Melatonin and necroptosis: therapeutic aspects based on cellular mechanisms

Necroptosis is a regulated form of programmed cell death. It is integral to the development of various diseases, such as neurological disorders, lung injuries, liver fibrosis, and testicular toxicity. This process is orchestrated by essential molecular pathways that involve receptor-interacting protein kinases (RIP1/RIP3) and mixed lineage kinase domain-like protein (MLKL), which lead to membrane disruption, the release of damage-associated molecular patterns (DAMPs), and subsequent inflammation. Melatonin, recognized for its potent antioxidant and anti-inflammatory properties, has emerged as a promising therapeutic agent that can inhibit necroptosis through various mechanisms. In neurological diseases such as intracerebral hemorrhage, traumatic brain injury, and cerebral ischemia-reperfusion, melatonin suppresses necroptosis by downregulating RIP1/RIP3/MLKL signaling, upregulating A20 (TNFAIP3), and inhibiting the HMGB1/TLR4/NF-κB pathway. In lung disorders, melatonin attenuates cadmium- and LPS-induced necroptosis by modulating the Ang-II axis, reducing TNF-α-mediated signaling, and acting through MT1/MT2 receptors. In liver fibrosis models, melatonin inhibits RIP1-RIP3 necrosome formation, reduces oxidative stress, and decreases DAMPs-mediated immune responses. Similarly, in testicular toxicity induced by tetrabromobisphenol A (TBBPA), melatonin suppresses necroptosis by inhibiting the several pathways and reducing ROS overproduction. These findings highlight melatonin's ability to modulate necroptosis across diverse tissues, offering protection against inflammation, oxidative stress, and cell death. By targeting necroptosis-related pathways, melatonin presents a versatile therapeutic strategy for treating diseases characterized by excessive cell death and inflammation, including stroke, myocardial infarction, pancreatitis, and autoimmune disorders. This review underscores the potential of melatonin as a novel intervention for necroptosis-related pathologies, emphasizing its role in restoring cellular homeostasis and mitigating tissue damage.