A yak−enriched CD4 ATF7IP+ subtype is associated with pulmonary endothelial stress resistance under hypoxia

Elucidating the regulatory mechanisms underlying adaptation to high-altitude hypoxia remains a central challenge in genetics. Yaks are exquisitely adapted to the plateau ecosystem, where the lung plays a pivotal role in gas exchange and blood oxygen homeostasis. To explore the cellular composition and molecular regulatory networks of the lung under hypoxic conditions, we constructed a single-cell transcriptomic atlas of the lungs of yak, dzho and cattle. We identified 51 cell subtypes, including 13 novel subtypes predominantly enriched in T&NK cells. Through integration of interspecies differential analysis, pseudotime analysis, and SCENIC analyses, we identified a unique CD4 ATF7IP+ subtype that is markedly enriched in yaks. This subtype exhibits a stepwise increase in abundance across cattle, dzhos and yaks, establishing it as a hallmark subtype associated with high-altitude adaptation in yak. Subsequent intercellular communication analysis revealed that the CD4 ATF7IP+ subtype displayed the strongest ligand–receptor interactions with the pulmonary gCap endothelial subtype. We further demonstrate that GPI/AMF secreted by the CD4 ATF7IP+ subtype likely interacts with its receptor gp78/AMFR. This AMFR-mediated signaling pathway appears to depend on PI3K phosphorylation to drive AKT activation, which helps suppress ROS accumulation while maintaining pulmonary gCap viability and survival during hypoxia. Furthermore, treatment with recombinant GPI/AMF protein under hypoxic conditions reproduced these protective effects and partially substituted for CD4 ATF7IP+ co-culture. In conclusion, this study reveals a previously unrecognized pulmonary immune-endothelial axis that supports gCap cell stress resistance under hypoxia, providing potential molecular targets for the conservation of yak germplasm and selective breeding programs.