Disulfiram Protects Against Diet-Induced Obesity by Reprogramming Systemic Lipid Partitioning Independent of GSDMD

SUMMARY Obesity remains a major global health challenge with limited durable pharmacotherapies. Disulfiram (DSF), an FDA-approved drug reported to inhibit gasdermin D (GSDMD), has been proposed to improve metabolic outcomes through suppression of inflammasome signaling. Here, we demonstrate that GSDMD is dispensable for high-fat diet–induced obesity and insulin resistance, as neither genetic deletion nor antisense-mediated inhibition of GSDMD confers metabolic protection. In contrast, DSF robustly protects against obesity and IR through a GSDMD-independent mechanism. These effects are not attributable to reduced caloric intake but instead reflect a coordinated reprogramming of systemic lipid handling. Under steady-state conditions, DSF suppresses basal lipid oxidation while promoting fecal fatty acid excretion. In striking contrast, during acute lipid challenge, DSF enhances tissue lipid utilization and accelerates systemic clearance. Together, these findings overturn the prevailing inflammasome-centric model and establish context-dependent regulation of lipid partitioning—rather than inflammasome inhibition—as the primary mechanism underlying DSF’s anti-obesity effects Competing Interest Statement The authors have declared no competing interest.