Melatonin attenuates burn-wound progression by inhibiting inflammation via mitophagy-related pathway.

Burn-wound progression contributes to early deterioration of burn severity and is closely associated with oxidative stress-induced inflammation in the zone of stasis, where mitochondria play a central role in regulating inflammatory responses and tissue damage. Melatonin is known to exert antioxidant and anti-inflammatory effects and to protect organelles from injury, suggesting a potential role in mitigating ischemia-related tissue damage. In this study, a "comb" scald rat model was used to investigate whether melatonin could prevent early burn-wound progression and to elucidate the underlying mechanisms. Melatonin was administered intraperitoneally at different doses immediately after injury, and wound conversion was assessed by histological analysis. Oxidative stress markers, inflammatory cytokines, and autophagy/mitophagy-related signals were evaluated using ELISA, immunostaining, qRT-PCR, and western blotting, with additional pharmacological modulation of autophagy and mitophagy to clarify mechanistic involvement. The results showed that melatonin significantly attenuated burn-induced activation of the HMGB1-NLRP3 inflammasome and reduced inflammatory cytokine release, while also alleviating oxidative stress, as indicated by decreased malondialdehyde (MDA) levels and restored superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. These protective effects were closely associated with preservation of mitochondrial integrity and regulation of reactive oxygen species (ROS) through autophagy, particularly PINK1-PARKIN-dependent mitophagy. Importantly, the autophagy inhibitor 3-MA abolished the beneficial effects of melatonin, confirming the essential role of autophagy-related pathways. Together, these findings demonstrate that melatonin prevents early burn-wound progression by promoting mitophagy-mediated mitochondrial repair and suppressing downstream inflammatory responses.