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

Sep 28, 2026

Anti-alcoholism drug disulfiram suppresses PANoptosis, a form of inflammatory cell death that coordinates pyroptosis, apoptosis, and necroptosis signaling, in murine macrophages and in vivo. Mitochondrial permeabilization occurs before lytic cell death, linking mitochondrial dysfunction to cardiolipin-dependent mitochondrial processes involving GSDMD-NT, GSDME-NT and p-MLKL. Disulfiram blocks mitochondrial permeabilization and reduces PANoptotic signaling by preventing GSDMD-NT, GSDME-NT and p-MLKL binding to mitochondria, limiting reactive oxygen species, release of components, and PANoptosome assembly. In an HLH mouse model, disulfiram decreases systemic inflammation and mitigates liver, lung, and kidney injury.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages23

Reading Time58 min

AccessFree to download

Introduction

Inflammatory cell death and PANoptosis

Methods

Macrophage induction and protein assays

In vivo HLH model

Results

Mitochondrial permeabilization and PANoptotic signaling

Disulfiram mechanism and PANoptosome assembly

Protective effects in HLH organs

Conclusion

TYPE Original Research PUBLISHED 19 December 2025 DOI 10.3389/fimmu.2025.1726408 OPEN ACCESS EDITED BY Daming Zuo, Southern Medical University, China REVIEWED BY Yungeng Wei, First Afﬁliated Hospital of Guangzhou Medical University, China Jie Xu, Iowa State University, United States *CORRESPONDENCE Dong-yun Ouyang [dongyun1967@aliyun.com](dongyun1967@aliyun.com)[ ](dongyun1967@aliyun.com)Xian-hui He [thexh@jnu.edu.cn](thexh@jnu.edu.cn)[ ](thexh@jnu.edu.cn)Qing-bing Zha [zhaqingbb@sina.com](zhaqingbb@sina.com) †These authors have contributed equally to this work RECEIVED 16 October 2025 REVISED 05 December 2025 ACCEPTED 08 December 2025 PUBLISHED 19 December 2025 CORRECTED 16 January 2026 CITATION Li Y-p, Niu X-j, Zhang G, Chan O-k, Sun N, Hu B, Shi Z-j, Ouyang D-y, He X-h and Zha Q-b (2025) Anti-alcoholism drug disulﬁram inhibits PANoptosis by blocking mitochondrial permeabilizationin macrophages. Front. Immunol. 16:1726408 . doi: 10.3389/fimmu.2025.1726408 COPYRIGHT © 2025 Li, Niu, Zhang, Chan, Sun, Hu, Shi, Ouyang, He and Zha. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Anti-alcoholism drug disulﬁram inhibits PANoptosis by blocking mitochondrial permeabilizationin macrophages Ya-ping Li 1,2†, Xin-jian Niu 2†, Ge Zhang 3†, On-kei Chan 2, Nuo Sun 2, Bo Hu 3, Zi-jian Shi 4, Dong-yun Ouyang 1,2*, Xian-hui He 2,4* and Qing-bing Zha 1,5* 1 Department of Clinical Laboratory, the Sixth Afﬁliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dongguan, China, 2 Department of Immunology and Microbiology, College of Life Science and Technology, Jinan University, Guangzhou, China, 3 Department of Nephrology, the First Afﬁliated Hospital of Jinan University, Guangzhou, China, 4 Department of Fetal Medicine, the First Afﬁliated Hospital of Jinan University, Guangzhou, China, 5Center of Reproductive Medicine, the First Afﬁliated Hospital of Jinan University, Guangzhou, China 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 accompanied by reduced activation of PANoptosis signaling in these organs. Conclusion: A previously unappreciated action of d

FAQs

What is PANoptosis and why is it relevant here?

PANoptosis is an inflammatory cell death modality that simultaneously activates pyroptosis, apoptosis, and necroptosis signaling. This work evaluates whether disulfiram can interfere with PANoptosis-related inflammatory disease processes.

How does disulfiram affect mitochondrial events during PANoptosis?

Disulfiram prevents mitochondrial permeabilization by blocking the binding of GSDMD-NT, GSDME-NT, and p-MLKL to mitochondria, which reduces mitochondrial dysfunction, release of PANoptotic components, and reactive oxygen species generation.

What therapeutic benefit does disulfiram show in the HLH mouse model?

In vivo, intraperitoneal disulfiram substantially decreases systemic inflammation and mitigates liver, lung, and kidney injury. These effects coincide with reduced activation of PANoptosis signaling in those organs.

Sep 28, 2026

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