Apoptosis, the first identified form of PCD, serves a critical role in the pathophysiology of IS. It is induced via three main pathways: i) The receptor-mediated extrinsic apoptotic pathway; ii) the mitochondria-mediated intrinsic apoptotic pathway; and iii) the p53-mediated intrinsic apoptotic pathway (33-35).

In the extrinsic pathway, ligands binding to 'death receptors' on the cell membrane is the main trigger of this apoptotic pathway (36). The ligands include TNF-α, TNF-related apoptosis-inducing ligand (TRAIL) and FasL, and the 'death receptors' include apoptosis-related factors (Fas/CD95), tumor necrosis factor receptor 1 (TNFR1) and TRAIL receptors (including DR4 and DR5) (37,38). The aforementioned ligands bind to the 'death receptor' and form a death-induced signaling complex with the caspase-8 precursor, which promotes the maturation of caspase-8 (39). The mature caspase-8 promotes the shearing of its downstream target caspase-3, which in turn promotes apoptosis (40). During the pathological process of IS, TNF-α released by injured neurons or glial cells will then mediate apoptosis through this extrinsic pathway (41,42).

The intrinsic pathway is primarily a cellular suicide mechanism triggered by intracellular signals (43). Internal signals for intrinsic apoptosis in IS include DNA damage, hypoxia and reactive oxygen species (ROS) (43). Disruption of calcium homeostasis allows calcium to enter the cell, activating calpain, which cleaves the BH3-interacting domain (BID) into its truncated (t) form, tBID (44). tBID interacts with pro-apoptotic proteins such as Bax, Bak and Bad in the mitochondrial membrane, causing mitochondrial membrane permeabilization (MMP) (45). This permeabilization leads to the release of cytochrome c, apoptosis-inducing factor (AIF), endonuclease G and other mitochondrial components (46). Cytochrome c binds to apoptotic protease activating factor 1, promoting the activation of caspase-9, which in turn enhances the pro-apoptotic function of caspase-3 (47,48).

The p53 protein, an oncogene and transcription factor, is associated with IS-induced neuronal damage and is upregulated during the pathological process of IS (49,50). Factors such as glutamate excitotoxicity, ROS, hypoxia and DNA damage can induce p53 upregulation (51,52). Additionally, upstream proteins such as JNKs, p38, death-associated protein kinase, apoptosis signal-regulated kinase-1 and Notch regulate p53 (35,53). p53 promotes the transcription of pro-apoptotic genes, including Bax, p53-upregulated modulator of apoptosis and NADPH oxidase activator (33). This promotion leads to MMP and the subsequent release of cytochrome c, activating the mitochondria-mediated intrinsic apoptotic pathway (52) (Fig. 1).

Autophagy is a highly coordinated process that sequesters misfolded or mutated proteins, aged organelles and other damaged cellular components into double-membrane vesicles known as autophagosomes. These autophagosomes then fuse with lysosomes, leading to the degradation of their contents (54). Under normal conditions, autophagy maintains a dynamic balance within the cell; however, pathological changes can disrupt this homeostasis (55). Autophagy can be categorized into selective and non-selective types based on the presence of target substrates (56,57). Selective autophagy encompasses various processes, including mitochondrial autophagy (mitophagy), endoplasmic reticulum (ER) autophagy (ER-phagy), lipid droplet autophagy, peroxisomal autophagy and ribosomal autophagy (57,58). In the pathophysiology of IS, increased excitotoxicity, mitochondrial dysfunction, ER stress and ROS are conditions that induce autophagy (59). However, autophagy serves a dual role in IS-induced injury. While moderate autophagy can help mitigate damage, inadequate, defective or excessive autophagy may worsen the injury (58). The activation of autophagy in IS is regulated by various intracellular signaling pathways (56). These include non-selective autophagy mediated by mTOR and MAPK pathways, as well as the Beclin-1/Bcl-2 signaling pathway (56). In addition, selective forms of autophagy such as Parkin-dependent mitophagy, LC3-mediated mitophagy and ER stress-mediated ER-phagy also serve important roles (58).

