Iron is crucial for numerous biological functions in the brain, playing key roles in processes like mitochondrial respiration, myelin formation, neurotransmitter production, and other cellular functions (22). Disruptions in iron homeostasis, leading to iron accumulation, can compromise these functions. In the context of cerebral I/R, ischemia causes the release and accumulation of iron in neurons and glial cells (23). Subsequent reperfusion, which reestablishes blood flow, induces oxidative stress and inflammatory responses, thereby exacerbating iron accumulation. Excess iron can generate highly reactive hydroxyl radicals via the Fenton reaction. These radicals attack the lipid components of cell membranes, intensifying LPO and ultimately leading to ferroptosis (24, 25). In response to hypoxic injury resulting from cerebral ischemia, levels of hypoxia-inducible factor 1-alpha (HIF-1α) significantly rise, which increases iron uptake through TfR1 (26). Research has shown that patients who have suffered a stroke demonstrate markedly higher serum levels of iron and hepcidin, leading to decreased expression of FPN, reduced iron export (27), and subsequent build-up of iron, thereby creating conditions conducive to ferroptosis (28). Additionally, the compromised integrity of the blood-brain barrier (BBB) allows a greater influx of circulating iron into the brain tissue (29). In the transient middle cerebral artery occlusion (tMCAO) model, following oxygen-glucose deprivation (OGD), transferrin leaks across the BBB, and after ischemic events, DMT-1 levels in the affected brain region double, causing an accumulation in neighboring neurons (30).

Uncontrolled LPO is a significant factor leading to the destruction of cellular membrane structures and is a primary contributor to the process known as ferroptosis (31). LPO is an oxidative process targeting polyunsaturated fatty acids (PUFAs), triggered by free radicals. PUFAs are essential for maintaining the fluidity and flexibility of cell membranes, which is vital for effective signal transmission within neural pathways (32). However, due to the presence of unstable double bonds, PUFAs are highly prone to oxidation, subsequently making them major contributors to LPO (33). During this process, lipid peroxides form through a chemical interaction among lipids, oxygen, and iron. Once these lipid peroxides are generated, they interact with Fe2⁺, resulting in the formation of peroxyl radicals. These radicals further extract hydrogen atoms from adjacent acyl chains in the membrane, thereby propagating the LPO cycle. This reaction not only undermines the structural integrity of cell membranes but also diminishes their functionality (31).

In the particular case of cerebral I/R, the overexpression of ACSL4 promotes the acylation of PUFAs such as arachidonic acid (AA) and adrenic acid (AdA), increasing their abundance in the cell membrane. This heightened presence makes the membrane more sensitive to oxidative stress, leading to LPO and exacerbating ferroptosis in ischemic brain injury. Conversely, knockout of ACSL4 provides protective effects for mice, significantly mitigating the associated brain damage caused by ischemic events (34). Enzymatic reactions also play a vital role in promoting LPO; for instance, the enzyme 12/15- LOX is found to be highly expressed and converts AA into 12/15-HETE, thus intensifying LPO in the pMCAO mouse model of cerebral I/R. Inhibiting this enzyme with a specific inhibitor, known as LOX Block-1 (LB-1), has proven effective in reducing LPO and significantly decreasing the infarct volume in these models (25). Moreover, studies have indicated that COX-2 and its product, prostaglandin E2 (PGE2), have the potential to exacerbate LPO in cerebral tissues, and that the inhibition of COX-2/PGE2 expression can significantly reduce the impacts of ferroptosis within the brain (35).

The antioxidant system markedly lowers levels of LPO by effectively neutralizing ROS and free radicals, thereby shielding cells from oxidative damage (36). The XC-System/GSH/GPx4 pathway is a critical component in the cellular defense against ferroptosis, a form of regulated cell death characterized by the accumulation of lipid peroxides (37). This protective mechanism centers around the XC-System, which consists of the cystine/glutamate antiporter formed by the proteins SLC7A11 and SLC3A2. These proteins regulate the balance of amino acids inside and outside the cell to synthesize GSH, thereby maintaining antioxidant status (38). In cases of cerebral I/R injury, there is a notable increase in the production of ROS, which can overwhelm the cellular defenses and hinder the functionality of the XC-System/GSH/GPx4 pathway (39). When the components of this pathway are compromised, the body’s overall antioxidant capacity is notably diminished. This decline contributes to an accelerated progression of LPO, which is detrimental to cell viability (40). However, the transcription factor Nrf2 has been identified as a key regulator in this context, as it can stimulate the expression of SLC7A11. When Nrf2 activates SLC7A11, it enhances the activity of the XC-System, leading to an increase in the expression levels of both GSH and GPx4. The subsequent upregulation of these components significantly fortifies the antioxidant defense system, thereby effectively countering lipid peroxidation and inhibiting ferroptosis, illustrating the pathway’s vital role in cellular resilience against oxidative stress (41, 42).

