YBX1 promotes angiogenesis after myocardial infarction by stabilizing HIF1α mRNA via m6A 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 HIF1α signaling. YBX1 interacts with IGF2BP1/3 to stabilize HIF1α mRNA via m⁶A modification, with YBX1 depletion accelerating HIF1α mRNA decay. Collectively, YBX1 promotes post-MI angiogenesis and cardiac repair through an m⁶A-dependent IGF2BP1/3-HIF1α axis, establishing YBX1 as a therapeutic target for ischemic heart disease.