Lactylation of HSC70 Impairs Chaperone‐Mediated Autophagy to Promote Pyrin Inflammasome‐Dependent PANoptosis in Macrophages During Sepsis
4 affiliations
- 1Department of Anesthesiology Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
- 2Department of Anesthesiology and Perioperative Medicine General Hospital of Ningxia Medical University Yinchuan China
- 3School of Anesthesiology Shandong Second Medical University Shandong China
- 4Department of Anesthesiology The Affiliated Hospital Southwest Medical University Luzhou Sichuan China
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.
Related
- Single-cell RNA sequencing reveals PANoptosis signatures of acinar cells, macrophages, and neutrophils during injury and repair in acute pancreatitis
- Inflammasome-mediated cell death pathways in female reproductive disorders: from apoptosis, pyroptosis, and necroptosis to PANoptosis.
- The cysteine-rich domain of SEP15, a selenoprotein co-chaperone of the ER chaperone, UDP-glucose:glycoprotein glucosyltransferase, adopts a novel fold
- Opposing Regulation of Tau Condensation by Phosphorylation Levels and Molecular Chaperone Interactions
- Panoramic characterization of proposed ligands for GPR3: oleoylethanolamide as a pharmacological chaperone
BibTeX
@article{chen2026lactylation,
title = {{Lactylation of HSC70 Impairs Chaperone‐Mediated Autophagy to Promote Pyrin Inflammasome‐Dependent PANoptosis in Macrophages During Sepsis}},
author = {Ying Chen and Yan Zhang and Pei Wang and Jiamin Ma and Xinru Zhao and Yi Li and Zhenghao Deng and Xueqing Meng and Jiali Zhu and Liangfang Yao and Jinbao Li},
journal = {Advanced Science},
year = {2026},
month = nov,
doi = {10.1002/advs.78586},
url = {https://doi.org/10.1002/advs.78586},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Lactylation of HSC70 Impairs Chaperone‐Mediated Autophagy to Promote Pyrin Inflammasome‐Dependent PANoptosis in Macrophages During Sepsis
AU - Ying Chen
AU - Yan Zhang
AU - Pei Wang
AU - Jiamin Ma
AU - Xinru Zhao
AU - Yi Li
AU - Zhenghao Deng
AU - Xueqing Meng
AU - Jiali Zhu
AU - Liangfang Yao
AU - Jinbao Li
PY - 2026
DA - 2026/11/03
JO - Advanced Science
DO - 10.1002/advs.78586
UR - https://doi.org/10.1002/advs.78586
AB - 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.
SN - 2198-3844
ER -