Title : Reversal of metabolic reprogramming as a therapeutic strategy in early sepsis
Abstract:
Sepsis is a critical condition characterized by dysregulated inflammation. In the early phase, innate immune cells undergo a metabolic shift from mitochondrial oxidative phosphorylation to glycolysis, fueling excessive cytokine production. To explore this phenomenon, we analyzed a publicly available RNA-sequencing dataset and found that CD14? monocytes from early sepsis patients exhibited elevated glycolytic gene expression and immune activation signatures.
To test the therapeutic relevance of reversing this metabolic state, we applied a small-molecule activator of the pyruvate dehydrogenase (PDH) complex to macrophages under inflammatory stimulation. This intervention enhanced mitochondrial function, restored TCA cycle activity, and suppressed lactate production and glucose uptake. Importantly, it reduced pro-inflammatory cytokine secretion without affecting upstream priming signals.
Targeted metabolomic analysis revealed that the treatment decreased the accumulation of metabolites, such as citrate and succinate, typically linked to inflammation-driven metabolic blockade. In a murine endotoxemia model, this metabolic intervention improved survival, reduced systemic cytokine levels, preserved liver function, and limited neutrophil infiltration in lung tissue.
Our findings highlight the role of metabolic reprogramming in the immunopathology of early sepsis and propose mitochondrial metabolic restoration as a therapeutic strategy. Targeting cellular bioenergetics in activated immune cells may attenuate early-phase inflammation and prevent subsequent organ damage in sepsis.
