The MQC-Metal-PANoptosis Axis in Sepsis: A Two-Hit Model of Immune Exhaustion

Sepsis has undergone a paradigm shift from isolated cytokine-driven models to integrated cellular fate decisions.A key clinical hallmark is the transition from early hyperinflammation to late immunosuppression, which is fundamentally linked to the functional exhaustion and massive depletion of CD4⁺ T cells.Here, we propose a testable two-hit model for sepsis-induced CD4⁺ T cell death and immune failure.In this model, the combined failure of mitochondrial quality control (MQC) and dysregulated iron/copper homeostasis constitutes the first hit -a catastrophic intracellular priming event characterized by oxidative stress and activation of metal-dependent death pathways (ferroptosis, cuproptosis) -which lowers the threshold for subsequent activation of the cell death network.The second hit is provided by aberrant cytosolic nucleic acid sensing via Z-DNA binding protein 1 (ZBP1), amplified by interferon signaling and the septic cytokine milieu, which directly drives PANoptosome assembly and execution of PANoptosis -an integrated cell death program encompassing pyroptosis, apoptosis, and necroptosis.Recent direct in vivo evidence demonstrates that Nuclear FMR1 Interacting Protein 1 (NUFIP1)-mediated ribophagy alleviates ZBP1-driven PANoptosome assembly in septic CD4⁺ T cells via the cGAS-STING pathway.However, the role of the IL-6/JAK/STAT3 axis remains contentious: although it can promote RIPK1-dependent PANoptosome assembly under certain experimental conditions, its blockade shows divergent outcomes across sepsis models, suggesting context-dependent rather than universal pro-death activity.We hypothesize that IL-6/JAK/STAT3 signaling functions as a context-dependent amplifier rather than a universal trigger, shifting from homeostatic protection to pro-death priming under conditions of MQC failure and NAD⁺ depletion.Importantly, throughout this review we explicitly distinguish mechanisms that have been directly validated in primary septic CD4⁺ T cells (Level A evidence) from those extrapolated from parenchymal or myeloid cell systems (Levels B-D), with the IL-6/JAK/STAT3-RIPK1 axis in T cells representing a testable hypothesis (Level D) that requires dedicated experimental validation.Finally, we outline a precision medicine roadmap guided by multidimensional biomarkers and phase-specific, combination regimens targeting distinct components of the MQC-Metal-PANoptosis axis.This model provides a rationale for biomarker-guided, phase-specific therapy in sepsis and highlights key experimental questions that must be addressed before clinical translation.