A Comprehensive Review of Melatonin as Multi-Pathway Neuroprotectant Against Methamphetamine-Induced Programmed Cell Death: Discovery of the Circadian-Ferroptosis Axis.

INTRODUCTION Methamphetamine (METH) abuse affects 34 million individuals globally, causing severe neurotoxicity through multiple programmed cell death (PCD) pathways. No approved pharmacotherapies exist. We comprehensively examined melatonin's neuroprotective mechanisms against METH-induced apoptosis, pyroptosis, necroptosis, and ferroptosis.

METHODS A comprehensive review of preclinical studies examining METH neurotoxicity mechanisms and melatonin's protective effects across all PCD pathways.

RESULTS METH activates apoptosis, pyroptosis, necroptosis, and ferroptosis via distinct molecular pathways. Melatonin inhibits all pathways through antioxidant, mitochondrial, anti-inflammatory, and direct signaling effects. A circadian-ferroptosis axis was identified, linking circadian disruption to ferroptosis.

CONCLUSIONS Melatonin exhibits strong multi-target neuroprotection and represents a promising candidate for clinical translation.