GDPPH1 induces cell cycle arrest by downregulation of CDK4/Cyclin D1 via the m6A-METTL14-YTHDF2 axis, attenuating glioblastoma progression.

Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor in adults, with current therapies failing to achieve significant clinical advancements. GDPPH1, a natural compound derived from Garcinia mangostana L., is known for its antioxidant properties; however, its anticancer effects and underlying mechanisms remain insufficiently understood. In this study, we demonstrate that GDPPH1 significantly inhibits GBM cell proliferation in a concentration-dependent manner by downregulating CDK4 and Cyclin D1 expression, inducing cell cycle arrest at G1/S checkpoint, and promoting apoptosis. Mechanistically, GDPPH1 reduces the m6A methylation of CDK4 and CCND1 through METTL14-YTHDF2-mediated transcript decay, resulting in decreased CDK4/CCND1 expression and subsequent decreased RB phosphorylation levels. Further studies revealed that m6A-METTL14-YTHDF2 axis is responsible for GDPPH1-induced downregulation of CDK4 and Cyclin D1. Additionally, the in vivo anti-GBM efficacy of GDPPH1 was confirmed using both xenograft and orthotopic intracranial mouse models. Collectively, these findings provide robust evidence supporting GDPPH1 as a promising therapeutic candidate for GBM and offer novel insights into the role of m6A RNA methylation in cell cycle regulation.