Ischemic stroke is a common cerebrovascular disease accompanied by a large number of neuronal death and severe functional impairment. In recent years, the role of ferroptosis and ferritinophagy in neuronal death after cerebral infarction has attracted great interest in the field of ischemic stroke. Ferroptosis is a newly discovered programmed cell death pattern characterized by iron overload, dysregulation of the xCT/GSH/GPX4 system, and lipid peroxidation system, which is closely associated with neurological damage after ischemic stroke. Ferritinophagy is a selective autophagy mediated by NCOA4 that regulates intracellular iron metabolism, and can be regulated by factors such as intracellular iron content and HERC2–FBXL5–IPR2 axis. Under normal physiological conditions, ferritinophagy maintains the balance of intracellular iron elements, and excessive activation can cause ferroptosis. Here, we mainly review the general mechanisms of ferroptosis and ferritinophagy, and focus on the relationship between ischemic stroke and ferroptosis/ferritinophagy. Specifically, we explored the crosstalk of ferroptosis and ferritinophagy in ischemic stroke and outlined current treatment strategies and key challenges. These observations may help to further understand the pathological events of ischemic stroke and bridge the gap between basic and translational research to provide novel insights for its treatment. Graphical Abstract

Background: Danhong injection (DHI), a standardized traditional Chinese medicine formulation, has shown clinical benefits in treating cerebrovascular diseases. Blood–brain barrier (BBB) disruption is a key pathological feature of ischemic stroke, but its modulation by DHI under hyperlipidemic conditions remains unclear. This study aimed to investigate the protective effects and mechanisms of DHI in cerebral ischemia/reperfusion injury (CI/RI) under hyperlipidemia, focusing on BBB integrity and the Wnt/β-catenin signaling pathway. Methods: Rats were divided into control, ischemic, hyperlipidemic, and treatment subgroups to evaluate DHI’s dose-dependent effects and pathway specificity using DKK1 inhibition. Assessments included neurological scores, TTC and Nissl staining, TEM, and molecular analyses (qRT-PCR/Western blot/immunofluorescence/immunohistochemistry). Results: DHI significantly improved neurological function, reduced cerebral infarct size, and alleviated cortical damage. DHI treatment upregulated the expression of tight junction proteins (Claudin-5, Occludin, ZO-1) and downregulated MMP-9 expression. Mechanistically, DHI promoted the nuclear translocation of β-catenin and increased the expression of Wnt3α, p-GSK-3β, and Cyclin D1, thereby activating the Wnt/β-catenin pathway. Additionally, DHI treatment increased the count of NeuN-positive neurons, suppressed astrocyte activation, and markedly reduced IgG infiltration in the ischemic cerebral cortex. These effects were reversed by DKK1. Conclusions: The results indicate that DHI protects BBB integrity and alleviates CI/RI in hyperlipidemic rats independently of direct lipid-lowering activity. Specifically, DHI activates the Wnt/β-catenin pathway by enhancing β-catenin nuclear translocation, which in turn mediates the upregulation of tight junction proteins and suppression of MMP-9, ultimately preserving BBB integrity. These findings support its therapeutic potential in ischemic stroke with comorbid hyperlipidemia.