Sheibani Mohammad, Hosseinzadeh Azam, Fatemi Iman, Mehrzadi Saeed
Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
Mol Biol Rep. 2025 Jun 17;52(1):606. doi: 10.1007/s11033-025-10713-x.
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.
坏死性凋亡是一种程序性细胞死亡的调控形式。它在多种疾病的发生发展中起着不可或缺的作用，如神经紊乱、肺损伤、肝纤维化和睾丸毒性。这一过程由涉及受体相互作用蛋白激酶（RIP1/RIP3）和混合谱系激酶结构域样蛋白（MLKL）的关键分子通路精心编排，这些通路会导致细胞膜破坏、损伤相关分子模式（DAMPs）释放以及随后的炎症反应。褪黑素因其强大的抗氧化和抗炎特性而闻名，已成为一种有前景的治疗药物，可通过多种机制抑制坏死性凋亡。在脑出血、创伤性脑损伤和脑缺血再灌注等神经疾病中，褪黑素通过下调RIP1/RIP3/MLKL信号通路、上调A20（TNFAIP3）以及抑制HMGB1/TLR4/NF-κB通路来抑制坏死性凋亡。在肺部疾病中，褪黑素通过调节血管紧张素-II轴、减少TNF-α介导的信号传导以及通过MT1/MT2受体发挥作用，减轻镉和脂多糖诱导的坏死性凋亡。在肝纤维化模型中，褪黑素抑制RIP1-RIP3坏死小体的形成，减少氧化应激，并降低DAMPs介导的免疫反应。同样，在四溴双酚A（TBBPA）诱导的睾丸毒性中，褪黑素通过抑制多种通路并减少活性氧的过度产生来抑制坏死性凋亡。这些发现突出了褪黑素调节不同组织中坏死性凋亡的能力，为抵御炎症、氧化应激和细胞死亡提供保护。通过靶向坏死性凋亡相关通路，褪黑素为治疗以细胞过度死亡和炎症为特征的疾病，包括中风、心肌梗死、胰腺炎和自身免疫性疾病，提供了一种通用的治疗策略。这篇综述强调了褪黑素作为坏死性凋亡相关病理的新型干预手段的潜力，强调了其在恢复细胞稳态和减轻组织损伤方面的作用。
