Gambogenic acid

Gambogenic acid (GNA) is a promising antitumor agent targeting EZH2 and modulating signaling pathways to inhibit proliferation, metastasis, enhance chemosensitivity, and overcome drug resistance. Acting in a time- and dose-dependent manner, GNA targets cancer hallmarks with broad activity by directly and covalently binding EZH2 (Cys668), disrupting PRC2, activating RIP1/p53/SLC7A11/GPX4, activating GSK3β while inhibiting Akt/mTOR, inducing ferroptosis, and downregulating metastasis proteins. These actions, mediated through pathways like Akt/mTOR, ROS/JNK, and NF-ĸB, result in tumor cell death and proliferation reduction, with GNA showing advantages over gambogic acid in antitumor effect and toxicity. In vitro and in vivo studies confirm GNA′s efficacy, but consideration should be given to potential drug-drug interactions due to GNA′s increase of liver CYP enzyme activity.