Cajaninstilbene acid in macrophage immunometabolism and angiogenesis: Mechanisms and therapeutic potential

Macrophage immunometabolism is an important regulator of inflammatory resolution and angiogenic responses. Aberrant macrophage polarization, accompanied by metabolic disturbances such as enhanced glycolysis and mitochondrial dysfunction, has been implicated in impaired angiogenesis in chronic inflammatory conditions. Cajaninstilbene acid (CSA), a natural stilbene derived from Cajanus cajan, exhibits anti-inflammatory, antioxidant, and metabolic regulatory activities. In non-diabetic inflammatory settings, including liver injury, ischemia-reperfusion injury, and inflammatory bowel disease, CSA promotes macrophage functional reprogramming and activates AMPK/Nrf2 signaling. Notably, these effects may facilitate a shift from glycolysis-associated inflammatory states toward oxidative phosphorylation-supported reparative macrophage states. VEGF, PDGF-BB, and SDF-1 are established mediators of macrophage-associated angiogenic responses. Their involvement in CSA-related regulation has yet to be examined. Several limitations warrant consideration. Direct experimental validation in disease-relevant contexts exhibiting sustained metabolic stress (e.g., diabetic wounds or chronic ischemia) has not yet been conducted. In addition, causal relationships between metabolic remodeling and macrophage phenotypic transition remain incompletely defined. The proposed involvement of CSA in exosomal miRNA regulation also awaits experimental confirmation. Throughout the article, experimentally supported findings are distinguished from mechanistic interpretation, with unresolved questions highlighted as priorities for future research. CSA may represent a potential modulator of immunometabolic dysfunction, although systematic validation in pathophysiologically relevant disease models is still required.