Anti-alcoholism drug disulfiram inhibits PANoptosis by blocking mitochondrial permeabilization in macrophages

作者：Yaping Li, X. H. Niu, Ge Zhang, On-kei Chan, Nan Sun, Bo Hu, Zijian Shi, Dong‐Yun Ouyang, Xian‐Hui He, Qingbing Zha · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1726408 · 被引用次数：3 · 研究领域：Inflammasome and immune disorders、Spondyloarthritis Studies and Treatments、Peroxisome Proliferator-Activated Receptors

Introduction PANoptosis is a form of inflammatory cell death that exhibits simultaneous activation of pyroptosis, apoptosis and necroptosis signaling. Disulfiram is a clinically used anti-alcoholism drug and can inhibit NLRP3 inflammasome activation and pyroptosis. However, it is unknown whether and how disulfiram interferes with PANoptosis and related inflammatory diseases. Methods PANoptosis was induced in murine macrophages and related protein levels were assayed by immunoblotting. The effects of disulfiram on PANoptosis were assessed both in macrophages in vitro and in a mouse model of hemophagocytic lymphohistiocytosis (HLH) in vivo . Results Mitochondrial permeabilization preceded lytic cell death upon PANoptosis and binding of GSDMD-NT, GSDME-NT and p-MLKL to mitochondria was linked to mitochondrial dysfunction, which was depending on cardiolipin synthesis in mitochondria. Intriguingly, disulfiram not only prevented mitochondrial permeabilization but also suppressed PANoptotic signaling activation in macrophages. Mechanistically, disulfiram prevented the binding of GSDMD-NT, GSDME-NT and p-MLKL from mitochondria to attenuate its permeabilization, release of its components and generation of reactive oxygen species. Furthermore, the assembly of PANoptosome was effectively blocked by disulfiram. In a mouse model of HLH, intraperitoneal administration of disulfiram substantially decreased systemic inflammation and mitigated liver, lung and kidney injury, which were accompa...