Neurons possess a remarkable susceptibility to ischemic conditions, which leads to a swift process of neuronal death. This neuronal demise prompts the release of various endogenous molecules, including ATP, UTP, HMGB1, HSPs, and others that act as DAMPs. These DAMPs are crucial because they are detected by immune cells utilizing pattern recognition receptors such as Toll-like receptors and NOD-like receptors. When these receptors recognize the DAMPs, they trigger the activation of inflammatory signaling pathways. This cascade results in the secretion of additional factors that intensify both localized and systemic inflammatory responses, thereby exacerbating the overall inflammatory condition in the affected tissues (46, 47). Microglia, which serve as the brain’s intrinsic immune defenders, play a critical role in surveilling and sustaining internal equilibrium under normal resting conditions (48). Upon the onset of cerebral ischemia, these microglial cells respond swiftly, transforming their morphology to an amoeboid shape within minutes. They possess the ability to polarize into two distinct phenotypes: the pro-inflammatory M1 and the anti-inflammatory M2 (49, 50). This polarization allows microglia to effectively regulate the inflammatory response, tailoring their actions to the specific needs of the surrounding environment. Following the initial injury to neurons, the damaged cells release a chemokine known as CX3CL1, also referred to as fractalkine. This signaling molecule is recognized by the CX3CR1 receptor expressed on microglial cells, facilitating communication between the damaged neurons and the immune response (51). As a result, the activated microglia migrate to the site of injury, where they actively engulf and eliminate dead cells and cellular debris. This phagocytic activity is vital as it not only helps clear away the remnants of damage but also plays a crucial role in preventing additional cell injury and the further propagation of inflammation in the affected area (52). Astrocytes serve a crucial and multifaceted regulatory function in the context of cerebral I/R. Their roles encompass the modulation of inflammatory responses, the maintenance of the BBB, and the regulation of iron homeostasis (53). Following an episode of cerebral ischemia, the release of cytokines by both neurons and microglia occurs within hours, which triggers the activation and reactive proliferation of astrocytes (54). This rapid response is critical for mitigating brain damage. Activated astrocytes exhibit the ability to polarize into two distinct phenotypes: the pro-inflammatory “A1” and the anti-inflammatory “A2” (55). At the onset of astrocytic activation, the predominant focus is on facilitating a pro-inflammatory response. This initial response aims to swiftly clear areas of brain damage. Simultaneously, it seeks to control excessive inflammation, thereby protecting neurons from sustaining further injury (47).

NF-κB functions as a crucial hub in the process of inflammation, playing a significant role in inflammatory responses, as depicted in Figure 3 . In the context of cerebral I/R, NF-κB engages with pathways including Nrf2 and NLRP3 to modulate inflammation (56, 57). TLR4, which is mainly found in microglia, triggers the activation of NF-κB via signaling pathways, thereby promoting microglial activation and subsequent inflammatory responses (58, 59). Additionally, the TLR4/NF-κB signaling axis is implicated in mediating inflammatory responses within type A1 astrocytes (60). The anti-inflammatory mechanism involving Nrf2 elevates cellular HO-1 levels through gene transcription driven by antioxidant response elements (ARE) while simultaneously promoting the degradation of IκB-α by the proteasome. This action inhibits the translocation of NF-κB into the nucleus, thereby contributing to the regulation of inflammation (61).

As a key downstream target of NF-κB, the NLRP3 inflammasome functions as an essential mediator in post-ischemic inflammation, leading to a series of inflammatory responses and consequent cell death (62). Gong et al. showed that (63) the activation of the NLRP3 inflammasome occurs initially in microglia following brain I/R injury, with further expression identified in microvascular endothelial cells and, notably, in neurons. Although the primary expression of NLRP3 is found in microglia, there is growing evidence suggesting its activation in astrocytes following I/R injury, where NLRP3 activation might lead to the neurotoxic reprogramming of astrocytes (64). Hence, the modulation of NLRP3 presents considerable therapeutic promise for managing inflammation linked to cerebral I/R.

