Fosl2/c-Jun dimer induces oxidative stress and endoplasmic reticulum stress by enhancing Lcn2 transcription to promote ischemic cerebral infarction.

Ischemic cerebral infarction (ICI) results in high disability and mortality rates. This study aims to validate that the Fosl2/c-Jun dimer promotes ICI via the transcriptional activation of Lcn2. Differentially expressed genes were identified and screened in the microvasculature of sham-operated and transient middle cerebral artery occlusion/reperfusion (tMCAO/R) mouse brains through bioinformatics analysis. Mouse models were established via tMCAO/R surgery, while mouse brain-derived Endothelial cells.3 (bEnd.3) were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R). Fosl2 and c-Jun expression levels were detected, and their interaction was validated. Knockdown of Fosl2 or c-Jun was performed in tMCAO/R mice and bEnd.3 cells, followed by detection of AP-1 transcriptional activity, oxidative stress levels, infarct extent, blood-brain barrier integrity, and endoplasmic reticulum stress (ERS)-related proteins. The downstream target of Fosl2 was predicted using bioinformatics databases. Lcn2 expression was detected via RT-qPCR and Western blot. The transcriptional regulatory relationship was validated through dual-luciferase and ChIP assays. Fosl2, c-Jun, and Lcn2 were highly expressed in mouse and cell models of ICI. Fosl2 interacted with c-Jun, and the Fosl2/c-Jun dimer transcriptionally activated Lcn2 by binding to its promoter. Fosl2 or c-Jun knockdown reduced cerebral infarction volume, alleviated blood-brain barrier injury, and suppressed oxidative stress and ERS. Overexpression of Lcn2 partially attenuated the suppressive effects of Fosl2 or c-Jun knockdown. Fosl2/c-Jun dimer induces Lcn2 transcription activation to promote oxidative stress and ERS, thereby contributing to ICI. This study reveals a potential mechanism for the clinical treatment of ICI.