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  3. Mechanistic Study of S100A8-mediated Ferroptosis in Vascular Dementia Through the JAK2/STAT3 Pathway

Mechanistic Study of S100A8-mediated Ferroptosis in Vascular Dementia Through the JAK2/STAT3 Pathway

  • Appl Biochem Biotechnol. 2026 Jan 15. doi: 10.1007/s12010-025-05527-3.
XiaoYu Liu 1,  XiuMin Zhao 1,  BaiKe Zhu 1,  YanHong Yu 1,  MeiLing Sun 2,  HaiLing Lv 1,  Jun Zhang 1,  AiJu Liu 3
Affiliations

Affiliations

  • 1 Department of Neurology, Shandong Provincial Third Hospital, Shandong University, No.11, Wuyingshan Middle Road, Tianqiao District, Jinan City, 250031, Shandong Province, China.
  • 2 Department of Rehabilitation, Shandong Provincial Third Hospital, Shandong University, Jinan City, 250031, Shandong Province, China.
  • 3 Department of Neurology, Shandong Provincial Third Hospital, Shandong University, No.11, Wuyingshan Middle Road, Tianqiao District, Jinan City, 250031, Shandong Province, China. [email protected].
PMID: 41538098 DOI: 10.1007/s12010-025-05527-3
Abstract

Objective: To explore the mechanism of S100 Calcium Binding Protein A8 (S100A8)-mediated Ferroptosis in vascular dementia (VaD) via the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway.

Methods: To establish models of VaD and study microglial responses, we employed bilateral carotid artery stenosis (BCAS) in mice and oxygen-glucose deprivation (OGD) in BV2 cells, respectively. The cognitive function of mice was assessed by Morris water maze experiments. The pathological changes of brain tissue were observed by Nissl staining and luxol fast blue staining. Inflammatory cytokines were determined by enzyme-linked immunosorbent assay. The co-localization of S100A8 was identified by immunofluorescence. Ferroptosis was assessed by related indices such as intracellular Fe2+ content, Reactive Oxygen Species, mitochondrial membrane potential and lipid peroxidation. JAK2/STAT3 pathway activation was evaluated by Western blot.

Results: In BCAS mice, cerebral hypoperfusion triggered the upregulation of S100A8 in hippocampal microglia. This upregulation showed a progressive increase following surgery, peaking at 28 days post-BCAS. Inhibition of S100A8 improved cognitive deficits, attenuated brain damage, reduced neuroinflammation, and suppressed Ferroptosis in BCAS mice. In BV2 cells, S100A8 silencing alleviated inflammation and Ferroptosis induced by OGD. The anti-inflammatory effects of S100A8 silencing were counteracted by Erastin but amplified by Ferrostatin-1‌. Furthermore, S100A8 inhibition blocked JAK2/STAT3 activation; however, the JAK2/STAT3 agonist Colivelin TFA reversed the protective effects of S100A8 silencing in OGD-treated BV2 cells.

Conclusion: S100A8 mediates Ferroptosis in VaD via JAK2/STAT3 pathway.

Keywords

Chronic cerebral hypoperfusion; Ferroptosis; JAK2/STAT3; S100A8; Vascular dementia.

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