Melatonin's Regulatory Influence on Pyroptosis: Biological Characteristics and Therapeutic Potentials

The dysregulation of pyroptosis, which is an inflammatory type of programmed cell death (PCD), plays a significant role in the development of various diseases. At the same time, melatonin has been recognized as a pleiotropic regulator that exhibits anti-pyroptotic effects in preclinical studies. However, the mechanistic relationship between melatonin and pyroptosis across organ systems has not been systematically reviewed. To this end, this review systematically elucidates the molecular mechanisms by which melatonin regulates pyroptosis. We elaborate on its inhibitory effects on inflammasome activation, with a particular focus on the NLRP3 pathway, through mechanisms such as TLR4/NF-κB, SIRT3/FOXO3α, and Nrf2 signaling. Additionally, this study provides a comparative assessment of the therapeutic evidence supporting melatonin's role in alleviating pyroptosis-related pathologies in cardiovascular, neurological, renal, hepatic, pulmonary, and obstetric disorders. By integrating dispersed preclinical findings, this review consolidates the rationale for melatonin as a targeted modulator of pyroptosis and delineates critical avenues for future translational research.