Natural Products Inhibiting Necroptosis: Molecular Mechanisms and Therapeutic Opportunities

Summary

Necroptosis, an immunogenic programmed cell death, drives inflammatory diseases, neurodegeneration, ischemia-reperfusion injury, and cancers. Natural products regulate RIPK1/3-MLKL pathway, oxidative stress, and mitochondrial dysfunction to exert therapeutic potentials against necroptosis-associated diseases. This review explores their mechanisms and clinical potential for developing necroptosis-related therapies.

Abstract

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.

Introduction

Cell death is essential for maintaining organismal homeostasis. Programmed cell death (PCD) is an actively triggered process regulated by multiple genetic mechanisms, serving not only as an essential step for tissue differentiation and development but also as the primary strategy for hosts to eliminate damaged, infected, or redundant cells. Although apoptosis was long regarded as the principal PCD pathway, emerging research has revealed additional regulated cell death mechanisms, including necroptosis, pyroptosis, and ferroptosis, all classified as forms of regulated necrosis¹. Laster et al. first discovered that tumor necrosis factor-....