Salidroside Alleviates Lung Ischemia–Reperfusion Injury by Inhibiting Ferroptosis Through the <scp>MAFK</scp> /lncRNA <scp>PTOV1</scp> ‐ <scp>AS2</scp> /miR‐525‐5p/ <scp>ACE2</scp> Axis

This study aimed to explore the mechanism by which salidroside alleviates lung ischemia-reperfusion injury (LIRI) through the lncRNA PTOV1-AS2/miR-525-5p/ACE2 axis, with a specific focus on its role in regulating ferroptosis. In the murine model of LIRI, we administered salidroside either alone or in combination with adenoviral vectors for overexpression or knockdown of PTOV1-AS2 or ACE2. Subsequently, we examined lung histopathological changes, evaluated the severity of pulmonary edema, and assessed the levels of lung damage and inflammation. Additionally, an in vitro model was established using MLE12 cells induced by oxygen-glucose deprivation/reoxygenation (OGD/R), and relative cell viability and reactive oxygen species (ROS) levels were measured. The interactions between PTOV1-AS2 and miR-525-5p, as well as between miR-525-5p and ACE2, were predicted and confirmed through a series of assays. Moreover, the relationship between the transcription factor MAFK and lncRNA PTOV1-AS2 was investigated. The results revealed that salidroside upregulated ACE2 expression, thereby reducing lung injury, inflammation, and ferroptosis in both LIRI mice and OGD/R-induced MLE12 cells. Mechanistically, PTOV1-AS2 served as a competing endogenous RNA (ceRNA) to sponge miR-525-5p, thereby enhancing ACE2 expression, and this regulatory effect was further strengthened by salidroside treatment. Furthermore, it was found that MAFK directly bound to the promoter of PTOV1-AS2, promoting its transcription and subsequent expression. In conclusion, salidroside enhances resistance to ferroptosis and alleviates LIRI through the MAFK/PTOV1-AS2/miR-525-5p/ACE2 signaling axis, which provides new insights into the therapeutic potential of salidroside in LIRI.