Repurposing disulfiram: targeting Zeb1 to attenuate paraquat-induced pulmonary fibrosis in rats

Pulmonary fibrosis is a fatal condition marked by excessive extracellular matrix deposition and myofibroblast activation, with paraquat (PQ) being a potent inducer via oxidative stress and profibrotic signaling. This study evaluated the antifibrotic effects of disulfiram (DSF), an FDA-approved medication, in rats with PQ-induced pulmonary fibrosis. Forty male Wistar rats were divided into eight groups receiving PQ (40 mg/kg) and DSF (1, 10, 100 mg/kg) for 21 days. Lung tissues were analyzed histopathologically (H&E, Mallory’s trichrome) for inflammation, alveolar septal thickening, vascular congestion, and fibrosis, while Zeb1 gene expression was assessed by real-time PCR. PQ exposure led to severe lung injury, collagen deposition, and significant upregulation of Zeb1 (p = 0.0022). DSF at 10 mg/kg provided the most effective protection, significantly reducing histopathological damage and Zeb1 expression (p < 0.001). The 1 mg/kg dose showed moderate efficacy, and the 100 mg/kg dose had limited benefits, suggesting a dose-dependent toxicity. These findings indicate that DSF at 10 mg/kg attenuates PQ-induced pulmonary fibrosis by reducing inflammation, collagen accumulation, and Zeb1-mediated profibrotic signaling, supporting DSF as a potential repurposed antifibrotic therapy for PQ-induced and possibly idiopathic pulmonary fibrosis.