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.