Metabolic Reprogramming and Immune Metabolism in Sepsis: Targeting the PPAR Pathway for Personalized Therapeutic...

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, in which metabolic reprogramming plays a critical role in disease progression and organ failure. Metabolic reprogramming involves alterations in glucose, lipid, and protein metabolism, leading to imbalanced energy production, immune dysregulation, and tissue damage. Immune cells, under septic stress, switch to aerobic glycolysis, enhancing energy production but causing lactate accumulation and mitochondrial dysfunction, which exacerbates inflammation and organ injury. This metabolic shift emphasizes the need for personalized therapeutic strategies that address the metabolic heterogeneity between pathogens and hosts. The peroxisome proliferator-activated receptor (PPAR) pathway serves as a central regulator of both metabolic and immune responses, offering protective effects through the promotion of fatty acid oxidation and suppression of inflammation. However, the translational application of PPAR-directed therapies is constrained by limited drug specificity and significant interpatient heterogeneity. Advances in multiomics technologies provide promising opportunities for identifying metabolic biomarkers and tailoring PPAR-targeted treatments. Future research should focus on integrating metabolic pathways, developing precise diagnostic tools, and refining personalized interventions to improve sepsis management and patient prognosis. Unlike previous reviews that primarily focus on general immunometabolic alterations in sepsis, this review is the first to systematically integrate PPAR isoform-specific regulatory mechanisms, multiomics-based patient stratification, and phenotype-driven therapeutic targeting, thereby offering a novel framework for precision medicine in sepsis management. We critically evaluate the controversies on the efficacy of PPAR agonists, highlight cross talk with HIF-1α/NF-κB/Nrf2, and propose a phenotype-based stratification for sepsis therapy, a perspective that has not been explored in the literature.