Inhibition of Gasdermin D by Disulfiram Attenuates Cardiac Inflammation and Fibrosis following Ischaemia Reperfusion Injury

Choi, J. S.; Pervin, M.; Kiriazis, H.; Yavari, P.; Lee, M. K.; Murphy, A. J.; Donner, D.; Vince, J. E.; Sharma, A.; de Haan, J. B.

doi:10.64898/2026.03.10.710794

bioRxiv · 10.64898/2026.03.10.710794

Inhibition of Gasdermin D by Disulfiram Attenuates Cardiac Inflammation and Fibrosis following Ischaemia Reperfusion Injury

Choi, J. S.·Pervin, M.·Kiriazis, H.·Yavari, P.·Lee, M. K.·Murphy, A. J.·Donner, D.·Vince, J. E.·Sharma, A.·de Haan, J. B.

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Abstract

IntroductionInadequately controlled inflammation is a key driver of adverse cardiac remodelling after acute myocardial infarction (AMI). Central to this process is activation of the NLRP3 inflammasome-gasdermin D (GSDMD) pathway, which promotes pyroptosis and the release of the pro-inflammatory cytokine interleukin-1{beta} (IL-1{beta}), a mediator strongly associated with infarct severity and poor clinical outcomes. This study investigates whether repurposing the FDA-approved therapeutic Disulfiram, recently shown to inhibit GSDMD pore formation, could reduce inflammation and thus improve cardiac injury after AMI. Methods and ResultsCardiac ischemia-reperfusion (I/R) injury was induced in C57BL/6 mice by 60-minute ligation of the left coronary artery followed by reperfusion. Disulfiram (25 or 50 mg/kg) was administered at reperfusion and daily thereafter. Cardiac function was assessed by echocardiography, while fibrosis and inflammation were evaluated by histology, RT-PCR, immunohistochemistry and immunoblotting. Leukocyte populations in blood, spleen, bone marrow and heart were analysed by flow cytometry. In vitro, mouse bone marrow-derived macrophages (BMDMs) and PMA-differentiated THP-1 cells were treated with Disulfiram. Cytokine secretion, inflammatory gene expression and changes in cell viability (propidium iodide (PI) staining and lactate dehydrogenase (LDH) release) were measured. Disulfiram (50 mg/kg) significantly improved cardiac function 7 days post-I/R. This was accompanied by a significant reduction in cardiac fibrosis and inflammation, as reflected by a lower abundance of inflammatory cells in circulation and cardiac tissue. In LPS- and ATP/Nigericin-stimulated BMDMs and THP-1 cells, Disulfiram dose-dependently (0.1-50 {micro}M) reduced IL-1{beta} and IL-6 secretion and attenuated membrane permeability and cell lysis. ConclusionsThis study demonstrates that Disulfiram improves cardiac function post-AMI by ameliorating inflammation and fibrosis, which was associated with reductions in cytokine release from inflammatory cells in vitro. Therefore, targeting GSDMD by "repurposing" the FDA-approved drug, Disulfiram, may represent a novel way to provide cardio-protection post-AMI. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/710794v1_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@7fd82eorg.highwire.dtl.DTLVardef@149de52org.highwire.dtl.DTLVardef@a2fe0eorg.highwire.dtl.DTLVardef@d56b4f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Choi, J. S., Pervin, M., Kiriazis, H., Yavari, P., Lee, M. K., Murphy, A. J., Donner, D., Vince, J. E., Sharma, A., de Haan, J. B.. 2026-03-12. Inhibition of Gasdermin D by Disulfiram Attenuates Cardiac Inflammation and Fibrosis following Ischaemia Reperfusion Injury. https://doi.org/10.64898/2026.03.10.710794

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