Nature's answer to Ferroptosis: how bioactive compounds rewire oxidative stress circuits in cerebral ischemia

Ischemic stroke is a cerebrovascular disease caused by the interruption of local blood flow in the brain. The mechanism of cerebral ischemia-reperfusion injury (CIRI) is complex and involves multiple pathological processes and signaling pathways. Ferroptosis, an iron-dependent regulated cell death form caused by excessive lipid peroxidation, is associated with the pathological occurrence and therapeutic response of various types of neurodegenerative diseases. Increased iron accumulation, free radical production, fatty acid supply, and lipid peroxidation are key factors in inducing ferroptosis. After acute ischemic stroke, the body experiences an over-accumulation of iron, lipid peroxidation, and reactive oxygen species in the cytoplasm by affecting neural system iron metabolism, lipid metabolism, and amino acid metabolism. This leads to the induction of ferroptosis. This article reviews the three metabolic pathways (iron metabolism pathway, amino acid metabolism pathway, lipid metabolism pathway, (seleno)thiol metabolism pathway, citric acid pathway, etc.) and multiple related regulatory signaling pathways (Nrf2 pathway; (hemi)cysteine/GSH/GPX4 pathway, NAD(P)H/FSP1/CoQ10 pathway; GCH1/BH4/DHFR signaling pathway; etc.) involved in ferroptosis occurrence in neural cells following acute ischemic stroke. It also highlights the changes in several key regulatory molecules, such as hypoxia-inducible factor-1α (HIF-1α), BTB and CNC homology 1 (BACH1), tumor suppressor gene p53, nuclear receptor coactivator 4 (NCOA4), and activating transcription factor 3 (ATF3), and the downstream mechanisms regulated by these molecules. Through an analysis of the potential mechanisms of ferroptosis occurrence and development in ischemic stroke, this article aims to provide reference for effective treatment of ischemic stroke and improvement of patient prognosis. Meanwhile, this review proposes a synergistic model of the "ferroptosis-oxidative stress-neuroinflammation" triad in ischemic stroke for the first time, providing a theoretical foundation for the development of neuroprotective agents based on natural compounds.