Lactate metabolism and lactylation: Therapeutic and pre-clinical implications in neovascularization in peripheral artery disease

Peripheral artery disease (PAD) is a progressive ischemic condition with limited therapeutic options at advanced stages. Current treatments predominantly target revascularization, often neglecting the metabolic dysregulation underlying this condition. Emerging evidence positions lactate not merely as a glycolytic byproduct but as a critical signaling metabolite that orchestrates neovascularization, vascular remodeling, and immune modulation. Furthermore, lactate-induced histone and nonhistone lactylation dynamically regulate gene expression in ischemic tissues, exerting stage- and cell type-specific effects that may be protective or deleterious. This duality underscores the complexity of lactate signaling and its context-dependent influence on PAD progression. Importantly, lactate and lactylation profoundly affect key vascular cell functions, including endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages, modulating neovascularization and remodeling. This review summarizes recent advances in the understanding of lactate and lactylation, focusing on their regulatory roles in PAD-associated neovascularization and therapeutic potential for PAD. • PAD involves ischemia-driven lactate accumulation and compensatory neovascularization. • Lactate regulates angiogenic cell behavior under hypoxia, directly or via protein lactylation. • The effects of lactate and lactylation in PAD vary with disease stage and microenvironment. • Targeting lactate metabolism and lactylation offers therapeutic potential but requires precise modulation based on pathological context.