Cheng Guilin, Liu Yan, Xing Yangkun, Shi Zhewei, Farag Mohamed Ali, Jin Songheng, Xia Bo
Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Jiyang College, Zhejiang A&F University, Zhuji 311800, China.
J Adv Res. 2026 Jan 3. doi: 10.1016/j.jare.2026.01.007.
Lysine lactylation has redefined lactate's biological role from a metabolic byproduct to a signaling molecule. This post-translational modification directly couples cellular energetics with gene regulation, creating a metabolic-epigenetic axis particularly relevant to cardiovascular pathophysiology. Ischemic and inflammatory stress drive glycolytic reprogramming and lactate accumulation in these diseases. Lactylation modifies both histone and non-histone proteins, enabling metabolic states to reshape chromatin accessibility and protein function. However, therapeutic translation faces critical barriers. These include incomplete characterization of the cardiovascular lactylome, absence of selective pharmacological modulators, and insufficient understanding of how lactylation effects vary across cell types, disease stages, and metabolic contexts.
We systematically dissect lactylation biology across 5 cardiovascular pathologies to define regulatory mechanisms and therapeutic vulnerabilities. We examine glycolysis-lactylation circuits driving pulmonary arterial smooth muscle hyperproliferation in hypertension; dual roles in atherosclerotic plaque stability versus calcification; M2 macrophage-mediated repair versus fibrotic remodeling in myocardial infarction; the metabolic paradox of lactate accumulation with reduced α-myosin heavy chain lactylation impairing contractility in heart failure; and neonatal glycolytic metabolism enabling histone lactylation-driven cardiomyocyte proliferation with metabolic barriers in diabetic contexts. Key Scientific Concepts of Review: Lactylation functions through dual substrates: histone modifications orchestrate inflammatory resolution and cell cycle activation, while non-histone modifications (α-myosin heavy chain, Snail1) directly govern contractility and pathological remodeling. Context-dependent dichotomies emerge across diseases, with protective angiogenesis versus maladaptive fibrosis in infarction and plaque stabilization versus calcification in atherosclerosis. Critically, metabolic paradoxes challenge lactate-lactylation correlations: heart failure shows lactate accumulation yet reduced modification, while diabetic advanced glycation end-products competitively inhibit lactylation. Therapeutic strategies require integrating metabolic reprogramming, site-selective targeting, and temporal control. This review systematically dissects these mechanistic complexities to establish a translational framework that guides precision cardiovascular medicine through metabolic-epigenetic intervention strategies.
赖氨酸乳酰化重新定义了乳酸的生物学作用，使其从代谢副产物转变为信号分子。这种翻译后修饰直接将细胞能量代谢与基因调控联系起来，形成了一个与心血管病理生理学特别相关的代谢-表观遗传轴。在这些疾病中，缺血和炎症应激会驱动糖酵解重编程和乳酸积累。乳酰化修饰组蛋白和非组蛋白，使代谢状态能够重塑染色质可及性和蛋白质功能。然而，治疗性转化面临关键障碍。这些障碍包括对心血管乳酰化组的表征不完整、缺乏选择性药理调节剂，以及对乳酰化效应如何在不同细胞类型、疾病阶段和代谢背景下变化的理解不足。
我们系统地剖析了5种心血管疾病中的乳酰化生物学，以确定调控机制和治疗靶点。我们研究了驱动高血压中肺动脉平滑肌过度增殖的糖酵解-乳酰化回路；在动脉粥样硬化斑块稳定性与钙化中的双重作用；心肌梗死中M2巨噬细胞介导的修复与纤维化重塑；心力衰竭中乳酸积累与α-肌球蛋白重链乳酰化减少损害收缩力的代谢悖论；以及新生儿糖酵解代谢使组蛋白乳酰化驱动的心肌细胞增殖在糖尿病环境中存在代谢障碍。综述的关键科学概念：乳酰化通过双重底物发挥作用：组蛋白修饰协调炎症消退和细胞周期激活，而非组蛋白修饰（α-肌球蛋白重链、Snail1）直接控制收缩力和病理重塑。不同疾病中出现了依赖于背景的二分法，如梗死中的保护性血管生成与适应性纤维化，以及动脉粥样硬化中的斑块稳定与钙化。至关重要的是，代谢悖论挑战了乳酸-乳酰化的相关性：心力衰竭显示乳酸积累但修饰减少，而糖尿病晚期糖基化终产物竞争性抑制乳酰化。治疗策略需要整合代谢重编程、位点选择性靶向和时间控制。本综述系统地剖析了这些机制复杂性，以建立一个转化框架，通过代谢-表观遗传干预策略指导精准心血管医学。
