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Interventional brachytherapy, such as iodine-125( 125 I), has improved the survival of obstructive late-stage esophageal cancer patients. However, most patients experience radioresistance after 125 I brachytherapy. It is key to decipher the underlying mechanism of 125 I radioresistance. In this study, we identified an endoplasmic reticulum-associated protein, P4HA2, which is upregulated and mediates resistance to 125 I treatment. Mechanistically, P4HA2 enhances mitochondrial autophagy (mitophagy) via the PINK1/parkin pathway by binding to ATAD3A. Clinically, high expression of P4HA2 correlates with shorter overall survival and predicts poor prognosis with 125 I brachytherapy. Moreover, the expression of P4HA2 is epigenetically increased by IGF2BP2 in an m 6 A-dependent manner. Notably, targeting P4HA2 with siRNA-based biocompatible nanomedicines significantly sensitizes ESCC to 125 I brachytherapy. Collectively, our results show the molecular mechanism of mitophagy-mediated 125 I radioresistance, which provides a potential therapeutic target and combinatorial strategy.
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Yao et al. (2025) studied this question.
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