Leucine-rich α2-glycoprotein1 (LRG1), a pleiotropic protein, plays a pathogenic role in multiple human diseases. However, its pathophysiological function in ischemia/reperfusion injury remains unclear. In this study, we discussed the function and mechanism of LRG1 in acute ischemic stroke from both basic and clinical research points of view. Mice underwent transient middle cerebral artery occlusion (tMCAO) surgery 2 weeks after LRG1 was overexpressed by the delivery of adeno-associated virus (AAV). For wild-type mice, both the protein and the transcript of LRG1 in the brain tissue were elevated after tMCAO. Meanwhile, the serum levels of LRG1 were decreased after tMCAO. The neuronal injury was shown aggravated in the AAV-LRG1 group (AAV-LRG1 mice with tMCAO) through infarction volume, neurological score, HE, and Nissl staining. Meanwhile, LRG1 significantly enhanced apoptosis and autophagy during tMCAO, as detected by caspase3, Bax, Bcl-2, LC3II/LC3I, Beclin1, p62, and a TUNEL assay. Furthermore, by overexpression of LRG1, the protein of ALK1 was upregulated and the TGFβ-smad1/5 signaling pathway was activated upon tMCAO. We also showed that patients with acute cerebral infarction had lower serum levels of LRG1 compared to healthy controls. In addition, LRG1 levels were associated with infarction volume, stroke severity, and prognosis in patients with supratentorial infarction. Taken together, the data from this study revealed that LRG1 promoted apoptosis and autophagy through the TGFβ-smad1/5 signaling pathway by up-regulating ALK1, which exacerbates ischemia/reperfusion injury VSports手机版. .