The JAK2/STAT3 signaling pathway is critical in mediating inflammatory responses, with TNF-α and IL-6 serving as major activators. These cytokines activate microglia and astrocytes in ischemic areas, affecting the expression of various inflammatory factors that contribute to brain damage caused by I/R injury (65, 66). In the setting of cerebral I/R, IL-6 functions as an initiator that fosters STAT3 phosphorylation, setting off a signaling cascade that triggers metabolic reprogramming in reactive astrocytes (67). Additionally, the interplay between the STAT3 and NF-κB pathways can amplify the activation of M1 microglia and reactive astrocytes, thus worsening neuroinflammation (68). — This revision maintains the original ideas while ensuring that phrases are restructured and synonyms are used where appropriate to avoid duplication concerns.

In cerebral I/R, the activation of glial cells and associated signaling pathways leads to iron accumulation, LPO, and decreased activity of the antioxidant system, forming critical pathways for inflammation-induced ferroptosis (73), as depicted in Figure 4 .

The buildup of iron ions enhances oxidative stress, leading to a significant increase in the generation of lipid peroxides and ROS. These oxidative byproducts not only inflict direct harm to cellular components but also trigger and escalate inflammatory responses via multiple pathways, which in turn inflicts additional damage on brain tissue (71), as demonstrated in Figure 5 .

Glycyrrhizin, a key ingredient found in the traditional herb licorice, acts as a blocker of HMGB1 and is utilized in treating cerebral I/R (123). Research by Zhu et al. demonstrated that (124) glycyrrhizin lowers the levels of TNF-α, IL-6, and IL-1β through the HMGB1/GPX4 pathway, effectively preventing neuroinflammation-related neuronal ferroptosis and alleviating damage from cerebral ischemic hypoxia. Icariin II, which is the main active component of the traditional herb horny goat weed, possesses anti-inflammatory, antioxidant, anti-ferroptotic, and anti-apoptotic attributes in the context of cerebral I/R (125). According to a study by Gao et al. (91), prior treatment with icariin II in astrocytes notably enhances Nrf2 expression, which subsequently reduces the secretion of IL-1β, IL-6, and TNF-α via the OXPHOS/NF-κB pathway. This mechanism leads to diminished production of mitochondrial ROS, MDA, and iron following ischemic stroke, while also increasing the ratios of NADPH/NADP, enhancing SOD2 activity, elevating GPX4 levels, and boosting SIRT5 activity, thereby averting LPO-triggered ferroptosis. These results suggest that icariin lessens inflammation-related ferroptosis through the Nrf2/OXPHOS/NF-κB pathway, offering significant neuroprotection after ischemic stroke. Findings from Zhang et al. indicate that (126) dimethyl fumarate (DMF), an activator of Nrf2, promotes the upregulation of IκBα while inhibiting the NF-κB pathway, resulting in increased expression of crucial ferroptosis mediators, including HO-1, NQO1, and GPx4, thereby safeguarding cells from oxidative stress and ferroptosis. Additionally, recent studies on cerebral I/R have demonstrated that (127) the Nrf2 activator sulforaphane (SFN) enhances the levels of Occludin and ZO1, which helps maintain the integrity of the blood-brain barrier (BBB). SFN also leads to decreased levels of NF-κB, IL-18, and IL-1β, diminishes inflammation, alleviates Fe2⁺ concentrations, and boosts GSH and GPX4 levels, ultimately mitigating ferroptosis and reducing iron buildup through the enhancement of the antioxidant defense system. Oxysophoridine (OSR), a bioactive alkaloid sourced from sophora flowers, displays antioxidant and anti-inflammatory characteristics while providing protection against cerebral I/R damage in mice (128, 129). The TLR/p38 MAPK pathway is acknowledged for its crucial role in modulating inflammation during cerebral I/R (130). Recent research indicates that (131) OSR restrains the activity of the TLR4/p38 MAPK signaling pathway in rats experiencing MCAO, resulting in a decrease in Fe2⁺ accumulation and a marked downregulation of ACSL4 and TFR1 protein levels. Simultaneously, OSR upregulates levels of FTH1 and GPx4, thereby countering ferroptosis. Salvia miltiorrhiza, commonly known as Danshen, is extensively employed in the treatment of cerebrovascular disorders owing to its properties that include anticoagulant, antioxidant, anti-inflammatory, and anti-apoptotic effects (132). It comprises active compounds like salvianolic acid B and tanshinone IIA, although their precise constituents remain to be thoroughly elucidated (133, 134). In a mouse model of tMCAO, the administration of Danshen markedly suppresses the activation of microglia and astrocytes, leads to a downregulation of TNF-α and IL-6 expressions, as well as the phosphorylation of STAT3. This sequence of events mitigates neuroinflammation-induced upsurge in ROS and ACSL4 levels, while also decreasing GPX4 and FPN1, thus providing an inhibition of ferroptosis, sustaining synaptic integrity, and lessening neuronal death. These actions illustrate lasting neuroprotection in the aftermath of ischemic brain damage (135). Nao Tai Fang (NTF), which is made up of traditional Chinese medicinal components like Astragalus, Chuanxiong, Dilong, and Jiangcan, has been found to safeguard rats against neuronal ferroptosis triggered by acute cerebral ischemia (136, 137). Research by Liao et al. revealed that (86) key active ingredients in Nao Tai Fang, such as ferulic acid, Ligustilide, astragaloside IV, and tetramethylpyrazine, impede M1 microglia polarization while encouraging M2 polarization. This adjustment results in a reduction of IL-1β and IL-6/STAT3 expression alongside an increase in IL-10 secretion. Additionally, NTF attenuates Fe2⁺ buildup and the excessive production of ROS induced by LPO through the BMP6/SMADs signaling pathway associated with iron metabolism, all while boosting the levels of GSH and GPx4, thereby inhibiting ferroptosis.

