《生命科学》 2026, 38(1): 70-81
乳酸化修饰在肝细胞癌发展中作用的研究进展
摘 要：
肝细胞癌（hepatocellular carcinoma，HCC）是一种常见的消化系统肿瘤，起病隐匿，致死率高。由于Warburg效应，在HCC中会产生并积累大量乳酸，使乳酸化修饰出现异常。乳酸化修饰作为一种新发现的蛋白质翻译后修饰，可通过影响相关基因表达及蛋白质功能，调节HCC的恶性进程。本文综述了乳酸的代谢及作用，探讨了乳酸化修饰对肝癌细胞增殖、代谢、转移等方面的影响，旨在探讨乳酸和乳酸化对HCC的影响，为肝癌进展预测、疗效评估以及个体化治疗方案的制定提供新的方法与思路。
通讯作者：陈光顺 , Email:2512445403@qq.com
Abstract:
This comprehensive review aims to systematically clarify how the newly identified post-translational modification—lysine lactylation—reprograms hepatocellular carcinoma (HCC) biology and to evaluate its potential as both a predictive biomarker and a druggable vulnerability. By integrating the most recent in-vitro, in-vivo and clinical proteomic data, we delineate three core messages. First, lactate is no longer a mere waste product of the Warburg effect: it is a central signalingmetabolite that accumulates up to ten-fold in HCC tissue, fuels an acidic micro-environment, and supplies the substrate for widespread protein lactylation. Second, lactylation operates through both enzyme-dependent (“writer” p300/GCN5/HBO1, “eraser” HDAC1-3/Sirtuins, “reader” Brg1) and enzyme-independent (methylglyoxal-derived lactoylglutathione) mechanisms, thereby modulating chromatin accessibility, transcription-factor stability, metabolic-enzyme activity and sub-cellular protein trafficking. Consequently, hyper-lactylation accelerates every hallmark of HCC aggressiveness—G1/S transition (H3K9/56la, CCNE2-K348la), anabolic rewiring (SCD1, AK2, LDHA feedback loops), epithelial–mesenchymal transition (TPX2, PKM2, Rab7A lactylation) and immune escape (PD-L1, NUPR1, MOESIN lactylation)—while also fostering stemness and resistance to lenvatinib, cisplatin and microwave ablation. Third, because lactylation levels correlate tightly with tumour grade, micro-vascular invasion and overall survival, site-specific lactylation signatures (H3K18la, AK2-K28la, CENPA-K124la, USP14-K336la, ABCF1-K430la) can complement classical AFP and imaging-based surveillance. Therapeutically, we propose a “lactylation clamp” strategy: combine (i) lactate-lowering agents (LDH inhibitors such as FX11, MCT1/4 blockers such as AZD3965, HK2 silencers), (ii) selective p300 catalytic inhibitors (e.g., C646 derivatives) to dampen writing, and (iii) SIRT3 agonists or CRISPR-based HDAC1-3 over-expression to enhance erasing, while monitoring target inhibition with quantitative lactyl-proteomics. Importantly, disruption of the lactylation axis resensitizes HCC to PD-1 checkpoint blockade, suggesting that lactylation-directed therapy can be synergistic rather than competitive with immunotherapy. Given the safety record of metabolic modulators in humans, we advocate rapid translation of these combinations into neoadjuvant or adjuvant clinical trials, with H3K18la and AK2-K28la as pharmacodynamic end-points. Aiming to dissect the impact of lactate and lactylation on hepatocellular carcinoma, this review seeks to furnish novel methodologies and conceptual frameworks for predictingtumour progression, evaluating therapeutic efficacy, and tailoring individualized treatment strategies for HCC patients.
Communication Author：CHEN Guang-Shun , Email:2512445403@qq.com
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