Disulfiram Attenuates Adenine‐Induced Renal Fibrosis by Modulating Inflammatory and Immunometabolic Responses

Abstract

Chronic kidney disease (CKD) is partly driven by excessive innate immune activation, which contributes to progressive renal injury and fibrosis. Disulfiram (DSF), an approved treatment for alcohol dependence, has recently emerged as an inhibitor of innate immune responses such as pyroptosis. In this study, we investigated whether DSF attenuates kidney injury in adenine‐induced nephropathy and explored the underlying mechanisms. DSF treatment markedly ameliorated kidney injury in adenine‐induced nephropathy, accompanied by suppression of inflammatory cell infiltration and inflammasome‐ and pyroptosis‐related markers. RNA sequencing revealed restoration of disrupted fatty acid metabolism in the kidneys following DSF treatment. Furthermore, DSF alleviated DNA damage, cellular senescence, and fibrosis. Importantly, activation of gasdermin D, a central executor of pyroptosis, was closely associated with disease severity in human CKD biopsy samples, supporting the clinical relevance of this pathway. Collectively, these findings suggest a potential role for DSF in modulating inflammatory and immunometabolic pathways in CKD.