The KLKB1-TFE3-BRAF/MEK/ERK axis regulates neuronal ferroptosis in vascular dementia

Increasing evidence suggests that ferroptosis has significant implications for the pathogenesis of vascular dementia (VaD). Although KLKB1 exacerbates neurological damage in VaD by promoting ferroptosis, the exact mechanism remains unclear. The aim of this study is to elucidate the specific pathway through which KLKB1 mediates ferroptosis in VaD and to identify effective therapeutic strategies.

Rat models of VaD were constructed by bilateral common carotid artery occlusion (BCCAO). Behavioral impairment in VaD rats was assessed, along with pathological damage to hippocampal neurons. Transcriptome sequencing, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Western blotting, and quantitative real-time polymerase chain reaction (qPCR) were used to identify the downstream pathways through which KLKB1 regulates ferroptosis. Immunoprecipitation-mass spectrometry (IP-MS), protein-protein interaction networks, coimmunoprecipitation (Co-IP), and immunofluorescence assays were used to screen for proteins that interact with KLKB1.

KLKB1 promotes ferroptosis in VaD model rats through its interaction with transcription factor E3 (TFE3). The knockdown of KLKB1 decreased TFE3 expression levels and suppressed ferroptosis through the inhibition of the BRaf/MEK/ERK signaling cascade. Consistent antiferroptotic effects were observed following TFE3 knockdown.

The KLKB1-TFE3-BRaf/MEK/ERK signaling axis represents a novel target for attenuating ferroptosis in VaD.