The study shows that the tiny protein MOTS‑c, which comes from mitochondria, can protect lung blood vessels from damage caused by loss of oxygen and then re‑oxygenation. It does this by hitching a ride with a protein called MYH9 into the cell nucleus, where it turns on antioxidant genes that fight harmful free radicals. Giving extra MOTS‑c to rats reduced lung injury, inflammation and death, and changes in blood MOTS‑c levels after heart‑lung surgery predicted who would get severe lung problems.

Acute respiratory distress syndrome (ARDS) following cardiopulmonary bypass (CPB) is driven by oxidative stress during lung ischemia-reperfusion injury (LIRI). Mitochondrial-derived peptide MOTS-c has emerged as a regulator of mitochondrial-nuclear communication, yet its role in CPB-induced ARDS remains unclear. Here, we identify MOTS-c as a critical mediator of endothelial protection against LIRI through MYH9-dependent nuclear translocation and transcriptional activation of antioxidant genes. In rat LIRI models, endothelial cells exhibited the most significant MOTS-c upregulation, correlating with barrier preservation and reduced oxidative stress. Mechanistically, hypoxia-reoxygenation (HR) triggered reactive oxygen species (ROS)-dependent phosphorylation of MYH9 at Ser1943 via casein kinase II subunit alpha (CK2A), enabling MOTS-c binding to MYH9-γ-Actin complexes for nuclear transport. RNA sequencing (RNA-seq) combined with chromatin immunoprecipitation sequencing (ChIP-seq) revealed direct MOTS-c interaction with promoters of antioxidant genes (e.g., HMOX1, NQO1), which harbor antioxidant response elements (AREs). Clinically, serum MOTS-c increments within 24 h post-CPB (ΔMOTS-c) outperformed traditional biomarkers in predicting ARDS incidence, with multivariate models incorporating ΔMOTS-c achieving superior discriminative power (AUC = 0.885). Exogenous MOTS-c administration in rats attenuated lung injury by reducing oxidative damage, inflammation, and mortality, recapitulating endogenous protective mechanisms. Our findings establish MOTS-c as a dual-function molecule-acting via ROS-CK2A-MYH9 signaling to activate nuclear antioxidant defenses and serving as a prognostic biomarker for CPB-related complications. This study bridges mitochondrial dynamics, nuclear transcriptional regulation, and clinical outcomes, offering novel preventive avenues for IRI-associated pathologies.