Li Chunwei, Liu Ziqiang, Kong Dezheng, Li Zhengze, Li Lifeng
National Engineering Laboratory for Internet Medical Systems and Applications, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, Henan, China.
Cancer Drug Resist. 2025 Aug 4;8:39. doi: 10.20517/cdr.2025.90. eCollection 2025.
Lactylation, a novel lactate-derived lysine post-translational modification (PTM), has emerged as a critical epigenetic regulator driving drug resistance within the tumor microenvironment (TME). This review systematically delineates the enzymatic underpinnings of lactylation, its induction via the glycolysis-lactate axis influenced by key TME features (hypoxia, inflammation), and its multifaceted roles in promoting resistance. Specifically, lactylation orchestrates transcriptional reprogramming of resistance-associated genes (e.g., oncogenes, immune checkpoints, epithelial-mesenchymal transition factors), enhances DNA damage repair capacity (e.g., via NBS1/MRE11 lactylation), activates pro-survival autophagy, and modulates immunosuppressive signaling pathways (e.g., PI3K/AKT, NF-κB, JAK/STAT). Furthermore, it facilitates critical resistance phenotypes including immune evasion, metastasis, and angiogenesis. The review summarizes emerging therapeutic strategies targeting lactylation, such as inhibition of lactate production (LDHA/LDHB), lactate transport (MCT1/4), lactyltransferases (e.g., p300), or downstream effectors, highlighting their potential to overcome multifactorial resistance. However, elucidating the context-dependent roles, crosstalk with other PTMs, and developing specific inhibitors remain crucial for translating these insights into effective clinical interventions against resistant tumors.
乳酰化是一种新的由乳酸衍生的赖氨酸翻译后修饰（PTM），已成为驱动肿瘤微环境（TME）中耐药性的关键表观遗传调节因子。本综述系统地阐述了乳酰化的酶学基础、通过受关键TME特征（缺氧、炎症）影响的糖酵解-乳酸轴对其诱导作用，以及它在促进耐药性方面的多方面作用。具体而言，乳酰化协调耐药相关基因（如癌基因、免疫检查点、上皮-间质转化因子）的转录重编程，增强DNA损伤修复能力（如通过NBS1/MRE11乳酰化），激活促生存自噬，并调节免疫抑制信号通路（如PI3K/AKT、NF-κB、JAK/STAT）。此外，它促进关键的耐药表型，包括免疫逃逸、转移和血管生成。该综述总结了针对乳酰化的新兴治疗策略，如抑制乳酸生成（LDHA/LDHB）、乳酸转运（MCT1/4）、乳酰转移酶（如p300）或下游效应器，强调了它们克服多因素耐药性的潜力。然而，阐明其在不同背景下的作用、与其他PTM的相互作用以及开发特异性抑制剂对于将这些见解转化为针对耐药肿瘤的有效临床干预措施仍然至关重要。
