Metformin sensitizes esophageal squamous cell carcinoma to radiation via mitophagy-apoptosis flux

Autophagy is widely recognized for its roles in supporting cell survival under stressful environments through self-digestion processes that contribute to cancer chemoresistance. Here, we show that mitophagy triggered by metformin (MET) enhances the sensitivity of esophageal squamous cell carcinoma (ESCC) to low doses of ionizing radiation (IR) by promoting excessive mitochondrial degradation and facilitating its connection with apoptosis. MET magnified IR-induced reactive oxygen species (ROS) and accelerated cellular energy deficiency, leading to activation of the AMPK-PINK1-dependent mitophagy signaling. MET-activated mitophagy resulted in mitochondrial damage and a decline in oxygen consumption rate (OCR). IR combined with MET increased apoptotic cell death by increasing caspase-3 activity and reducing the Bcl-2/Bax ratio. Consequently, Inhibition of the AMPK-PINK1 axis effectively protected ESCC cells by suppressing MET-activated mitophagosome fusion. Additionally, chloroquine (CQ), a lysosomal inhibitor, restored the radioresistance of ESCC cells by blocking autophagolysosome fusion. Together, the findings suggest that MET-activated mitophagy leads to excessive mitochondrial clearance, further exacerbating IR-induced cell death by activating the apoptotic pathway. MET acts as a radiosensitizer, offering a promising approach to improve the efficacy of low-dose radiation therapy.