α-Lipoic Acid and Deferoxamine Restore Redox–Metallomic Homeostasis in Dapsone Toxicity: Integrated Biochemical, Histological, and Molecular Modeling Evidence

Abstract Dapsone (DDS), a sulfone antibiotic widely used in the treatment of leprosy and autoimmune diseases, is associated with hematotoxicity and hepatotoxicity due to its metabolic conversion into hydroxylamine derivatives that promote methemoglobinemia, iron dysregulation, oxidative stress, and tissue injury. In addition to CYP-mediated bioactivation, DDS may contribute to lysosomal stress-associated iron imbalance and oxidative propagation. Conventional antioxidants or iron-chelating therapies alone may provide only partial protection against these interconnected mechanisms. This study evaluated the protective effects of α-lipoic acid (ALA) and deferoxamine (DFO), administered individually or in combination, against DDS-induced oxidative and hematological disturbances using integrated in vivo and in silico approaches. Male Swiss mice received DDS (40 mg/kg, gavage) for 5 days, followed by treatment with ALA (25 mg/kg, gavage), DFO (40 mg/kg, i.p.), or their combination for an additional 5 days. Methemoglobin (MetHb), reduced glutathione (GSH), nitric oxide (NO), malondialdehyde (MDA), and plasma iron levels were evaluated. Histopathological analysis and molecular docking studies involving cytochrome P450 isoforms (CYP2C9, CYP2C19, CYP3A4, and CYP2E1) and hemoglobin were performed to investigate potential mechanisms underlying DDS-induced toxicity and the protective effects of ALA and DFO. DDS markedly increased MetHb, nitric oxide, malondialdehyde, and plasma iron levels, accompanied by depletion of GSH and hepatocellular degeneration. ALA and DFO individually attenuated oxidative and iron-related disturbances, whereas combined treatment effectively reduced methemoglobin formation and preserved hepatic architecture; however, plasma ferric iron levels remained comparable to those in DDS-treated animals. Molecular docking suggested preferential interactions of DDS with CYP2E1 and CYP3A4, supporting the biological plausibility of their involvement in oxidative bioactivation pathways, whereas DFO showed predicted interactions with CYP2C9, CYP2E1, and hemoglobin-associated iron sites. Collectively, these findings indicate that ALA and DFO each attenuate DDS-induced hepatotoxicity and hematotoxicity through distinct but complementary antioxidant, iron-chelating, and redox-modulating mechanisms. Combined treatment effectively improved selected endpoints, including methemoglobin formation and hepatic architecture, although its protective effects were endpoint-dependent. The molecular modeling results provide supportive mechanistic insights and should be interpreted as hypothesis-generating evidence complementary to the in vivo findings.