mTOR is a conserved serine/threonine protein kinase that serves a crucial role in the initiation of autophagy by inhibiting autophagy through the phosphorylation of the autophagy-related 1/UNC-51-like kinase 1 (ULK1) protease complex (60,61). In the pathological process of IS, the PI3K/AKT signaling pathway regulates mTOR, and its inhibition markedly suppresses mTOR activity (62). Additionally, the NF-κB-dependent p53 signaling pathway has been shown to inhibit autophagy via mTOR during IS (63). Ca²⁺ disruption in IS can activate 5'-AMP-activated protein kinase (AMPK) via Ca²⁺/calmodulin-dependent protein kinase kinase β, leading to mTOR inhibition and autophagy activation (64-66). The MAPK family, including JNK, ERK and p38MAPK, serves a role in autophagy regulation. Notably, activation of the MAPK pathway in early IS stages can inhibit autophagy through MAPK kinase, C/EBP homologous protein 10, ETS transcription factor ELK1 and lymphoid enhancer-binding factor 1, while promoting neuronal survival (67-70).

Beclin-1, a protein containing a BH3 domain, is a key regulator of autophagy and is involved in autophagosome membrane formation (71). Beclin-1 expression increases in IS, promoting autophagy (72). Beclin-1 forms a complex with Bcl-2, which inhibits Beclin-1-induced autophagy (73,74). Although the mechanism of complex dissociation during ischemia remains unclear, it has been observed that autophagy increased during ischemia-reperfusion injury (IRI) via a Beclin-1-dependent but AMPK-independent pathway (75).

Mitochondria serve a vital role in regulating intracellular homeostasis, ATP production and Ca²⁺ balance (76). Mitophagy helps remove damaged mitochondria, promoting mitochondrial renewal (77). In IS, mitophagy is primarily mediated by the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway, with ROS, hypoxia and excitatory amino acids promoting PINK1 activation, which phosphorylates Parkin on the outer mitochondrial membrane (78). Additionally, LC3 can mediate mitophagy through mitochondrial receptors such as Nip3-like protein X, Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and FUN14 domain containing 1, which interact with LC3 to induce LC3-II expression and promote mitophagy (79).

The ER is essential for protein processing and metabolism (80). ER stress leads to fragmentation of the ER and induces ER-phagy to form autophagosomes, mediated by three main signaling pathways: i) protein kinase R-like endoplasmic reticulum kinase (PERK); ii) activating transcription factor 6; and iii) inositol-requiring enzyme 1α (IRE1α) (81-83). Disruption of Ca²⁺ homeostasis during IS-induced injury is also a main cause of ER stress (79) (Fig. 2).

Necroptosis exhibits distinct features compared with those of traditional apoptosis. Morphologically, necroptosis resembles unregulated necrosis, characterized by early loss of cytosolic membrane integrity, increased cell volume and swelling of organelles. By contrast, apoptosis is marked by cell shrinkage, plasma membrane blistering, and condensation and fragmentation of the nucleus and organelles (84). Mechanistically, necroptosis is caspase-independent and is regulated by receptor interacting serine/threonine kinase 1 (RIPK1) and receptor interacting serine/threonine kinase 3 (RIPK3), along with mixed lineage kinase domain-like protein (MLKL) (22).

In the pathological context of IS, TNF-α serves as a key initiator of necroptosis (85). Following cerebral ischemia, TNF-α binds to its receptor, TNFR1 (85). This interaction recruits components to form pro-survival complex I, which includes the TNFRSF1A associated via death domain, RIPK1, TNF receptor associated factor 2, the ubiquitin E3 ligase linear ubiquitin chain assembly complex and cellular inhibitor of apoptosis protein ½ (86). Within complex I, RIPK1 undergoes polyubiquitination, leading to its disassembly into complex II through proteasomal action (86). Under normal conditions, complex II mediates apoptosis via the caspase-8 pathway. However, hypoxia induced by cerebral ischemia inhibits caspase-8 and activates complex II (87,88). Upon activation, RIPK3 binds to RIPK1, forming a complex where both proteins are phosphorylated and activated (89). The oligomerization and subsequent phosphorylation of RIPK3 in this complex trigger the phosphorylation and activation of MLKL, which mediates necroptosis and promotes the release of DAMPs (90). The leakage of DAMPs can further exacerbate necroptosis and inflammation (90) (Fig. 3).

