Post-translational modifications in sepsis: mechanisms and therapeutic potential in macrophage polarization

Sepsis is a life-threatening syndrome caused by organ dysfunction resulting from a dysregulated host response to infection, characterized by early hyperinflammation and subsequent immune paralysis or immunosuppression. Macrophage dysregulation is a major driver of this immune imbalance. Tissue-resident macrophages mediate inflammatory injury and repair, while recruited monocytes share key post-translational modification (PTM) regulatory mechanisms with macrophages. Macrophage responses in sepsis span heterogeneous and dynamic functional states, with M1-like inflammatory and M2-like immunoregulatory programs representing only two reference poles within this broader spectrum. Macrophage tolerance, characterized by hyporesponsiveness to repeated pathogenic stimulation, further contributes to late-stage immunosuppression and cooperates with aberrant polarization to promote immune paralysis. PTMs are central regulators of macrophage function and polarization homeostasis. By modifying key signaling molecules, they regulate pathways such as NF-κB and MAPK, while metabolism-linked PTMs couple metabolic reprogramming to macrophage functional states. Crosstalk among multiple PTMs collectively shapes macrophage plasticity. During sepsis progression, disruption of the PTM-macrophage polarization axis contributes to excessive inflammation, organ injury, metabolic dysfunction, autophagy-apoptosis imbalance, and organ-specific immunosuppression. This review systematically examines the cooperative and antagonistic PTM networks governing macrophage polarization, with particular emphasis on PTM-metabolism crosstalk, macrophage tolerance, and tissue-resident macrophage heterogeneity. It further evaluates translational strategies ranging from small-molecule PTM modulators to gene editing and targeted delivery. Together, these insights establish an integrated framework for understanding sepsis immunopathology and support the development of PTM-tailored immunotherapeutic strategies.