Caffeic Acid (CA), a naturally occurring phenolic compound generally found in medicinal plants, serves as an inhibitor of COX-2/PGE2 (138). In studies involving the pMCAO rat model, CA has been shown to hinder the activation of COX-2 induced by ferroptosis and reduce the associated increase in ROS, thus preventing the activation of both microglia and astrocytes. Moreover, CA diminishes the release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, effectively reversing the damage resulting from cerebral I/R (139). Furthermore, it has been shown that CA acts as a 5-LOX inhibitor, mitigating inflammation related to brain I/R (140). In rat models, CA administration leads to a reduction in 5-LOX expression, downregulating NF-κB p65 activation, and decreasing the release of iNOS (141). Researchers, including Keuters (142), have discovered a novel small molecule, ADA-409-052, which features an arylthiazine framework and inhibits LPO, thereby preventing neuronal cell death caused by GSH depletion or GPx4 inhibition. In addition, ADA-409-052 curtails the pro-inflammatory activation of BV2 microglia, lessens the release of TNF-α, IL-6, and IL-1β, and provides protection to N2a neuronal cells from inflammation-induced cell death mediated by RAW 264.7 macrophages. Similar to well-established ferroptosis inhibitors like Fer-1, which can alleviate neuroinflammation (143), ADA-409-052 interacts with the COX-2/PGE2 pathway to target ferroptosis, helping to reduce both severe neuronal injury and inflammation, making it a potential therapeutic approach for neurological disorders (142). Edaravone represents a highly effective neuroprotective agent that functions as a potent scavenger of free radicals, thereby inhibiting both ferroptosis and inflammation associated with ischemic stroke (144, 145). Recent studies have shown that following cerebral I/R, there is a notable decrease in the expression levels of Nrf2 and FPN; however, these alterations can be reversed with edaravone treatment (146). This therapeutic intervention not only diminishes the concentrations of Fe2+ and MDA within the brain tissue of MCAO/R rats but also elevates GSH levels, suppresses ferroptosis, and reduces the concentrations of inflammatory markers such as IL-6, IL-1β, and TNF-α. These observations suggest that edaravone mitigates cerebral I/R injury through the activation of the Nrf2/FPN signaling pathway, which leads to the inhibition of both ferroptosis and inflammation. Nonetheless, additional research is necessary to clearly define the relationship between reduced inflammation and the Nrf2/FPN pathway. Moreover, edaravone lowers extracellular levels of leukotrienes by blocking the 5-LOX pathway, thus safeguarding SD rats and PC12 cells from inflammatory damage induced by ischemia (147). Panax notoginseng saponins (PNS), which are extracted from the Chinese medicinal herb Panax notoginseng, display various beneficial effects including antioxidation, anti-inflammation, anti-apoptosis, and the promotion of angiogenesis (148). In MCAO/R rat models, the administration of PNS activates the Nrf2 signaling pathway, suppresses Fe2⁺ and ACSL4 expression, decreases levels of LPO, and enhances the concentrations of GSH, GPX4, and SLC7A11, thereby strengthening the antioxidant defense system, inhibiting ferroptosis, and subsequently reducing the levels of IL-6, IL-1β, and TNF-α to mitigate neuroinflammation and address cerebral I/R (149). Moreover, polysaccharides from Gastrodia elata, a traditional Chinese herb, exhibit properties such as antioxidant, anti-inflammatory, and anti-ferroptotic effects (150). In models of MCAO mice, treatment with these polysaccharides leads to a marked activation of the NRF2/HO-1 signaling pathway, a decrease in the harmful buildup of Fe2⁺, and an enhancement of GSH and GPx4 activities. By obstructing LPO, the treatment helps avert damage to cell membranes and the ensuing release of HMGB1 and ROS, thus mitigating neuronal ferroptosis. This mechanism is associated with the stimulation of the NLRP3 pathway, which subsequently triggers the release of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, ultimately reducing neuroinflammation (151). These findings highlight the protective effects of Gastrodia elata polysaccharides against ferroptosis and inflammation induced by cerebral ischemia/reperfusion. The Ferrostatin-1 derivative, Srs11-92 (AA9), has been shown to impede iron accumulation and ROS generation, boost GPX4 and Nrf2 expression, and inhibit the levels of HMGB1 and NF-κB p65 within the hippocampal region. This intervention led to a reduction in infarct size, lessened neuronal injury, and improved neurological outcomes in the MCAO/R mouse model. Conversely, the Nrf2 inhibitor ML385 negated the protective effects of AA9, suggesting that AA9 alleviates neuronal ferroptosis and neuroinflammation induced by OGD/R through the Nrf2 pathway (152).

