Zhu Ziheng, Huang Chuanbing, Chen Junjie, Wan Lei, Zhang Chuanwei, Wang Jianing
The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, China.
College of Traditional Chinese Medicine, Anhui University of Chinese Medicine, Hefei, 230012, China.
J Transl Med. 2025 Nov 29;24(1):25. doi: 10.1186/s12967-025-07498-9.
Lactate was traditionally regarded as merely the end product of glycolysis; however, recent discoveries of lactylation have revealed that lactate can also directly serve as a substrate for epigenetic modification, filling a critical gap in the understanding of "metabolite-epigenetic regulation." In rheumatic immune diseases such as rheumatoid arthritis and systemic lupus erythematosus, the affected tissues, including the joint synovium and internal organs, are typically hypoxic. These regions demonstrate pronounced inflammatory infiltration and metabolic reprogramming, leading to the accumulation of lactate within the local microenvironment. In this context, lactylation directly links the metabolic state (lactate levels) of the microenvironment with epigenetic regulation of gene expression. This offers valuable insights into how metabolic cues specifically modulate the functions of immune cells, including polarization, activation, and cytokine secretion, as well as the behavior of tissue-resident cells, such as synovial fibroblasts. Conventional immunosuppressants demonstrate limited efficacy in correcting such metabolic abnormalities; thus, exploring novel mechanisms and therapeutic targets at the intersection of metabolism and epigenetics is urgently needed. Investigating the mechanistic role of lactylation, therefore, represents a crucial step toward developing innovative therapies for rheumatic autoimmune disorders.
This review systematically summarizes the pivotal functions of lactylation within the immune-metabolic and epigenetic regulatory networks, examining its influence on metabolic pathways, chromatin modification, and disease progression. Furthermore, it discusses the modulatory roles of lactylation in immune cell activity, signaling pathway activation, and the generation of disease-specific modification patterns.
In summary, current evidence indicates that lactylation serves as a molecular bridge connecting "immunometabolism-epigenetic dysregulation-chronic inflammation." Its tissue specificity and diverse modification substrates contribute to a complex regulatory network. Therefore, targeting the lactylation regulatory axis may enable the conversion of pathological metabolic features into therapeutic opportunities.
Future research should emphasize single-cell lactylome profiling and the development of tissue-specific delivery systems to elucidate better and control the dual physiological and pathological functions of lactylation.
乳酸传统上仅被视为糖酵解的终产物；然而，最近对乳酸化的发现表明，乳酸还可直接作为表观遗传修饰的底物，填补了对“代谢物 - 表观遗传调控”理解中的关键空白。在类风湿性关节炎和系统性红斑狼疮等风湿性免疫疾病中，包括关节滑膜和内脏器官在内的受影响组织通常处于缺氧状态。这些区域表现出明显的炎症浸润和代谢重编程，导致局部微环境中乳酸的积累。在此背景下，乳酸化直接将微环境的代谢状态（乳酸水平）与基因表达的表观遗传调控联系起来。这为代谢信号如何具体调节免疫细胞的功能提供了有价值的见解，包括极化、激活和细胞因子分泌，以及组织驻留细胞（如滑膜成纤维细胞）的行为。传统免疫抑制剂在纠正此类代谢异常方面疗效有限；因此，迫切需要探索代谢与表观遗传学交叉点的新机制和治疗靶点。因此，研究乳酸化的机制作用是开发针对风湿性自身免疫性疾病的创新疗法的关键一步。
本综述系统总结了乳酸化在免疫代谢和表观遗传调控网络中的关键功能，研究其对代谢途径、染色质修饰和疾病进展的影响。此外，还讨论了乳酸化在免疫细胞活性、信号通路激活以及疾病特异性修饰模式产生中的调节作用。
总之，目前的证据表明，乳酸化是连接“免疫代谢 - 表观遗传失调 - 慢性炎症”的分子桥梁。其组织特异性和多样的修饰底物促成了一个复杂的调控网络。因此，靶向乳酸化调控轴可能使病理性代谢特征转化为治疗机会。
未来的研究应强调单细胞乳酸化组分析和组织特异性递送系统的开发，以更好地阐明和控制乳酸化的生理和病理双重功能。
