乳酰化-免疫调节轴：偏头痛防治的潜在治疗靶点。

The lactylation-immune regulatory axis: a potential therapeutic target for migraine prevention and treatment.

作者信息

Wang Liu, Lan Zhixuan, He Ying, Cheng Yue, He Ruilin, Jiang Zongbin

机构信息

Department of Pain Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530007, China.

Department of Pain Medicine, The First People's Hospital of Qinzhou, Qinzhou, Guangxi, 535000, China.

出版信息

J Headache Pain. 2025 Jun 4;26(1):134. doi: 10.1186/s10194-025-02075-3.

DOI:10.1186/s10194-025-02075-3

PMID:40468199

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12139184/

Abstract

BACKGROUND

Migraine is a debilitating neurological disorder. Emerging evidence suggests that metabolic dysregulation and immune dysfunction contribute to migraine pathogenesis while the molecular mechanisms linking these processes remain unclear. Lactylation may serve as a crucial integrator of metabolic and immune signals in migraine.

METHODS

We performed a comprehensive multi-omics Mendelian randomization study integrating DNA methylation, gene expression, and protein abundance data with genome-wide association studies on migraine. Summary-data-based Mendelian randomization, Bayesian colocalization, and two-sample MR analyses were conducted to identify lactylation-related genes causally associated with migraine. We further explored immune cell mediation using genetic data from 731 immune phenotypes and validated findings through single-cell RNA sequencing of peripheral blood mononuclear cells from migraine patients and controls.

RESULTS

EP300, SIRT1, and SLC16A1 were identified as key regulators of migraine susceptibility across methylation, expression, and protein levels. EP300 and SLC16A1 were associated with increased migraine risk, while SIRT1 conferred a protective effect. Mediation analyses revealed that genetic effects of these genes were partially transmitted through specific immune cell subsets, particularly B cells and natural killer T cells. Single-cell transcriptomic profiling further demonstrated EP300 upregulation in B cells and T cells of migraine patients. These findings support a novel “lactylation–immune mediation–migraine axis” linking metabolic and immune dysregulation to migraine pathogenesis.

CONCLUSION

This integrative multi-omics analysis uncovers lactylation-related genes as causal drivers of migraine through immunometabolic pathways. Targeting lactylation-regulated metabolic and immune mechanisms may offer novel precision therapeutic strategies for migraine, particularly in patients with inflammatory or metabolic endophenotypes.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1186/s10194-025-02075-3.

摘要

背景

偏头痛是一种使人衰弱的神经系统疾病。新出现的证据表明，代谢失调和免疫功能障碍促成了偏头痛的发病机制，而将这些过程联系起来的分子机制仍不清楚。乳酰化可能是偏头痛中代谢和免疫信号的关键整合因子。

方法

我们进行了一项全面的多组学孟德尔随机化研究，将DNA甲基化、基因表达和蛋白质丰度数据与偏头痛的全基因组关联研究相结合。进行了基于汇总数据的孟德尔随机化、贝叶斯共定位和两样本孟德尔随机化分析，以确定与偏头痛因果相关的乳酰化相关基因。我们使用来自731种免疫表型的遗传数据进一步探索免疫细胞介导作用，并通过对偏头痛患者和对照的外周血单个核细胞进行单细胞RNA测序来验证研究结果。

结果

EP300、SIRT1和SLC16A1被确定为跨甲基化、表达和蛋白质水平的偏头痛易感性关键调节因子。EP300和SLC16A1与偏头痛风险增加相关，而SIRT1具有保护作用。中介分析表明，这些基因的遗传效应部分通过特定的免疫细胞亚群传递，特别是B细胞和自然杀伤T细胞。单细胞转录组分析进一步证明偏头痛患者B细胞和T细胞中EP300上调。这些发现支持了一个新的“乳酰化-免疫介导-偏头痛轴”，将代谢和免疫失调与偏头痛发病机制联系起来。