Sola Vendrell, EmmaMorales García, José ÁngelRamos Alonso, EvaRomero Martínez, Manuel Alejandro2025-07-032025-07-032025Sola, E., Morales-García, J. A., López-Muñoz, F., Ramos, E., & Romero, A. (2025). In Vivo Evidence of Melatonin's Protective Role in Alkylating-Agent-Induced Pulmonary Toxicity: A Systematic Review. Antioxidants (Basel, Switzerland), 14(6), 712. https://doi.org/10.3390/antiox1406071210.3390/antiox14060712https://hdl.handle.net/20.500.14352/122172Author Contributions: Conceptualization, A.R. and E.R.; formal analysis, E.R. and E.S.; investigation, A.R., E.R. and E.S.; resources, E.R., J.A.M.-G., F.L.-M. and E.S.; writing—original draft preparation, E.S., E.R. and A.R.; writing—review and editing, E.S., E.R., J.A.M.-G., F.L.-M. and A.R.; supervision, A.R. and E.R.; project administration, A.R. and E.R.; funding acquisition, A.R., E.R. and J.A.M.-G. All authors have read and agreed to the published version of the manuscript.Alkylating agents, historically employed as chemical warfare agents and currently used as chemotherapeutic drugs, are known to induce significant pulmonary toxicity. Current clinical interventions often fail to fully prevent or reverse these pathological changes, highlighting the urgent need for safe, broad-spectrum therapeutic agents that are effective across diverse exposure scenarios. Melatonin has emerged as a promising protective agent due to its antioxidant, anti-inflammatory, and immunomodulatory properties, along with a well-established safety profile. This systematic review evaluates the potential of melatonin in mitigating vesicant-induced pulmonary damage, synthesizing and critically analyzing preclinical evidence in accordance with the PRISMA guidelines. Three in vivo rodent studies met the inclusion criteria and were analyzed. In all cases, melatonin demonstrated protective effects against alkylating agents such as mechlorethamine (HN2) and cyclophosphamide (CP). These effects were dose-dependent and observed across various animal models, administration protocols, and dosages (ranging from 2.5 to 100 mg/kg), highlighting the importance of context-specific considerations. The human equivalent doses (HEDs) ranged from 12 to 973 mg per day, suggesting that the effective doses may exceed those typically used in clinical trials for other conditions. Melatonin’s pleiotropic mechanisms, including a reduction in oxidative stress, the modulation of inflammatory pathways, and support for tissue repair, reinforce its therapeutic potential in both prophylactic and treatment settings for alkylating agent exposure. Nonetheless, this review underscores the critical need for further randomized clinical trials to establish the optimal dosing strategies, refine treatment protocols, and fully elucidate melatonin’s role in managing alkylating-agent-induced pulmonary toxicityengAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal article2076-3921https://doi.org/10.3390/antiox1406071240563344open access615.01/.03616-006.04Alkylating agentsHistopathologyHuman equivalent dosesInflammationLung toxicityMelatoninOxidative stressSystematic reviewOncologíaFarmacología veterinariaToxicología (Medicina)3214 Toxicología3201.01 Oncología3209 Farmacología