Degradation of LOX-1 via Neuronal Autophagy Alleviates Cerebral Ischemia/Reperfusion Injury in Mice.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is critically involved in atherosclerotic plaque formation. Recent clinical evidence suggest that the LOX-1 polymorphisms are linked to the susceptibility and outcomes of ischemic stroke (IS). However, the mechanisms through which LOX-1 influences cerebral ischemia/reperfusion (I/R) injury are not fully understood. In this study, blood samples were obtained from 295 patients with acute IS (AIS), and parallel experimental models including middle cerebral artery occlusion and reperfusion (MCAO/R) in male C57BL/6 mice and oxygen glucose deprivation (OGD) in primary neurons, were used to simulate cerebral I/R injury. Elevated serum soluble LOX-1 (sLOX-1) levels were detected in patients with AIS and showed positive correlations with both infarct volume and the 3-month modified Rankin scale (mRS) score. In mice, LOX-1 overexpression increased infarct volume, aggravated neurological deficits, and reduced cerebral blood flow (CBF), whereas LOX-1 knockdown produced the opposite effects. Co-immunoprecipitation demonstrated that LOX-1 interacts with key autophagy-lysosome pathway proteins (LC3B, P62, and LAMP2) in primary neurons. Western blotting, immunofluorescence and transmission electron microscopy showed that LOX-1 overexpression suppresses neuronal autophagic flux in peri-infarct brain tissue, while LOX-1 knockdown restores it. Moreover, early activation of autophagy with rapamycin (RAPA) promoted LOX-1 degradation, reduced infarct volume, improved neurological deficits, and restored CBF following cerebral I/R. Collectively, these findings indicated that LOX-1 exacerbates cerebral I/R injury by inhibiting neuronal autophagic flux. Early autophagy activation may therefore represent a promising neuroprotective strategy by facilitating LOX-1 degradation during acute cerebral ischemia.