School of Medicine, Xiamen University; Xiamen, China.
Department of Basic Medical Sciences, School of Medicine, Xiamen University; Xiamen, China.
J Biol Chem. 2025 Jul 10;301(8):110471. doi: 10.1016/j.jbc.2025.110471.
Menin, encoded by the Men1 gene, is a scaffold protein broadly involved in regulating the cell phenotype through multiple histone modifications. Here, we discuss how menin contributes to liver macrophage (MAC) and hepatic stellate cell (HSC) fate determination, placing this contribution in the context of liver fibrosis pathogenesis. We revealed that Men1 loss promoted CCL4- or high-fat diet-induced liver fibrosis. Menin regulated liver fibrogenesis primarily by modulating the activation of Kupffer cells (KCs)/HSCs rather than hepatocytes. The myeloid cell-specific knockout of Setd2 but not Kmt2a mimicked the phenotype of Men1 deletion. Menin/SETD2 suppressed the regeneration and activation of KCs by regulating IL-10 pathway activity through H3K36me3. In addition, the menin/SETD2/PPARγ complex coregulated SMAD7 expression through H3K36me3 in HSCs. JIB-04, an H3K36me3 agonist, effectively suppressed KC activation induced by Men1 or Setd2 deletion by reactivating IL-10 expression and further alleviated CCL4-induced liver fibrosis symptoms. Our results provide an interesting proof-of-concept for the therapeutic targeting of H3K36me3 remodeling to block liver fibrosis.
由Men1基因编码的Menin是一种支架蛋白，广泛参与通过多种组蛋白修饰来调节细胞表型。在此，我们讨论Menin如何促进肝巨噬细胞（MAC）和肝星状细胞（HSC）的命运决定，并将这一作用置于肝纤维化发病机制的背景中。我们发现Men1缺失会促进四氯化碳或高脂饮食诱导的肝纤维化。Menin主要通过调节库普弗细胞（KC）/肝星状细胞的激活而非肝细胞来调控肝纤维化的发生。Setd2而非Kmt2a的髓系细胞特异性敲除模拟了Men1缺失的表型。Menin/SETD2通过H3K36me3调节IL-10通路活性，从而抑制肝巨噬细胞的再生和激活。此外，Menin/SETD2/PPARγ复合物通过H3K36me3在肝星状细胞中共同调节SMAD7的表达。H3K36me3激动剂JIB-04通过重新激活IL-10表达有效抑制了Men1或Setd2缺失诱导的肝巨噬细胞激活，并进一步减轻了四氯化碳诱导的肝纤维化症状。我们的结果为靶向H3K36me3重塑以阻断肝纤维化的治疗提供了一个有趣的概念验证。
