Abstract
values, reactive oxygen species generation, mitochondrial depolarization, BCL-2-family remodeling, caspase activation, and PI3K/Akt or NF-κB inhibition. Although informative, these mechanisms do not fully explain why the same phytochemical induces apoptosis in some cancer cells, and cytostasis or adaptation in others, while normal cells frequently activate cytoprotective responses. Rather than replacing conventional compound-centered approaches, we integrate established concepts into a complementary vulnerability-state framework for interpreting plant-derived natural-product-induced selective apoptosis. In this framework, selective apoptosis occurs when phytochemical-induced stress intersects with pre-existing cancer-cell vulnerabilities, overwhelms adaptive buffering, and remains below the injury threshold of normal cells. We organize current evidence around redox imbalance, mitochondrial priming, membrane remodeling, ion-channel and cell-volume dysregulation, and survival-pathway addiction, emphasizing that pathway modulation becomes mechanistically meaningful when linked to differential cellular sensitivity. We further highlight membrane-ion biology as an underexplored contributor to phytochemical responses and discuss how chemical standardization, orthogonal cell-death assays, matched normal-cell models, organoids, and pharmacokinetic/pharmacodynamic considerations can advance the field from descriptive cytotoxicity toward mechanism-informed phytopharmacology.