Hypertension is a major contributor to cardiovascular morbidity and mortality, largely driven by oxidative stress, mitochondrial dysfunction, endothelial injury, and chronic vascular inflammation. Emerging evidence suggests that targeting vascular bioenergetics may provide complementary therapeutic strategies beyond conventional antihypertensive drugs. This review explores the mitochondrial protective mechanisms of Piper retrofractum and its major bioactive compounds in the context of hypertension and oxidative vascular injury. The phytochemical profile of P. retrofractum, particularly piperine, piplartine, pipernonaline, and retrofractamides, demonstrates significant antioxidant, anti-inflammatory, and metabolic regulatory activities. Mechanistically, these compounds may attenuate mitochondrial reactive oxygen species (mtROS), restore endothelial nitric oxide synthase (eNOS) coupling, activate AMPK-SIRT1-PGC-1α signaling, induce Nrf2-HO-1 antioxidant pathways, and modulate mitochondrial dynamics and mitophagy. Collectively, these effects contribute to improved endothelial function, reduced vascular remodeling, suppression of inflammatory cascades, and enhanced mitochondrial resilience. In addition, emerging omics technologies, network pharmacology, and AI-assisted nutraceutical discovery offer new opportunities to elucidate multitarget mechanisms and optimize P. retrofractum-based interventions. Despite promising preclinical evidence, important limitations remain, including insufficient clinical studies, limited mitochondrial-specific investigations, and challenges related to bioavailability and standardization. Overall, P. retrofractum represents a promising mitochondria-centered nutraceutical candidate for hypertension management and vascular protection, warranting further translational and clinical investigation.
