Histone lactylation is associated with METTL3-dependent LCN2 m6A modification and astrocyte activation after intracerebral hemorrhage

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international Pub Date : 2025-10-06 DOI:10.1016/j.neuint.2025.106069

Ling Gao , Xiaobin Zheng , Cong Tan , Li Peng , Chuang Wang , Zhongtao Zheng , Jiangli Han , Jian Wang , Zhao Yang , Weiming Chen

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引用次数: 0

Abstract

Background

Intracerebral hemorrhage (ICH) is a major cause of secondary brain injury (SBI), which results in severe neurological deficits and poor clinical outcomes. Elevated serum lactate levels have been associated with unfavorable outcome in ICH patients. However, the role of lactate in ICH-induced SBI remain poorly understood.

Method

An autologous blood injection mouse model of ICH and lactate-treated C8D1A cells were employed as the in vivo and in vitro models, respectively. The establishment of ICH model was validated by behavior tests, and brain injury was assessed by H&E and Nissel staining. qRT-PCR, Western blot and IHC analysis were used to detect the expression of key molecules. Immunofluorescent (IF) staining was employed to evaluate astrocyte activation. Pro-inflammatory cytokine release was monitored by ELISA assay. The interaction between H3K18la and METTL3 was assessed by ChIP assay, and the association between METTL3 and LCN2 mRNA was assessed by RNA immunoprecipitation (RIP) assay.

Results

The levels of lactate, METTL3 and LCN2 are elevated in ICH model in mice. The inhibition of lactate decreased METTL3 expression and alleviated ICH-induced SBI. Mechanistically, histone H3K18 lactylation was associated with the upregulated levels of METTL3 and m⁶A in mouse brains. METTL3 regulated the m⁶A modification of LCN2 and upregulated its expression. In ICH mice, silencing of LCN2 inhibited A1 astrocyte activation. Histone lactylation-modulated LCN2 m⁶A modification is involved in astrocyte activation and the regulation of SBI in ICH mice.

Conclusion

These results suggested a mechanism whereby histone lactylation is implicated in the activation of A1 astrocytes through METTL3-mediated LCN2 m⁶A modification.

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脑出血后，组蛋白乳酸化与mettl3依赖性LCN2 m6A修饰和星形胶质细胞活化有关。

背景：脑出血（Intracerebral hemorrhage， ICH）是继发性脑损伤（secondary brain injury， SBI）的主要原因，可导致严重的神经功能缺损和较差的临床预后。血清乳酸水平升高与脑出血患者的不良预后有关。然而，乳酸盐在ich诱导的SBI中的作用仍然知之甚少。方法：采用自体血液注射小鼠脑出血模型和乳酸处理的C8D1A细胞作为体内模型和体外模型。行为学实验验证脑缺血模型的建立，H&E和Nissel染色评价脑损伤程度。采用qRT-PCR、western blot和免疫组化分析检测关键分子的表达。免疫荧光（IF）染色评价星形胶质细胞活化。ELISA法检测促炎细胞因子释放情况。采用ChIP法评估H3K18la与METTL3的相互作用，采用RNA免疫沉淀（RIP）法评估METTL3与LCN2 mRNA的相关性。结果：小鼠脑出血模型中乳酸、METTL3、LCN2水平升高。乳酸的抑制降低了METTL3的表达，减轻了ich诱导的SBI。机制上，组蛋白H3K18乳酸化与小鼠大脑中METTL3和m6A水平上调有关。METTL3调控LCN2的m6A修饰，上调其表达。在脑出血小鼠中，LCN2的沉默抑制了A1星形胶质细胞的激活。组蛋白乳酸化调控的LCN2 m6A修饰参与脑出血小鼠星形细胞活化和SBI的调控。结论：这些结果提示了一种机制，即组蛋白乳酸化通过mettl3介导的LCN2 m6A修饰参与A1星形胶质细胞的激活。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurochemistry international 医学-神经科学

CiteScore

8.40

自引率

2.40%

发文量

128

审稿时长

37 days

期刊介绍： Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.