Physiologia

Background: Exercise adaptation is increasingly recognized as an immunometabolic process driven by coordinated interactions among inflammatory signaling, mitochondrial regulation, metabolic homeostasis, and recovery-associated physiology. Within this framework, NLRP3 inflammasome activation and PPARD-mediated metabolic signaling have emerged as biologically relevant pathways potentially involved in exercise-induced physiological adaptation. However, the contribution of regulatory genetic variations linking these pathways remains poorly characterized. Objective: To synthesize current evidence regarding the integration of NLRP3- and PPARD-related pathways in exercise immunometabolism and adaptive physiological responses to exercise, with particular emphasis on the regulatory variants NLRP3 rs10754558 and PPARD rs2267668 as potential contributors to interindividual variability in exercise adaptation. Methods: A structured narrative review complemented by exploratory systems-level in silico analyses was conducted using the PubMed, Scopus, and Web of Science databases until March 2026. Evidence related to exercise physiology, inflammatory regulation, metabolic adaptation, and exercise-associated phenotypes involving the NLRP3 and PPARD pathways was evaluated. Complementary analyses included functional annotation, protein–protein interaction network analysis, and pathway enrichment using STRING, Reactome, KEGG, Gene Ontology, and other publicly available genomic databases. Particular attention was given to the functional and regulatory context of rs10754558 and rs2267668 within the interconnected inflammatory and metabolic pathways relevant to exercise adaptation. Results: The reviewed evidence identified recurrent interactions among the inflammatory and metabolic pathways involved in exercise adaptation and recovery. NLRP3 rs10754558 and PPARD rs2267668 were identified as candidate regulatory variants potentially positioned at the interface between inflammatory responsiveness and metabolic flexibility, providing a biologically plausible framework for understanding the interindividual variability in exercise adaptation. Exploratory system-level analyses identified recurrent associations among inflammatory signaling, mitochondrial function, energy-sensing pathways, and metabolic regulation. These findings primarily reflect the functional annotations and system-level pathway associations identified through exploratory analyses. Conclusions: Current evidence supports a systems-level physiological framework in which inflammatory and metabolic pathways interact dynamically during exercise adaptation and recovery. NLRP3- and PPARD-related pathways, including the candidate regulatory variants rs10754558 and rs2267668, may contribute to interindividual variability in exercise-associated physiological responses and represent promising targets for future hypothesis-driven investigations in exercise immunometabolism, exercise genomics and precision exercise medicine. Full article