Progress of Traditional Chinese Medicine in Targeting Ferroptosis to Combat Cerebral Ischemia–Reperfusion Injury

Cerebral ischemia-reperfusion injury (CIRI) often results in significant morbidity and mortality. The effectiveness of current reperfusion therapies is hindered by substantial secondary damage, which highlights the need for novel molecular targets and neuroprotective strategies. Ferroptosis, a form of programmed cell death driven by iron dysregulation and lipid peroxidation, has emerged as a key player in CIRI pathogenesis. Traditional Chinese medicine (TCM) has demonstrated considerable potential in managing IS, and increasing evidence suggests its neuroprotective effects are primarily mediated through modulation of ferroptotic pathways. This review evaluates the efficacy of various TCM approaches in combating CIRI, and offers a specific focus on the roles of active compounds (e.g., astragaloside IV, rhein, baicalein, ginkgolide B, and berberine), classic herbal formulas (e.g., Buyang Huanwu Decoction, Tongqiao Huoxue Decoction, and Naotaifang), and acupuncture therapies. This review outlines how these interventions attenuate CIRI by targeting critical ferroptosis-related mechanisms. These mechanisms include enhancing anti-oxidant defenses (Nrf2/SLC7A11/GPX4), modulating lipid metabolism (ACSL4), restoring iron homeostasis, and maintaining the ischemic microenvironment (including blood-brain barrier integrity and microglial polarization). However, current research faces challenges such as the insufficient understanding of the pharmacological basis of complex formulas, unclear dose-response relationships, and a lack of comprehensive validation along the "ingredient-target-phenotype" continuum. Future research should focus on leveraging advanced technologies - such as network pharmacology, multi-omics, and artificial intelligence - to unravel the antiferroptotic networks of TCM. Such integrative approaches will drive the modernization of TCM and facilitate the development of precision medicine to thus present new opportunities for neuroprotection in CIRI.