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. 2025 Jun 21;40(6):231.
doi: 10.1007/s11011-025-01660-4.

Tanshinone IIA inhibits neuronal ferroptosis and relieves cerebral ischemia‒reperfusion injury by regulating miR-449a/ACSL4

Huimin Yu #  1 , Yili Li #  1 , Yuehong Yang  1 , Yanjin Qian  1 , Xia Gao  1 , Xichan Wang  1 , Ping Zhan  1 , Dekun Tang  1 , Mei Qin  1 , Yan Qian  2
Affiliations

Tanshinone IIA inhibits neuronal ferroptosis and relieves cerebral ischemia‒reperfusion injury by regulating miR-449a/ACSL4

Huimin Yu et al. Metab Brain Dis. .

Abstract

Cerebral ischemia‒reperfusion injury (CI/RI) plays a significant role in the initiation of ischemic stroke. This study aimed to explore the influence of Tan (tanshinone) IIA in the treatment of neuronal ferroptosis induced by CI/RI, along with the associated molecular mechanisms. A CI/RI model was created by occluding the middle cerebral artery in rats (MCAO/R). A cellular CI/RI model was established with SH-SY5Y cells that were subjected to oxygen‒glucose deprivation followed by subsequent reperfusion (OGD/R). The optimal concentration for maintaining cell viability was evaluated through the CCK-8 assay. The expression levels of ferroptosis and oxidative stress-related genes in rat brain tissue and SH-SY5Y cells were determined, and the molecular mechanism by which Tan IIA regulates ferroptosis during CI/RI treatment was verified by bioinformatics analysis, RT‒qPCR, and dual-luciferase reporter assays. The results revealed that Tan IIA relieved CI/RI injury and inflammation by inhibiting ferroptosis in MCAO/R rat brain neurons. Our experimental results demonstrated that Tan IIA suppressed the progression of OGD/R and alleviated inflammation in SH-SY5Y cells. Ferroptosis affected the concentrations of Fe2+, ROS, and MDA in the CI/RI model while simultaneously increasing the expression of miR-449a. In terms of the molecular mechanism, Tan IIA inhibited OGD/R-induced neural ferroptosis, and this mechanism of action may involve Tan IIA promoting the downregulation of ACSL4 expression by targeting miR-449a within cells, thereby inhibiting ferroptosis in cells induced by OGD/R. Our research results indicate that Tan IIA relieved CI/RI injury and inflammation by alleviating neuronal ferroptosis, and this regulatory effect may be achieved through the miR-449a/ACSL4 molecular axis.

Keywords: Cerebral ischemia‒reperfusion injury; Ferroptosis; MiR-449a/ACSL4; Neuronal cells; Tan IIA.

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Conflict of interest statement

Declarations. All animal experimental protocols were approved by the Animal Experiment Ethics Committee, and the animal procedures adhered to the ARRIVE guidelines 2.0. Competing interests: The authors declare no competing interests.

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