Hint2 deficiency aggravates mitochondria-associated ferroptosis in lung ischemia-reperfusion injury

Mitochondria-associated ferroptosis is critical in lung ischemia-reperfusion (LI/R) injury. This study examined the role of mitochondrial protein Hint2 in LI/R using mouse models and alveolar epithelial cells. We found that LI/R and hypoxia/reoxygenation (H/R) reduced Hint2 expression. AT2-specific Hint2 knockout exacerbated lung injury, inflammation, and ferroptosis, while promoting mitochondrial fission. Conversely, Hint2 overexpression alleviated H/R-induced oxidative damage and ferroptosis, shifting mitochondria toward fusion by inhibiting DRP1 phosphorylation. Hint2 overexpression enhanced its interaction with DRP1, which H/R disrupted. The Hint2 agonist calcitriol suppressed mitochondria-associated ferroptosis. These findings reveal that upregulating Hint2 protects against LI/R injury, offering a potential therapeutic strategy.