Icaritin alleviates cerebral ischemia-reperfusion injury by reducing ferroptosis via inhibiting excessive mPTP opening

This is a preprint and has not been peer reviewed. Data may be preliminary. Icaritin alleviates cerebral ischemia-reperfusion injury by reducing ferroptosis via inhibiting excessive mPTP opening Abstract The narrow therapeutic window of reperfusion therapy highlight the urgent need for novel neuroprotective strategies against ischemic stroke, wherein ferroptosis is a key contributor to neuronal death in the ischemic penumbra. This study demonstrates that icaritin (ICT) treatment significantly improved functional outcomes, reduced infarct size,and enhanced neuronal viability in middle cerebral artery occlusion (MCAO) rats and oxygen-glucose deprivation and reoxygenation (OGD/R) PC-12 cells. Transcriptomic and biochemical analyses confirmed that ICT’s neuroprotection was associated with the suppression of ferroptosis. Mechanistically, ICT inhibited pathological mitochondrial permeability transition pore (mPTP) opening, thereby preserving mitochondrial membrane potential and attenuating reactive oxygen species (ROS) production. This action was essential, as the protective effect was mimicked by cyclosporin A (CsA) and abolished by lonidamine (LND). Molecular docking revealed stable binding of ICT to voltage-dependent anion channel (VDAC) and cyclophilin D (CypD.) In conclusion, ICT confers neuroprotection by inhibiting mPTP excessive opening, which in turn blocks the downstream ferroptosis cascade. This work elucidates a detailed mechanism for ICT and validates the “mPTP-ferroptosis” axis as a promising therapeutic target for ischemic stroke. Supplementary Material File (figure1.tif) - Download - 5.44 MB File (figure10.tif) - Download - 1.75 MB File (figure2.tif) - Download - 771.64 KB File (figure3.tif) - Download - 2.91 MB File (figure4.tif) - Download - 2.26 MB File (figure5.tif) - Download - 1.30 MB File (figure6.tif) - Download - 1.05 MB File (figure7.tif) - Download - 2.33 MB File (figure8.tif) - Download - 1.42 MB File (figure9.tif) - Download - 3.96 MB File (manuscript.docx) - Download - 84.32 KB Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Metrics & Citations Metrics Article Usage 136views 63downloads Citations Download citation Tianlun Wang, Wenjing Dai, Yuanqi Yu, et al. Icaritin alleviates cerebral ischemia-reperfusion injury by reducing ferroptosis via inhibiting excessive mPTP opening. Authorea. 26 March 2026. DOI: https://doi.org/10.22541/au.177452353.30311359/v1 DOI: https://doi.org/10.22541/au.177452353.30311359/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.