NORAD induced by DNA damage mediates oxidative stress through regulating ferritinophagy in lung transplantation

Autophagy is essential for mitigating excessive reactive oxygen species (ROS) to protect cells from ischemia-reperfusion injury (IRI), which often results in target organ damage and, consequently, lung transplant failure in clinical practice in thoracic surgery. However, excessive autophagy exacerbates IRI. Therefore, inducing or inhibiting autophagy is a paradoxical problem. Based on cell, rat and patient-derived organoid models, ROS accumulated as ischemia time increased. Moreover, ROS levels surged after a certain period of ischemia. Furthermore, autophagy is activated in response to IRI; however, with increased ischemia time, ferritinophagy is induced, leading to a ROS surge. Besides, we observed that ROS-induced DNA damage repair response was associated with ferritinophagy induction. Additionally, our results indicated that ROS-induced DNA damage induces NORAD expression to activate ferritinopahgy through regulating FOXO1-NCOA4 interaction. In this respect, we constructed siNORAD/LNP and NORAD knockout mice to further validate that NORAD is a candidate to suppress oxidative stress during lung ischemia-reperfusion by suppressing NCOA4 mediated ferritinophagy. In conclusion, understanding the interplay between ROS-induced DNA damage, mitophagy, and ferritinophagy is essential for deciphering IRI-associated cell death and for developing therapeutic candidates.