Gambogic acid induces ferroptosis and suppresses colorectal cancer progression by modulating the m6A modification of p62.

Ferroptosis has emerged as a novel therapeutic target in cancer treatment. RNA N6-methyladenosine (m6A) methylation, plays a critical role in regulating ferroptosis and mediating tumor progression and therapy resistance. Gambogic acid (GA), a plant-derived compound with potent antitumor activity, was investigated for its role in inducing ferroptosis in colorectal cancer (CRC). In this study, we demonstrated that GA induces ferroptosis in CRC cells, as evidenced by increased Fe, reactive ROS, and MDA levels, alongside reduced GSH levels. These effects were reversed by ferroptosis inhibitors, iron chelators and autophagy inhibitors. Mechanistically, GA reduced global m6A contents by downregulating methyltransferase3 (METTL3) expression. Overexpression of METTL3 reversed GA-induced ferroptosis and associated biochemical changes. Importantly, METTL3-mediated m6A modification enhanced the stability of p62 mRNA in an IGF2BP1-dependent manner. GA decreased METTL3 protein stability through the ubiquitin-proteasomal degradation. Collectively, these findings reveal that GA induces ferroptosis in CRC by modulating METTL3-mediated m6A modification of p62, connecting RNA epigenetics to autophagy-ferroptosis crosstalk. This study provides novel insights into the therapeutic potential of targeting the METTL3/p62 axis for ferroptosis-based cancer therapy.