A Comprehensive Review on Necroptosis Inducing Phytochemicals for Cancer Therapy: Preclinical Evidence

Evading programmed cell death, particularly by inhibiting apoptotic pathways, is an iconic feature of cancer. Necroptosis, a controlled type of necrosis, is now recognized as an appealing alternative for overcoming apoptotic resistance and increasing therapeutic effectiveness. This kind of cell death is coordinated by key mediators such as receptor-interacting protein kinases (RIPK1, and RIPK3) and mixed lineage kinase domain-like protein (MLKL), which together modulate inflammatory cascades and immunological responses. However, necroptosis plays a paradoxical role in cancer, acting both as a tumor suppressor and a driver of metastasis. To disentangle the remaining riddles regarding necroptosis in cancer, a deeper understanding of its mechanism, physiological and pathological activities is desperately needed. This review addresses the innovative approach of targeting necroptosis as a new way to combat apoptosis resistance in tumor therapy, and it summarizes the latest data on its connection with cancer. In the last few decades, phytochemicals have gained plenty of attention for their potential to influence necroptotic pathways, which opens up new options for oncological therapies. Phenolics, alkaloids, and terpenoids are instances of bioactive compounds that possess resilient anti-cancer potential through oxidative stress induction and RIPK1/RIPK3-dependent necroptotic signaling activation. The evidence of phytochemical-induced necroptosis is methodically amalgamated in this review. An in-depth literature search across five leading databases culminated in a shortlist of 314 meticulously vetted articles. This review emphasizes the therapeutic potential of necroptosis-inducing phytochemicals, delineates molecular breakthroughs, and addresses the barriers regarding clinical application.