Ceramide-1-phosphate alleviates high-altitude pulmonary edema by stabilizing circadian ARNTL-mediated mitochondrial dynamics. Mus musculus

Our findings demonstrated that CERK-derived C1P was protective against HAPE. Inhibition of CERK exacerbated the severity of HAPE under hypobaric hypoxic conditions. Specifically, we uncovered a novel mechanism in which aryl hydrocarbon receptor nuclear translocator-like (ARNTL) autophagic degradation was induced by CERK inhibition, impairing the circadian rhythm and triggering mitochondrial damage by controlling the expression of the proteins required for mitochondrial fission and fusion. The decrease in ARNTL driven by CERK inhibition impaired mitochondrial dynamics, induced oxidative stress damage, and caused defects in mitophagy, especially under hypoxia. Exogenous C1P blocked ARNTL degradation, relieved mitochondrial damage, neutralized oxidative stress induced by CERK inhibition, and ultimately alleviated HAPE.