Phytochemical Modulation of Oxidative Stress–Inflammation Coupling in Cardiovascular Disease: From Nrf2 and NADPH Oxidases to NLRP3 and Endothelial Dysfunction

Abstract

Oxidative stress and inflammation are increasingly recognized as reciprocally reinforcing components of cardiovascular disease rather than independent pathological processes. Their interaction is organized through a network that includes mitochondrial dysfunction, NADPH oxidases (NOX), redox-sensitive NF-κB signaling, NLRP3 inflammasome activation, endothelial nitric oxide synthase (eNOS) uncoupling, and loss of nitric oxide bioavailability. Within this framework, phytochemicals are more appropriately viewed as modulators of endogenous redox–inflammatory signaling than as simple radical scavengers. This review critically examines the evidence linking major phytochemical classes to the Nrf2–NOX–ROS–NF-κB/NLRP3–eNOS/NO axis and evaluates how these mechanisms translate across cardiovascular phenotypes, with emphasis on mechanistic hierarchy, as simultaneous pathway changes may reflect propagation from limited upstream targets rather than direct multi-target activity. The review addresses disease-stage dependence, context-specific roles of Nrf2 and NOX isoforms, mitochondrial–NOX crosstalk, pyroptosis, endothelial dysfunction, and the translational importance of pharmacokinetics, formulation, microbial biotransformation, and drug interactions. Current evidence supports a shift from generalized antioxidant supplementation toward mechanism-matched intervention in biologically selected patients, with the greatest credibility achieved when the active molecular species, dominant mechanism, cardiovascular phenotype, disease stage, clinically relevant exposure, molecular target engagement, functional benefit, and clinical outcomes are evaluated within an integrated framework.