Metabolic and post-translational modifications in sepsis-associated immune dysfunction: a conceptual framework.

Sepsis is characterized by a progressive collapse of immune signal transduction, in which post-translational modifications (PTMs) act as critical execution layers that help shape the amplitude, duration, and reversibility of immune responses. Although often framed as a transition from cytokine storm to immune paralysis, the molecular logic governing this shift remains poorly defined. Growing evidence suggests that immune dysfunction in sepsis arises not from simple signal attenuation but from a loss of signaling competence, driven by coordinated changes in PTM networks, cellular metabolism, and chromatin structure. Here, we propose a metabolic-PTM temporal switch model as a conceptual framework in which immune signaling is rewired through context-dependent, PTM-associated configurations constrained by metabolic availability and chromatin accessibility. In early sepsis, permissive metabolic conditions and open chromatin may support fast, reversible PTMs-such as phosphorylation and scaffold-forming ubiquitination-that amplify innate immune signaling. As metabolic stress accumulates, a transition may occur in which ubiquitin linkage editing and increased deacetylation become more prominent and may contribute to the dismantling of signaling complexes and the restriction of transcriptional output. In late-stage sepsis, sustained metabolic exhaustion and chromatin condensation are associated with persistent PTMs, including histone lactylation, thereby potentially contributing to a low-plasticity immune state that becomes refractory to reactivation. Rather than implying a fixed temporal sequence, this framework is intended to describe representative PTM-associated patterns that may emerge across overlapping sepsis-related immune states. This framework may help explain why immune stimulation frequently fails in late sepsis: receptors and ligands may remain intact, yet signaling architecture and transcriptional competence can be substantially impaired. By identifying context-associated PTM patterns and signaling constraints, this model provides a conceptual basis for understanding context-dependent immune dysfunction and offers conceptual guidance for interpreting the variable outcomes of immune-targeted interventions in sepsis.