EM2, a Novel <i>Elephantopus mollis</i> H.B.K. Monomer, Enhances Radiosensitivity in Cervical Cancer Through Dual Inhibition of AKT and Autophagy

Radiotherapy activates both the PI3K/AKT pathway and autophagy in cervical cancer, contributing to radioresistance. To address this, EM2, a dual AKT/autophagy inhibitor, was investigated for its potential to enhance radiosensitivity. RNA-Seq, Western blot, qRT-PCR, and transmission electron microscopy were employed to analyze PI3K/AKT and autophagy pathways following irradiation, while CCK8, clone formation, and flow cytometry assays evaluated proliferation, apoptosis, and cell cycle effects. KEGG and GSEA analyses confirmed irradiation-induced activation of the PI3K/AKT pathway. Both PI3K and autophagy inhibitors significantly improved efficacy, whereas EM2 suppressed AKT pathway activation and autophagy, synergistically inducing G2/M phase arrest, and increasing apoptosis. In vivo experiments using a nude mouse xenograft model demonstrated that EM2 combined with irradiation effectively suppressed tumor growth, PI3K/AKT activation, and autophagy without significant toxicity. These results underscore EM2 as a promising therapeutic agent to overcome radioresistance by simultaneously targeting the PI3K/AKT pathway and autophagy.