Enriched environments (EE) serve as a rehabilitation approach for stroke patients, aimed at offering greater space, innovative game tools, and more social interactions. This method fosters improved sensory, cognitive, motor, and social engagement, which supports neuronal reorganization and functional recovery after injury, while also enhancing the central immune response (153, 154). Research indicates that EE can reduce the activation of IL-6-induced STAT3 phosphorylation in MCAO rats, leading to lower hepcidin levels in astrocytes, reduced TfR1 and DMT1 expression, increased FPN1 activity, and a decrease in iron accumulation due to neuroinflammation (155). Moreover, EE effectively reduces iron accumulation and mitigates the downregulation of GPX4 induced by inflammatory cytokines like TNF-α, IL-6, and IL-1β in the brain tissues of MCAO rats. This intervention also boosts HIF-1α expression while inhibiting the upregulation of ACSL4, thereby reducing ferroptosis and aiding in the recovery of function following brain I/R injury (156).

Exosomes are tiny membrane-bound vesicles that are expelled from cells and are being researched for their potential in treating a range of neurological conditions (157). In cases of cerebral ischemia, exosomes have demonstrated their ability to lessen neuronal injury and enhance the brain’s microenvironment by modulating inflammation, preventing ferroptosis, mediating apoptosis in cells, fostering axonal development, and facilitating vascular remodeling (158). Research by Wang et al. revealed that (159) exosomes derived from adipose stem cells (ADSC-Exo) act as inhibitors of ferroptosis, significantly decreasing M2 microglial sensitivity to this process and suppressing M1 microglial marker expression through the Fxr2/Atf3/Slc7a11 signaling pathway in MCAO mice. Furthermore, these exosomes diminish the levels of MDA, ROS, and Fe2⁺, leading to a decrease in pro-inflammatory cytokines such as IL-1β, IL-2, IL-6, IL-12 p70, IL-23, TNF-α, while simultaneously increasing the levels of anti-inflammatory cytokines like IL-10, TGF-β1, IL-4, and IL-13, which further mitigates inflammation and supports neuronal survival. Additionally, exosomes that overexpress steroid receptor coactivator-3 (SRC-3-exo) significantly elevate the GSH/GSSG ratio while decreasing the activity of catalase, MDA, and LPO, thereby preventing neuronal ferroptosis induced by OGD/R. This action also leads to the inhibition of microglial and astrocytic activation, resulting in a lowered production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in the brains of MCAO mice. SRC3-exo treatment additionally reduces brain edema and infarction size in mice, promoting neuronal recovery and enhancing neurological performance (160). These findings suggest that exosomes may bolster the antioxidant defense mechanisms to counteract LPO-induced ferroptosis during cerebral I/R, further inhibiting the overactivation of neuroglial cells that plays a role in neuroinflammation. Additionally, extracellular vesicles derived from bone marrow mesenchymal stem cells (MSCs-EVs) are capable of transporting Fer-1 to neurons in the hippocampus. The combination of MSCs-EVs and Fer-1 enhances the levels of GPX4, suppresses COX-2 expression, and decreases the expression of TNF-α and IL-1β via the COX-2/PGE2 signaling pathway, thereby reducing neuroinflammation caused by ferroptosis and offering protection during cerebral I/R events (161).

