Currently, lung transplantation is the only viable last-resort option for end-stage lung diseases such as idiopathic pulmonary fibrosis and COPD(Chronic Obstructive Pulmonary Disease) [1]. The main challenge in lung transplantation is early postoperative complications, which may be caused by the lung ischemia-reperfusion injury (IRI) of the donor lungs, usually experiencing complete cessation of blood flow and ventilation for several hours [1]. Lung IRI is characterized by excessive endogenous reactive oxygen species (ROS) is characterized by excessive endogenous reactive oxygen species (ROS) level [2]. Thus, eliminating reactive oxygen species (ROS) is central to preventing lung ischemia–reperfusion injury (IRI).

Numerous studies have revealed that autophagy was activated during IRI to either suppress or induce oxidative stress [3].Thus, merely induce or suppress autophagy is not optimal to eliminate ROS. For example, Slough Lin's group has established an orthotopic rat lung transplant model demonstrating that prolonged cold ischemia induces autophagy to protect lung tissues from oxidative stress [4], autophagy activation can lead to increased oxidative stress during IRI as well, further indicating the harmful role of autophagy [3]. Further study indicated that selective autophagy, such as mitophagy and ferritinophagy, shapes divergent oxidative-stress outcomes by either restraining or amplifying ROS, providing a mechanistic explanation for the dual-edged role of autophagy in cell fate [5], [6]. Mitophagy recognizes and eliminates damaged mitochondria, which are the primary source of intracellular ROS during IRI, efficiently clearing ROS [5]. Therefore, triggering mitophagy might be a feasible approach to mitigate oxidative stress. Besides mitophagy, ferritinophagy, a special form of selective autophagy, is initiated to substantially enhance the intracellular ROS levels. Ferritinophagy is characterized by the degradation of ferritin, releasing ferrous (Fe2+), and by enhanced lipid peroxidation, contributing to oxidative stress [7]. Activating autophagy by rapamycin can induce ferritinophagy as well, leading to lipid peroxidation [8]. Therefore, it can be hypothesized that inducing autophagy to suppress oxidative stress might induce ferritinophagy, resulting in excessive lipid peroxidation and explaining the paradoxical roles played by autophagy. In this context, it is important to investigate an in-depth understanding of the mechanisms by which ferritinophagy and mitophagy are activated, thereby enabling the identification of ferritinophagy inhibitors that do not interfere with mitophagy.

Accumulating evidences have shown that ROS associated DNA damage plays an important role in regulating autophagy [9].Excessive ROS mainly damages the sugar backbone of DNA or oxidizes nucleoside bases to induce DNA damage, leading to a DNA damage repair response (DDR) [9], triggering autophagy to maintain ROS levels; however, excessive mitochondrial DNA stress induces ferritinophagy, resulting in exacerbated oxidative stress [10]. Moreover, suppressing DDR using a PARP inhibitor can suppress SLC7A11 expression to trigger ferroptosis, further indicating the vital DDR role in regulating ferritinophagy [11]. Therefore, we hypothesized that targeting DDR might be key to suppressing ferritinophagy related lipid peroxidation. Previously, our study reported that NORAD(Non-coding RNA activated by DNA damage), a DNA damage induced lncRNA, is a vital DDR regulator and can be epigenetically upregulated by increased ROS levels to promote autophagy flux, resulting in autophagic cell death [12]. In this study, we aimed to study the NORAD role in regulating mitophagy and ferritinophagy during lung IRI to lay the foundation for therapeutic strategies targeting autophagy regulation.