Post-translational control of macrophage plasticity in cardiovascular inflammation: lactylation, citrullination, palmitoylation, and therapeutic opportunities

Macrophages adopt diverse, tissue- and stage-specific states during cardiovascular inflammation, and these states are incompletely captured by the conventional M1/M2 framework. Post-translational modifications (PTMs) provide a rapid biochemical layer through which metabolic and inflammatory cues alter protein function, localization, chromatin activity, and innate immune signaling. This review critically examines three emerging PTMs: lysine lactylation, arginine citrullination, and cysteine S-palmitoylation, and their roles in cardiovascular macrophage plasticity. Lactylation links lactate metabolism to histone and non-histone regulation; substrate- and site-specific mechanisms influence reparative transcription after myocardial injury, plaque macrophage behavior, innate DNA sensing, and mitochondrial metabolism. Citrullination, mediated principally by peptidylarginine deiminase 2 and 4, connects macrophage-intrinsic signaling with neutrophil extracellular trap biology and extracellular citrullinated proteins, thereby shaping endothelial dysfunction, chronic vascular inflammation, thrombosis, and context-dependent post-infarction responses. S-palmitoylation controls membrane localization, trafficking, inflammasome assembly, and pyroptosis, with residue-specific regulation of NLRP3 and gasdermin D illustrating how the same PTM class can generate divergent functional outcomes. We further identify the NLRP3 inflammasome and cGAS–STING signaling as candidate convergence nodes among these PTMs, while distinguishing established mechanisms from testable hypotheses. Preclinical interventions targeting lactate metabolism, PAD activity, or palmitoylation demonstrate pharmacological tractability but also expose major challenges related to substrate specificity, disease stage, cell type, and host defense. Integration of site-resolved PTM proteomics with single-cell and spatial profiling will be essential to define causal modification states in human cardiovascular tissues. A residue-, substrate-, cell-, and stage-specific framework may ultimately enable more precise macrophage-directed cardiovascular immunotherapy than broad anti-inflammatory suppression.