The treatment strategies derived from basic research provide promising avenues for addressing the interplay between ferroptosis and inflammation in brain I/R. Anti-inflammatory drugs and environmental enrichment (EE) reduce inflammation by regulating pathways like HMGB1, Nrf2/NF-κB, TLR/p38 MAPK, and IL-6/STAT3, thereby mitigating ferroptosis (91, 124, 131, 155). Ferroptosis inhibitors and exosomes, on the other hand, target COX-2/PGE2, 5-LOX/leukotrienes, and Nrf2-mediated pathways, reducing the inflammatory impact of ferroptosis on inflammation (147, 152, 161). Innovations such as the regulation of M1/M2 microglial polarization by NTF, which influences the BMP6/SMADs pathway, demonstrate novel mechanisms to alleviate inflammation-induced ferroptosis (86). Bone morphogenetic protein 6 (BMP6), a regulator of hepcidin and iron metabolism, is upregulated in response to increased iron levels, triggering a SMAD signaling cascade that activates the hepcidin gene—a potential new approach to manage iron level alterations caused by microglia (162). Additionally, the ferroptosis inhibitor ADSC-Exo protects M2 microglia through the Fxr2/Atf3/Slc7a11 pathway, managing the inflammatory microenvironment (163, 164). Under ADSC-Exo’s influence, Fxr2 is upregulated, indirectly suppressing Atf3 while boosting SLC7A11 under oxidative stress, thus enhancing antioxidant defenses and inhibiting ferroptosis (159). New pharmacological developments like ADA-409-052 target the COX-2/PGE2 pathway to improve outcomes in severe neuronal death and neuroinflammation (142), while AA9 reduces hippocampal damage, inhibits iron deposition and ROS accumulation to alleviate ferroptosis, and subsequently suppresses neuroinflammation via the Nrf2 pathways (152).

Despite their innovative mechanisms offering new therapeutic possibilities, the potential risks and side effects of these strategies cannot be ignored. When evaluating their large-scale clinical application, initial small-scale clinical trials are crucial. These trials should thoroughly assess patient-specific conditions, drug safety, and potential interactions with other treatments. Possible side effects include immune suppression and elevated blood pressure from anti-inflammatory drugs. For instance, glycyrrhizin might increase blood pressure and lead to hypokalemia and hypernatremia—risks that necessitate cautious use, especially in hypertensive patients (165). Dimethyl fumarate may cause lymphocytopenia, a risk manageable with preemptive blood tests (166). Furthermore, using high doses of ferroptosis inhibitors, like caffeic acid, might impair iron absorption, leading to deficiency if not carefully managed (167).

Additionally, treatment plans should be tailored based on patient age, gender, and the specific brain regions affected. For example, elderly patients, who typically have diminished neuroplasticity and are more susceptible to iron accumulation, might benefit from combinations of iron chelators and stem cell exosomes (168). Female patients, potentially responding better to treatments due to the neuroprotective effects of estrogen, may have better outcomes (169, 170). Regional differences in brain sensitivity also dictate tailored approaches; for instance, the hippocampal region’s high demand for oxygen and glucose and its active iron metabolism make it particularly vulnerable to ischemic damage and ferroptosis. Therefore, treatment of the hippocampal region may primarily involve ferroptosis inhibitors, coupled with appropriate anti-inflammatory agents, and improving mitochondrial energy supply to neurons to support their survival and functional recovery (171, 172). The basal ganglia, critical for controlling muscle strength and tone, are frequently affected by strokes (173). Cerebral ischemia/reperfusion can increase the permeability of the blood-brain barrier (BBB) in this region (174). Therefore, we should increase the use of anti-inflammatory drugs and employ drug delivery systems to more effectively target the basal ganglia, protecting the integrity of the BBB. Additionally, combining ferroptosis inhibitors and motor neuron nutrients should be considered to mitigate the effects of ferroptosis and inflammation in this area. By fully understanding these variables, clinicians can develop more effective, personalized treatment strategies, ultimately improving patient outcomes in brain I/R scenarios.