P4HA2 interacted with ATAD3A to modulate PINK1/parkin-dependent mitophagy and 125I brachytherapy sensitization in esophageal carcinoma.

Interventional brachytherapy, such as iodine-125(125I), has improved the survival of obstructive late-stage esophageal cancer patients. However, most patients experience radioresistance after 125I brachytherapy. It is key to decipher the underlying mechanism of 125I radioresistance. In this study, we identified an endoplasmic reticulum-associated protein, P4HA2, which is upregulated and mediates resistance to 125I 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 125I brachytherapy. Moreover, the expression of P4HA2 is epigenetically increased by IGF2BP2 in an m6A-dependent manner. Notably, targeting P4HA2 with siRNA-based biocompatible nanomedicines significantly sensitizes ESCC to 125I brachytherapy. Collectively, our results show the molecular mechanism of mitophagy-mediated 125I radioresistance, which provides a potential therapeutic target and combinatorial strategy. Schematic diagram of the role of P4HA2 in 125I brachytherapy for tumors.