Lactylation of HSC70 Impairs Chaperone‐Mediated Autophagy to Promote Pyrin Inflammasome‐Dependent PANoptosis in Macrophages During Sepsis

ABSTRACT Sepsis‐related cytokine storm is associated with poor prognosis in septic patients. IFNγ/LPS can synergistically trigger a sepsis‐associated proinflammatory cytokine storm and induce macrophage death in the form of PANoptosis. The ensuing release of proinflammatory cytokines further amplifies macrophage death, leading to subsequent multiple organ damage. Concurrently, the IFNγ/LPS induced inflammatory cascade also downregulates chaperone‐mediated autophagy (CMA) activity, and this dysregulation further exacerbates the inflammatory response in macrophages and in vivo. Thus, a positive feedback loop between dysfunctional CMA and the inflammatory cascade is established. Enhancing CMA activation reduces macrophage death and organ damage, whereas inhibiting CMA exacerbates macrophage PANoptosis and organ injury. Mechanistically, impaired CMA leads to accumulation of the transcription factor CUX1, which subsequently upregulates Pyrin expression and promotes Pyrin‐mediated PANoptosome assembly, thereby driving macrophage PANoptosis. In addition to the cytokine storm, the lacylation at lysine 561 (K561) of HSC70, a core component of the CMA machinery, is associated with reduced CMA activity. Blocking lactylation can similarly attenuate macrophage death and multiple organ injury in sepsis. Taken together, this “Kla‐CMA‐CUX1/Pyrin‐PANoptosis” signaling axis, linking metabolic reprogramming to immune dysregulation in sepsis, suggests that targeting key nodes of this axis may represent a promising therapeutic strategy to reduce sepsis‐associated mortality.