biostudies-literatureBi FNatural Science Foundation of Xiamen MunicipalityNational Natural Science Foundation of ChinaHarbin Medical UniversityDepartment of Education, Fujian Province114810https://www.ebi.ac.uk/biostudies/studies/S-EPMC12924730biostudies-literatureUnknown29(3)Angiogenesis is essential for myocardial repair after myocardial infarction (MI). While Y-box binding protein 1 (YBX1) is well-established in cancer biology, its role in post-MI angiogenesis remains unknown. Here, we show that YBX1 expression is increased in endothelial cells after MI, with higher levels observed in the peri-infarct region, and is also induced in hypoxic HUVECs. <i>In vitro</i>, YBX1 overexpression enhances HUVEC viability, migration, and proliferation, whereas siRNA-mediated knockdown impairs these functions. <i>In vivo</i>, endothelial-specific AAV9-YBX1 delivery improves cardiac function, reduces fibrosis, and enhances angiogenesis in murine MI models, while AAV9-shYBX1 exacerbates cardiac injury. Mechanistically, RNA sequencing reveals that YBX1 deficiency disrupts HIFiScienceYBX1 promotes angiogenesis after myocardial infarction by stabilizing HIF1α mRNA via m&lt;sup&gt;6&lt;/sup&gt;A signaling.PMC1292473082470248HYDYYXQN202405210482821702993502Z202373125Liu HCao MLi JShan HTian HWang HKong CZhou YBi FHe YXiao HYu TLiu FWu YfalseYBX1 promotes angiogenesis after myocardial infarction by stabilizing HIF1α mRNA via m&lt;sup&gt;6&lt;/sup&gt;A signaling.Angiogenesis is essential for myocardial repair after myocardial infarction (MI). While Y-box binding protein 1 (YBX1) is well-established in cancer biology, its role in post-MI angiogenesis remains unknown. Here, we show that YBX1 expression is increased in endothelial cells after MI, with higher levels observed in the peri-infarct region, and is also induced in hypoxic HUVECs. <i>In vitro</i>, YBX1 overexpression enhances HUVEC viability, migration, and proliferation, whereas siRNA-mediated knockdown impairs these functions. <i>In vivo</i>, endothelial-specific AAV9-YBX1 delivery improves cardiac function, reduces fibrosis, and enhances angiogenesis in murine MI models, while AAV9-shYBX1 exacerbates cardiac injury. Mechanistically, RNA sequencing reveals that YBX1 deficiency disrupts HIF2026-01-01T00:00:00Z2026 Mar2026-07-16T18:48:29.069Z2026-07-12T03:08:35.763ZS-EPMC129247304173227810.1016/j.isci.2026.114810