From Antioxidants to Enzyme Inhibitors: A Systematic Review and Meta-Analysis of Bioactive Natural Products Targeting Oxidative Stress, Mitochondrial Function, and Microbial Virulence

Natural products continue to serve as a foundational source of pharmacologically relevant molecules due to their chemical diversity and evolutionary optimization for biological interaction. This systematic review and meta-analysis synthesize current evidence on selected classes of bioactive natural products, including L-ascorbic acid and its derivatives, Annonaceous acetogenins, methylxanthines, butenolides, and marine-derived sesterterpenes, with a focus on their mechanistic actions and therapeutic potential. Emphasis is placed on compounds that modulate oxidative stress, mitochondrial bioenergetics, epigenetic regulation, and pathogen-specific metabolic pathways. Pharmacological concentrations of L-ascorbic acid demonstrate prooxidant activity that selectively induces cytotoxicity in cancer cells while also functioning as a cofactor for epigenetic enzymes involved in DNA demethylation. Annonaceous acetogenins, particularly chatenaytrienins, show potent inhibition of mitochondrial complex I, leading to reactive oxygen species generation and programmed cell death, although concerns regarding neurotoxicity remain. Marine suvanine sesterterpenes selectively inhibit isocitrate lyase in the glyoxylate cycle, a pathway essential for fungal virulence but absent in humans, highlighting a promising antivirulence strategy. Butenolide derivatives exhibit a wide spectrum of activities ranging from cytoprotection and cytoproliferation to antifungal and antibacterial effects, with structure–activity relationships guiding potency optimization. Quantitative synthesis of cytotoxicity and antifungal efficacy data supports the therapeutic relevance of these compounds while underscoring the importance of mechanistic specificity. Collectively, this review integrates biochemical, cellular, and computational evidence to evaluate the translational potential and limitations of these natural products in drug discovery.