Macrophage Metabolic Reprogramming in Sepsis: New Insights for Targeted Therapy

Sepsis remains a formidable clinical challenge, characterized by life-threatening organ dysfunction. Recent research highlights macrophage metabolic reprogramming as a central driver of this complex syndrome. These innate immune cells play a pivotal role throughout the initiation, progression, and eventual resolution of the septic response. Understanding these metabolic shifts is essential for developing more precise clinical interventions.

The HIF-1α Axis and Glycolytic Flux

The primary regulator of inflammatory signaling in sepsis involves the mTOR-HIF-1α-PKM2 axis. This specific pathway shifts cellular metabolism toward glycolysis, which significantly increases pro-inflammatory cytokine production. Consequently, this metabolic shift helps the cell meet high energy demands during the acute phase. However, excessive glycolytic flux often exacerbates systemic inflammation and leads to secondary tissue damage.

Mechanisms of Macrophage Metabolic Reprogramming

Interruption of the tricarboxylic acid (TCA) cycle leads to the abnormal accumulation of succinate within the cell. This metabolite acts as a signaling molecule that further amplifies HIF-1α activity. Specifically, succinate promotes the release of interleukin-1β through G protein-coupled receptor 91. Furthermore, impairment of fatty acid oxidation leads to lipid accumulation within macrophages, further driving their pro-inflammatory activation. Moreover, amino acid depletion plays a significant role, often contributing to the immune paralysis seen in late-stage sepsis.

Moving Toward Precision Immunometabolic Therapy

Current treatment strategies for sepsis focus largely on supportive care. Nevertheless, the high global mortality rate, which reached 21.4 million in 2021, necessitates a shift toward targeted interventions. Modulating specific metabolic nodes within macrophages offers a promising direction for individualized therapy. By integrating glucose, lipid, and amino acid networks, clinicians may soon deploy treatments that address the underlying immune dysregulation of sepsis. Therefore, targeted immunometabolism represents a vital frontier in critical care medicine.

Frequently Asked Questions

How does the HIF-1α axis affect sepsis?

The HIF-1α axis acts as a master regulator of glycolytic flux in macrophages. It drives the production of pro-inflammatory cytokines, which can worsen organ dysfunction if left unchecked during the early stages of infection.

What is the impact of succinate accumulation?

Succinate builds up when the TCA cycle is interrupted. It acts through GPCR91 to enhance inflammatory signals and promote the release of cytokines like IL-1β, thereby exacerbating systemic inflammation.

Can targeting metabolism improve sepsis survival?

Yes, transitioning from general support to precise metabolic modulation allows for individualized therapy. This approach aims to restore immune balance and reduce the high mortality associated with septic shock and immune paralysis.

Disclaimer: This content is for informational and educational purposes only. It does not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified healthcare provider with any questions you may have regarding a medical condition. Refer to the latest local and national guidelines for clinical practice.

References

Zhao T et al. Macrophage metabolism reprogramming in sepsis: Pathogenesis and therapeutic implications (Review). Int J Mol Med. 2026 Jun undefined. doi: undefined. PMID: 41930580.

GBD 2021 Sepsis Collaborators. Global, regional, and national sepsis incidence and mortality, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Glob Health. 2025 Oct. doi: 10.1016/S2214-109X(25)00356-0.

Li X et al. Immunometabolic reprogramming in sepsis: mechanisms, clinical endotypes, and therapeutic opportunities. Front Immunol. 2024;15:1350000. doi: 10.3389/fimmu.2024.1350000.