Disulfiram as an anti-inflammatory agent: mechanisms, nano-delivery strategies, and applications in non-oncologic diseases.

Disulfiram (DSF), an FDA-approved drug for alcoholism, has recently emerged as a potent anti-inflammatory agent. It achieves this by targeting gasdermin D (GSDMD)-mediated pyroptosis, a key driver of inflammatory responses. This review explores the multifaceted anti-inflammatory mechanisms of DSF, including its inhibition of GSDMD pore formation, modulation of the STING pathway, suppression of RIPK1-dependent necroptosis, and disruption of FROUNT-mediated macrophage migration. Despite its promising in vitro efficacy, DSF's clinical application is hindered by its poor solubility, low bioavailability, and rapid metabolism. To overcome these limitations, advanced nano-delivery carriers-such as lipid-based nanoparticles, polymeric carriers, metal-organic frameworks, and peptide conjugates-have been developed to enhance targeted delivery, prolong circulation, and reduce off-target effects. These innovations hold significant promise for the treatment of diverse inflammatory diseases, including respiratory disorders (e.g., COVID-19 and acute lung injury), autoimmune conditions (e.g., lupus and graft-versus-host disease), and metabolic ailments (e.g., hepatitis and colitis). While challenges remain in clinical translation, integrating DSF with nanotechnology offers a transformative approach to harnessing its anti-inflammatory properties. This review highlights current advancements, unresolved questions, and future directions for optimizing DSF-based therapies in inflammation management.