CKLF1介导脂质过载卒中模型的内皮细胞线粒体损伤与血管重塑障碍OA

Aim Post-stroke vascular remodeling is fundamental for neurological recovery but is often im-paired in obese patients through poorly understood mo-lecular mechanisms.This study aims to elucidate the pathological role of chemokine-like factor 1(CKLF1)in impaired post-stroke revascularization under lipid overload conditions,to investigate the underlying mito-chondrial mechanisms,and to evaluate the potential of targeted intervention.Methods We established a mu-rine model using a high-fat diet combined with distal middle cerebral artery occlusion(dMCAO)and an in vitro model of endothelial lipid overload induced by palmitic acid(PA).A comprehensive approach,in-cluding behavioral assessments,two-photon in vivo im-aging,transcriptomic sequencing,and mitochondrial function analysis,was used to investigate the role of CKLF1.A neutralizing antibody against CKLF1 was used for interventional validation.Results Lipid over-load significantly exacerbated sensorimotor deficits and suppressed peri-infarct revascularization in dMCAO mice,accompanied by an abnormal upregula-tion of CKLF1 in brain tissue.Mechanistically,CKLF1 led to severe mitochondrial network fragmenta-tion,dissipation of mitochondrial membrane potential,and bursts of oxidative stress in endothelial cells.We identified a pathological crosstalk between CKLF1 and the PINK1/PRKN-mediated mitophagy pathway,lead-ing to aberrant expression of related proteins(PINK1,PRKN,SQSTM1).Application of the CKLF1 neutral-izing antibody effectively reversed this mitochondrial dysfunction and impairment of revascularization.Con-clusions CKLF1 is a key pathogenic factor that medi-ates the lipid overload-induced exacerbation of post-stroke revascularization and neurological recovery.It exerts its damaging effects by disrupting mitochondrial homeostasis in endothelial cells,suggesting that CKLF1 may be an effective therapeutic target for pro-moting stroke recovery in the obese population.