Shou Yiyi, Liu Ruiqi, Xiong Hao, Chen Xiaoyan, Huang Luanluan, Huang Ran, Sheng Hailong, Zhang Haibo, Lu Yanwei, Guo Haiwei
Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
School of Clinical Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
J Transl Med. 2025 Aug 19;23(1):941. doi: 10.1186/s12967-025-06959-5.
Therapeutic resistance in cancer is increasingly understood as a dynamic outcome of the interplay among tumour metabolism, epigenetic regulation, and immune modulation, rather than a consequence of genetic mutations alone. At this intersection, lactylation-a recently discovered lactate-derived post-translational modification (PTM)-acts as a molecular bridge linking metabolic rewiring to transcriptional and post-transcriptional control. Meanwhile, microRNAs (miRNAs) have emerged as essential regulators of metabolic adaptation and epigenetic plasticity. However, the interaction between lactylation and miRNA networks remains largely underexplored. Herein, we present a comprehensive and structured assessment of this emerging interdisciplinary field. We begin with a focused overview of tumour metabolic reprogramming and the enzymology of lactylation, establishing the biochemical context for its regulatory functions. We then examine how miRNAs interpret and reinforce metabolic cues, particularly through three interrelated regulatory frameworks. Lactylation of histones and DNA repair proteins has been shown to activate oncogenic miRNA clusters; these same miRNAs, in turn, enhance glycolytic flux and fine-tune the activity of lactylation enzymes, forming bidirectional feedback loops. Under stress conditions such as hypoxia or chemotherapy, lactate accumulation selectively suppresses DNA-repair-targeting and Pro-apoptotic miRNAs, stabilising BRCA1/RAD51-mediated repair programs. Furthermore, lactylation-dependent miRNA signals disseminate via extracellular vesicles, contributing to T cell exhaustion and macrophage M2 polarisation, thus shaping an immunosuppressive tumour microenvironment. Based on these converging mechanisms, we highlight potential therapeutic strategies, including the co-targeting of LDHA and oncogenic miRNAs (e.g., nanoparticle-mediated delivery of anti-miR-21), as well as liquid biopsy-based monitoring of circulating H3K18la and miRNA signatures to predict emerging resistance. By integrating metabolic, epigenetic, and immunologic perspectives, we position lactylation-miRNA crosstalk as a central regulatory axis in cancer therapy resistance and offer a conceptual framework to inform the development of future mechanism-driven interventions.
癌症中的治疗抗性越来越被理解为肿瘤代谢、表观遗传调控和免疫调节之间相互作用的动态结果，而不仅仅是基因突变的结果。在这个交叉点上，乳酰化——一种最近发现的源自乳酸的翻译后修饰（PTM）——充当了连接代谢重编程与转录和转录后控制的分子桥梁。与此同时，微小RNA（miRNA）已成为代谢适应和表观遗传可塑性的重要调节因子。然而，乳酰化与miRNA网络之间的相互作用在很大程度上仍未得到充分探索。在此，我们对这个新兴的跨学科领域进行全面而系统的评估。我们首先重点概述肿瘤代谢重编程和乳酰化的酶学，为其调节功能建立生化背景。然后，我们研究miRNA如何解读和强化代谢信号，特别是通过三个相互关联的调节框架。组蛋白和DNA修复蛋白的乳酰化已被证明可激活致癌miRNA簇；反过来，这些相同的miRNA会增强糖酵解通量并微调乳酰化酶的活性，形成双向反馈回路。在缺氧或化疗等应激条件下，乳酸积累会选择性抑制靶向DNA修复和促凋亡的miRNA，稳定BRCA1/RAD51介导的修复程序。此外，依赖乳酰化的miRNA信号通过细胞外囊泡传播，导致T细胞耗竭和巨噬细胞M2极化，从而塑造免疫抑制性肿瘤微环境。基于这些趋同机制，我们强调了潜在的治疗策略，包括共同靶向LDHA和致癌miRNA（例如，纳米颗粒介导的抗miR-21递送），以及基于液体活检监测循环中的H3K18la和miRNA特征以预测新出现的抗性。通过整合代谢、表观遗传和免疫学观点，我们将乳酰化-miRNA串扰定位为癌症治疗抗性中的核心调节轴，并提供一个概念框架，为未来基于机制的干预措施的开发提供参考。
