Telomeres are nucleoprotein structures located at the end of each chromosome, which function in terminal protection and genomic stability. Telomeric damage is closely related to replicative senescence in vitro and physical aging in vivo. As relatively long-lived mammals based on body size, bats display unique telomeric patterns, including the up-regulation of genes involved in alternative lengthening of telomeres (ALT), DNA repair, and DNA replication. At present, however, the relevant molecular mechanisms remain unclear. In this study, we performed cross-species comparison and identified EPAS1, a well-defined oxygen response gene, as a key telomeric protector in bat fibroblasts. Bat fibroblasts showed high expression of EPAS1, which enhanced the transcription of shelterin components TRF1 and TRF2, as well as DNA repair factor RAD50, conferring bat fibroblasts with resistance to senescence during long-term consecutive expansion. Based on a human single-cell transcriptome atlas, we found that EPAS1 was predominantly expressed in the human pulmonary endothelial cell subpopulation. Using in vitro-cultured human pulmonary endothelial cells, we confirmed the functional and mechanistic conservation of EPAS1 in telomeric protection between bats and humans. In addition, the EPAS1 agonist M1001 was shown to be a protective compound against bleomycin-induced pulmonary telomeric damage and senescence. In conclusion, we identified a potential mechanism for regulating telomere stability in human pulmonary diseases associated with aging, drawing insights from the longevity of bats.
端粒是位于染色体末端的核酸-蛋白复合结构，在染色体末端保护和基因组稳定性中发挥重要功能。端粒损伤与细胞衰老和机体衰老均密切相关。作为长寿哺乳动物，蝙蝠表现出独特的端粒调控模式，例如显著上调端粒选择性延长(ALT)通路、DNA修复通路和DNA复制通路众多关联基因的表达水平。然而，具体的上游促进因子仍不清楚。该研究通过跨物种比较解析，确定经典的低氧响应因子EPAS1在蝙蝠端粒保护中发挥重要功能。蝙蝠成纤维细胞持续高表达EPAS1。EPAS1促进端粒蛋白复合体（shelterin）核心组分TRF1和TRF2，以及DNA修复因子RAD50的转录表达，使蝙蝠成纤维细胞在长期连续扩增过程中保持端粒稳定，避免细胞衰老。通过挖掘人类肺脏单细胞转录组图谱，发现EPAS1主要表达于人肺内皮细胞亚群，且在60至70岁人群的肺内皮细胞中的表达量显著降低。利用体外培养的人肺内皮细胞模型和博来霉素诱导的活体小鼠肺损伤模型，证实EPAS1在蝙蝠和人端粒保护中的功能和机制高度保守，发现外源添加EPAS1激动剂M1001能够显著改善博莱霉素诱导的肺端粒损伤和衰老表型。综上所述，该研究聚焦蝙蝠端粒特征，发现了EPAS1在端粒保护中的新功能和新机制，评估了化合物M1001在端粒稳定和抗衰老中的应用价值，强调了从长寿物种蝙蝠中发掘抗衰老新策略的路径可行性。.
Keywords: Bat; EPAS1; M1001; Pulmonary endothelial cell; Senescence; Telomere.