Sex-biased RNA editing in Tibetan Placentas enhances hypoxia adaptation via developmental and immune pathways

Background Tibetans have evolved remarkable reproductive fitness at high altitudes, yet the underlying molecular mechanisms remain poorly understood. RNA editing, a dynamic posttranscriptional modification, is increasingly recognized as a key regulator of environmental adaptation, but its role in high-altitude reproductive adaptation remains uncharacterized. Here, we systematically profiled RNA editing landscapes across seven placental tissues from 35 indigenous Tibetans and 35 Han immigrants residing at high altitudes, combined with sex-stratified analyses and hypoxic challenge experiments in human umbilical vein endothelial cells (HUVECs). Results Tibetan placentas exhibited globally elevated RNA editing levels, with the most pronounced differences in the amnion and chorion, and male infants showing greater population-specific variation. Differential editing sites (DESs) in these tissues were enriched in pathways critical for fetal survival under hypoxia, including protein synthesis, embryonic development, and immunity—notably, RNA editing of FAM20B may modulate extracellular matrix remodeling to enhance nutrient exchange. Sex-stratified analyses revealed striking sexual dimorphism: male-specific DESs were enriched in immune regulation and apoptosis pathways (e.g., CTSB editing, which balances lysosomal activity to promote hypoxia tolerance), while female-specific DESs were concentrated in iron metabolism (e.g., SPPL2A ) and neurodevelopment pathways. Co-editing network analysis linked male chorion editing to amniotic fluid depth and female chorion editing to placental volume, directly associating RNA editing with fetal phenotypic traits. Hypoxic challenges in HUVECs recapitulated these editing patterns, confirming evolutionary conservation. Conclusions Our findings demonstrate that sex-biased RNA editing fine-tunes placental function via developmental, immune, and metabolic pathways, representing a novel posttranscriptional regulatory layer in high-altitude adaptive evolution. This work advances understanding of the genetic architecture of hypoxia tolerance and highlights RNA editing as a potential driver of adaptive phenotypic divergence.