Macrophage metabolism reprogramming in sepsis: Pathogenesis and therapeutic implications (Review)

Sepsis is a life-threatening syndrome of organ dysfunction caused by infection, characterized by complex pathogenesis and high clinical mortality.As innate immune cells, macrophages serve a pivotal role in the initiation, progression and resolution of sepsis.The present review focuses on the key molecular nodes and signaling pathways of macrophage metabolic reprogramming in the process of sepsis.Key mechanisms include: i) The mammalian target of rapamycin-hypoxia inducible factor-1 (HIF-1)-pyruvate kinase M2 axis as the primary regulator of glycolytic flux and pro-inflammatory cytokine production; ii) tricarboxylic acid cycle interruption leading to succinate accumulation, which amplifies HIF-1a signaling and promotes interleukin-1 release via G protein-coupled receptor 91, thereby exacerbating inflammation; iii) triggering receptor expressed on myeloid cells 2-SH2-containing protein tyrosine phosphatase-1 axis-mediated impairment of fatty acid oxidation, promoting lipid accumulation and pro-inflammatory activation; and iv) amino acid depletion contributing to immune paralysis.In view of the 31.5% global mortality (21.4 million mortalities in 2021) caused by sepsis, a shift from supportive treatment to precise immune metabolism intervention is needed.The present article uniquely integrates the coordinated regulation of glucose, lipid and amino acid metabolic networks of macrophages in sepsis, and expounds the research status of immune metabolism in sepsis, in order to provide reference for the clinical treatment of sepsis.Targeted modulation of macrophage metabolism offers a new direction for individualized immunometabolic therapy in sepsis. Contents1. Introduction 2. Search strategy and selection criteria 3. Phenotype transition of macrophages in sepsis 4. Glycometabolism of macrophages in sepsis 5. Lipid metabolism of macrophages in sepsis 6.Amino acid metabolism of macrophages in sepsis 7. Targeting macrophage metabolism in sepsis therapy 8. Integrative analysis of translational challenges and metabolic interventions 9.