Goniothalamin as a Styryl‐Lactone Toxicophore in Cancer Models: Electrophile‐Driven DNA Damage, Reactive Oxygen Species–Endoplasmic Reticulum Stress Signaling and Detoxification‐Relevant Safety Considerations

ABSTRACT Goniothalamin (GTN), a natural styryl‐lactone from the Goniothalamus genus, has demonstrated cytotoxic properties against a variety of human cancer cell lines with minimal effects on normal cells. Its traditional medicinal use and preliminary preclinical evidence suggest potential as a selective anticancer agent. The purpose of this review is to summarize the preclinical anticancer activity, molecular mechanisms, and therapeutic potential of GTN and its semi‐synthetic derivatives across cancer cell lines and animal models. A comprehensive literature search was conducted on the anticancer effects of GTN using databases including PubMed, Scopus, and ScienceDirect. Studies reporting in‐vitro cytotoxicity, half‐maximal inhibitory concentration (IC50) values, mechanisms of action, synergistic drug effects, and in‐vivo antitumor efficacy were included. Data on GTN enantiomers and semisynthetic derivatives were also analyzed. GTN exhibited potent, dose‐ and time‐dependent cytotoxicity in breast, colorectal, hepatoma, leukemia, and other cancer cell lines (IC 50 in the low micromolar range), while sparing normal cells. Mechanistically, GTN induced DNA damage, reactive oxygen species (ROS) generation, cell cycle arrest, endoplasmic reticulum stress, apoptosis, autophagy, necroptosis, and anoikis. The anticancer activity of GTN enantiomers appears to be cell‐line dependent: although the (R)‐enantiomer showed higher potency in several cancer models, the (S)‐enantiomer displayed greater activity in selected cancer cell lines. GTN synergized with chemotherapeutics such as paclitaxel, vinblastine, and cisplatin, enhancing apoptosis and reducing cell viability. Semi‐synthetic derivatives, including methoxy‐ and nitro‐substituted analogs, demonstrated enhanced potency and selectivity. In animal models, GTN exhibited antitumor activity without detectable toxicity. GTN is a promising natural anticancer agent with multimodal mechanisms of action and selective cytotoxicity. Semisynthetic derivatives further improve its potency and specificity. Further in‐vivo studies, bioavailability, and pharmacokinetic investigations are warranted to advance GTN towards clinical application.