Natural Products Inhibiting Necroptosis: Molecular Mechanisms and Therapeutic Opportunities

Necroptosis is a genetically regulated form of necrotic cell death initiated by diverse signals, including death receptor ligands, which activate the receptor-interacting protein kinases 1/3 (RIPK1/3) and mixed-lineage kinase domain-like pseudokinase (MLKL) pathway. Necroptosis plays a pivotal role in the pathophysiology of inflammatory diseases, ischemia/reperfusion injury, and neurodegenerative disorders. Therapeutically inhibiting necroptosis holds promise for these conditions, driving significant interdisciplinary interest, particularly from researchers in biology and medicinal chemistry. In addition to synthetic necroptosis inhibitors, numerous natural products have been identified as inhibitors of necroptosis, demonstrating promising therapeutic potential in various diseases. This review aims to elucidate the established and emerging molecular mechanisms underlying necroptosis as well as its contribution to human diseases. The therapeutic effects and mechanistic insights of natural products in inhibiting necroptosis and associated diseases are further summarized, with particular emphasis on their regulatory roles in the RIPK1/3-MLKL signaling pathway, oxidative stress modulation, and mitochondrial dysfunction. These progresses are expected to not only facilitate the design and development of natural products-based necroptosis modulators, but also promote the clinical application of natural product-derived therapies for necroptosis-associated diseases.