Significance of the PI3K/AKT pathway in coronary microvascular dysfunction and advances in natural compound therapeutic research 

Introduction: Coronary microvascular dysfunction (CMD) contributes to myocardial ischemia and adverse cardiovascular outcomes, but effective treatments remain limited. Objective: This review aims to clarify the role of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway in CMD and assess the therapeutic potential of natural compounds that modulate it. Methods: Available mechanistic and preclinical evidence on PI3K/AKT-mediated regulation of endothelial dysfunction, oxidative stress, inflammation, apoptosis, angiogenic repair, and microvascular homeostasis in CMD was reviewed. Natural compounds were classified into flavonoids, saponins, phenolic compounds, alkaloids, and polysaccharides, and their reported effects on PI3K/AKT-related downstream signaling axes were summarized. Results: The PI3K/AKT pathway acts as a context-dependent signaling hub in CMD. Appropriate activation supports endothelial survival, vasodilation, antioxidant defense, anti-inflammatory responses, and inhibition of cardiomyocyte apoptosis through signaling axes including AKT/eNOS, AKT/NRF2, AKT/mTOR, and BCL-2/BAX/caspase. Preclinical studies indicate that several natural compounds can ameliorate cardiovascular injury by modulating these axes, thereby reducing oxidative stress and inflammation, limiting apoptosis and autophagy-related injury, and promoting angiogenesis and microvascular repair. However, most evidence derives from non-CMD-specific cellular and animal models and relies primarily on changes in pathway phosphorylation or pharmacological inhibitor experiments. Direct genetic validation, pharmacokinetic characterization, formulation standardization, and clinical evidence remain insufficient. Conclusion: Natural compounds represent promising multi-target modulators of PI3K/AKT-related signaling in CMD, but their efficacy and pathway dependence require rigorous validation. Future studies should employ CMD-relevant models, objective microvascular endpoints, genetic approaches, optimized delivery systems, and integrative platforms such as organoids, multi-omics, artificial intelligence, and network pharmacology to facilitate clinical translation.