Abstract：
Liver fibrosis is a significant health concern globally due to its association with severe liver conditions like cirrhosis and liver cancer. Histone lactylation has been implicated in the progression of hepatic fibrosis, but its specific role in liver fibrosis, particularly regarding H3K18 lactylation, remained unclear. To investigate this, we established in vivo and in vitro models of liver fibrosis using carbon tetrachloride (CCl4) injection in rats and stimulation of hepatic stellate cells (HSCs) with TGF-β1, respectively. We found that histone lactylation, particularly H3K18 lactylation, was upregulated in both CCl4-induced rats and TGF-β1-activated HSCs, indicating its potential involvement in liver fibrosis. Further experiments revealed that lactate dehydrogenase A (LDHA) knockdown inhibited H3K18 lactylation and had a beneficial effect on liver fibrosis by suppressing HSC proliferation, migration, and extracellular matrix (ECM) deposition. This suggests that H3K18 lactylation promotes liver fibrosis progression. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that H3K18 lactylation facilitated the transcription of SOX9, a transcription factor associated with fibrosis. Importantly, overexpression of SOX9 counteracted the effects of LDHA silencing on activated HSCs, indicating that SOX9 is downstream of H3K18 lactylation in promoting liver fibrosis. In summary, this study uncovers a novel mechanism by which H3K18 lactylation contributes to liver fibrosis by activating SOX9 transcription. This finding opens avenues for exploring new therapeutic strategies for hepatic fibrosis targeting histone lactylation pathways.
摘要：
肝纤维化是全球重要的健康问题，因为它与肝硬化和肝癌等严重的肝脏疾病有关。组蛋白乳酸化与肝纤维化的进展有关，但它在肝纤维化中的特定作用，特别是关于H3K18的乳酸化，仍然不清楚。为了调查这一点，我们分别使用四氯化碳（CCl4）在大鼠中注射和用TGF-β1刺激肝星状细胞（HSC）建立了体内和体外肝纤维化模型。我们发现组蛋白的乳酸化,特别是H3K18乳酸化，在CCl4诱导的大鼠和TGF-β1激活的HSC中上调，表明其可能参与肝纤维化。进一步的实验表明，乳酸脱氢酶A（LDHA）敲除抑制H3K18的乳酸化，并通过抑制HSC增殖对肝纤维化有有益的作用，迁移,和细胞外基质（ECM）沉积。这表明H3K18乳酸化促进肝纤维化进展。染色质免疫沉淀（ChIP）和荧光素酶报告基因测定表明，H3K18的乳酸化促进了SOX9的转录，SOX9是与纤维化相关的转录因子。重要的是,SOX9的过表达抵消了LDHA沉默对活化HSC的影响，表明SOX9在促进肝纤维化中处于H3K18乳酸化的下游。总之,这项研究揭示了H3K18乳酸化通过激活SOX9转录促进肝纤维化的新机制。这一发现为探索针对组蛋白乳酸化途径的肝纤维化新治疗策略开辟了途径。
