Exploring melatonin as a therapeutic approach for mustard vesicants

Abstract

Sulfur mustard and nitrogen mustard (NM) are highly toxic chemical agents that inflict severe damage to the lungs, skin, eyes, and other tissues through mechanisms involving oxidative stress, DNA alkylation, and inflammation. Despite extensive research, no definitive antidote exists, highlighting the need for innovative therapeutic strategies. Melatonin, a pleiotropic molecule with potent antioxidant, antiinflammatory, and DNA-protective properties, has shown promise as a therapeutic agent against mustard-induced toxicity. Melatonin’s ability to scavenge reactive oxygen and nitrogen species, including peroxynitrite (ONOO−), reduces oxidative and nitrosative stress, mitigating lipid peroxidation and protein and DNA damage. Furthermore, melatonin enhances endogenous antioxidant defenses by upregulating superoxide dismutase, glutathione peroxidase, and glutathione, thereby bolstering cellular resilience. Its antiinflammatory effects are mediated through inhibition of NF-κB signaling and modulation of the NLRP3 inflammasome, reducing cytokine release and immune activation. Experimental evidence demonstrates melatonin’s efficacy in animal models, including its ability to reduce lung damage, improve respiratory function, and prevent oxidative DNA damage. It also protects against injury caused by NM analogs and supports DNA repair by stabilizing cellular homeostasis. Melatonin’s safety profile, affordability, and availability make it a viable candidate for mitigating both acute and long-term effects of mustard exposure. These findings establish melatonin as a promising therapeutic intervention for mustard vesicants, warranting further research to optimize dosing, delivery, and application in both military and civilian scenarios. © 2026 Elsevier Inc. All rights reserved.