TNFSF9 Silence Impedes Cerebral Ischemia-Reperfusion Injury via Modulating SLC3A2 Expression in Brain Microvascular Endothelial Cells.

Cerebral ischemia-reperfusion injury (CIRI), which stays unresolved in the clinic, occurs after recanalization of blood vessels serving brain tissues in acute ischemic stroke patients and can result in massive brain cell death, and cell ferroptosis contributes greatly to this process. Our research firstly found that TNFSF9 expression harbored diagnostic value on CIRI patients and intended to further investigate its regulatory mechanism in CIRI, which might facilitate its diagnostic and therapeutic application in the clinic. The level of TNSF9 mRNA was augmented in the plasma of CIR patients, and its silence impeded ferroptosis, apoptosis, and release of inflammatory mediators of BMECs with OGD/R treatment. Besides, SP1 positively regulated TNFSF9 expression as one of its transcription factors, and TNFSF9 overexpression reversed SP1 silence-mediated inhibition on ferroptosis, apoptosis, and release of inflammatory mediators in OGD/R-treated BMECs. In addition, silencing SLC3A2 could neutralize the benefit effects of TNFSF9 downregulation on BMECs under OGD/R context in vitro, and silencing TNFSF9 neutralized necrotic volumes in rat brain induced by CIRI via modulating SLC3A2 expression in vivo. TNFSF9 regulated by SP1 aggravated CIRI via boosting ferroptosis, apoptosis, and release of inflammatory mediators of BMECs under OGD/R situation by suppressing SLC3A2 expression in vitro and in vivo.