Histone lactylation-augmented IRF4 is implicated in arsenite-induced liver fibrosis via modulating Th17 cell differentiation

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions Pub Date : 2025-04-08 DOI:10.1016/j.cbi.2025.111507

Weiyong Chen , Peiwen Wang , Yan Xie , Daxiao Xie , Hailan Wang , Ning Bu , Jiaheng Lin , Meng Wu , Haibo Xia , Cheng Cheng , Yuanzhong Zhou , Qizhan Liu

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Abstract

Arsenic, a ubiquitous environmental toxicant, has been implicated in causing liver fibrosis through chronic exposure. Histone lactylation is involved in various inflammatory diseases, among which liver fibrosis is included, and is also closely related to the regulation of immune cells. This work focuses on the mechanisms of histone lactylation and Th17 cell differentiation in arsenite-induced liver fibrosis through animal and cellular experiments. Chronic arsenite exposure of mice led to liver fibrosis, elevated glycolysis in liver, and increased lactate levels in both serum and liver, which promoted Th17 cell differentiation of CD4⁺ T cells and increased IL-17A secretion. Treatment with oxamate, a lactate dehydrogenase inhibitor, suppressed Th17 cell differentiation and alleviated fibrosis in the liver. For HepG2 cells, arsenite exposure enhanced glycolysis and lactate levels, leading to increased global lactylation (Kla), H3K18la, interferon-regulatory factor 4 (IRF4), retinoic acid receptor-related orphan receptor gamma t (RORγt), and IL-17A expression and secretion in co-cultured Jurkat cells. Furthermore, in Jurkat cells, reducing lactate production and transport decreased these protein levels, suppressed Th17 cell differentiation, decreased IL-17A secretion, and ultimately inhibited the activation of hepatic stellate cells (HSCs). These results indicate that lactate derived from hepatocytes promotes Th17 cell differentiation by upregulating IRF4 through H3K18la, thereby enhancing IL-17A secretion and the activation of HSCs, contributing to arsenite-induced liver fibrosis. Our work reveals a new mechanism of histone lactylation in arsenite-induced liver fibrosis and offers a fresh perspective for the development of strategies for prevention and treatment of this condition.

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组蛋白乳酰化增强的IRF4通过调节Th17细胞分化与亚砷酸盐诱导的肝纤维化有关

砷是一种无处不在的环境毒物，长期接触会导致肝纤维化。组蛋白乳化参与多种炎症性疾病，肝纤维化也是其中之一，并且与免疫细胞的调控密切相关。本研究通过动物和细胞实验，重点研究了组蛋白乳化和 Th17 细胞分化在亚砷酸盐诱导的肝纤维化中的作用机制。小鼠长期接触亚砷酸盐会导致肝纤维化、肝脏糖酵解升高、血清和肝脏中乳酸水平升高，从而促进CD4+ T细胞的Th17细胞分化，增加IL-17A的分泌。用乳酸脱氢酶抑制剂草氨酸处理可抑制 Th17 细胞分化，缓解肝脏纤维化。对于 HepG2 细胞，亚砷酸盐暴露会增强糖酵解和乳酸盐水平，导致共培养的 Jurkat 细胞中的全乳化（Kla）、H3K18la、干扰素调节因子 4（IRF4）、视黄酸受体相关孤儿受体 gamma t（RORγt）以及 IL-17A 的表达和分泌增加。此外，在 Jurkat 细胞中，减少乳酸盐的产生和运输会降低这些蛋白水平，抑制 Th17 细胞的分化，减少 IL-17A 的分泌，并最终抑制肝星状细胞（HSCs）的活化。这些结果表明，来自肝细胞的乳酸盐通过H3K18la上调IRF4，促进Th17细胞分化，从而增强IL-17A的分泌和造血干细胞的活化，导致亚砷酸盐诱导的肝纤维化。我们的研究揭示了亚砷酸盐诱导的肝纤维化中组蛋白乳酰化的新机制，为制定预防和治疗这种疾病的策略提供了新的视角。

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来源期刊

Chemico-Biological Interactions 生物-毒理学

CiteScore

7.70

自引率

3.90%

发文量

410

审稿时长

36 days

期刊介绍： Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.