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

ABSTRACT

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.