Li Yu, Zhang Tao, Zhou Lin, Huang Ying, Li Junjie, Xu Houxi, Wu Xudong
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, No.163 Xianlin Avenue, Nanjing 210023, China.
Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China.
Int Immunopharmacol. 2025 Sep 23;162:115177. doi: 10.1016/j.intimp.2025.115177. Epub 2025 Jul 11.
Elevated circulating lactate serves as a critical biomarker in sepsis, yet the epigenetic mechanisms by which lactate influences disease progression remain unclear. This study aims to identify lactate-associated genes in sepsis, decode their regulatory roles, and assess their potential as therapeutic targets. We performed transcriptome-wide bioinformatic analyses to identify lactylation-related differentially expressed genes (DEGs) between sepsis patients and healthy controls. Pathway enrichment highlighted immune signaling circuits. Five DEGs (ZC3H4, RBM10, PCBP2, RBM25, HNRNPM) were prioritized via ROC analysis, and their combined expression formed a prognostic signature with strong predictive power (AUC > 0.85). Validation in murine sepsis-induced acute lung injury (ALI) models (cecal ligation-puncture and LPS challenge) confirmed significant upregulation of these five genes by qRT-PCR. RBM25 was selected for deeper functional study. Mechanistic assays implicate an RBM25-Acly axis that couples altered metabolism to histone lactylation and transcriptional reprogramming. Notably, we propose the RBM25-Acly axis that couples altered metabolism to histone lactylation and transcriptional reprogramming. Our work uncovers a novel metabolic-epigenetic circuit in sepsis driven by lactylation, with RBM25 and its regulation of ACLY as a key node. The lactylation-based gene signature offers a high-fidelity prognostic tool, and targeting the RBM25-Acly pathway may open new therapeutic avenues. These findings lay a foundation for precision interventions that integrate metabolic and epigenetic strategies in sepsis care.
循环乳酸水平升高是脓毒症的关键生物标志物，然而乳酸影响疾病进展的表观遗传机制仍不清楚。本研究旨在识别脓毒症中与乳酸相关的基因，解读其调控作用，并评估它们作为治疗靶点的潜力。我们进行了全转录组生物信息学分析，以识别脓毒症患者和健康对照之间与乳酰化相关的差异表达基因（DEG）。通路富集突出了免疫信号通路。通过ROC分析确定了五个DEG（ZC3H4、RBM10、PCBP2、RBM25、HNRNPM），它们的联合表达形成了一个具有强大预测能力的预后特征（AUC>0.85）。在小鼠脓毒症诱导的急性肺损伤（ALI）模型（盲肠结扎穿刺和LPS攻击）中的验证通过qRT-PCR证实了这五个基因的显著上调。选择RBM25进行更深入的功能研究。机制分析表明存在一个RBM25-Acly轴，该轴将代谢改变与组蛋白乳酰化和转录重编程联系起来。值得注意的是，我们提出了RBM25-Acly轴，该轴将代谢改变与组蛋白乳酰化和转录重编程联系起来。我们的工作揭示了脓毒症中由乳酰化驱动的一种新的代谢-表观遗传回路，其中RBM25及其对ACLY的调控是关键节点。基于乳酰化的基因特征提供了一种高保真的预后工具，靶向RBM25-Acly途径可能开辟新的治疗途径。这些发现为在脓毒症护理中整合代谢和表观遗传策略的精准干预奠定了基础。