The gasdermin (GSDM) family has been recognized as a key regulator of pyroptosis (91). This family comprises five protein molecules (GSDMA, GSDMB, GSDMC, GSDMD and GSDME), all of which can mediate pyroptosis (91). The primary mechanism by which the GSDM family induces pyroptosis involves forming pores in the cell membrane. This leads to changes in intraand extracellular osmotic pressure, ultimately causing cell rupture and the release of intracellular DAMPs, which promote inflammation (92). Among these proteins, GSDMD is considered to be the most prominent executor of pyroptosis (14). GSDMD consists of two conserved structural domains, the N-terminal functional domain (N-GSDMD) and the C-terminal autoinhibitory domain (C-GSDMD), linked by a ring structure (93). Under normal conditions, GSDMD is non-toxic to cells and does not mediate pyroptosis. GSDMD only promotes pyroptosis when cleaved into N-GSDMD by caspase-1 (94). Caspase-1 also cleaves the inflammatory precursors pro-IL-18 and pro-IL-1β; once N-GSDMD opens non-ion channels in the cell membrane, it facilitates the release of these inflammatory factors, triggering a cascade of inflammatory responses (95). Additionally, caspases-4, -5 and -11, as well as -3 and -8, can cleave GSDMD into N- and C-GSDMD; however, their impact on pyroptosis is less pronounced (96-98).

In the pathophysiological process of IS, pyroptosis acts as a proinflammatory inducer primarily occurring in the ischemic penumbral region of the brain (99). The initiation of pyroptosis in this area is mainly due to DAMPs released from dying cells, including excitotoxins, double-stranded DNA and TNF-α (100). Pattern recognition receptors (PRRs) on the cell membrane, including NOD-like receptors (NLRs) and toll-like receptors (TLRs), recognize these DAMPs (100). Pyroptosis in IS is primarily triggered by the activation of intracellular inflammasomes by DAMPs (4). Inflammasomes are multiprotein complexes composed of three main components: i) Sensors; ii) adapters; and iii) effectors (101). In IS, the sensors involved in pyroptosis include NLRs [NLR family pyrin domain containing (NLRP)1, NLRP3 and NLR family CARD domain containing 4 (NLRC4)] and absent in melanoma 2 (AIM2) (102,103). NLRP1 features a pyrin domain (PYD), NACHT domain, leucine-rich repeat (LRR) domain, function to find (FIIND) domain and caspase recruitment domain (CARD). The FIIND domain of NLRP1 cleaves into ZO-1 and Unc5-like domain 5 and ubiquitin protease associated domain, splitting NLRP1 into N- and C-terminal fragments, with the latter participating in the formation of the NLRP1 inflammasome (104). NLRP3 comprises PYD, NACHT and LRR domains (105), while NLRC4 includes CARD, NACHT and LRR domains (106). AIM2 consists of PYD and hematopoietic interferon-inducible nuclear protein with a 200-amino acid repeat domains (103). Under pathological conditions, the adapter protein, apoptosis-associated speck-like protein containing CARD and PYD domains, interacts with the effector caspase-1, which is primarily responsible for cleaving GSDMD (14,101). When PRRs on the cell membrane recognize signals from external DAMPs such as K⁺, ROS and double-stranded DNA, they promote the maturation of caspase-1. This, in turn, cleaves GSDMD into N-GSDMD and facilitates the maturation of IL-18 and IL-1β, ultimately inducing cellular pyroptosis and inflammatory cascades (107) (Fig. 4).

In the past decade, there has been an increase in research on ferroptosis, revealing its links to various diseases, including cancer and IRI neurodegeneration (29). Ferroptosis is driven by lipid peroxidation and abnormal iron metabolism (108). Mechanisms that confer resistance to ferroptosis include the glutathione (GSH)-glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1-reduced coenzyme Q10 (CoQH2), dihydroorotate dehydrogenase-CoQH2 and GTP cyclohydrolase 1-tetrahydrobiopterin pathways (109). Previous studies have identified ferroptosis as a potential therapeutic target for IS (110,111). During IS, lipid peroxidation products accumulate and iron levels rise, while GPX4 expression decreases, and acyl-CoA synthetase long-chain family member 4 (ACSL4), cyclooxygenase-2 and ROS levels are increased (112). This suggests that ferroptosis may be a potential therapeutic target for IS.

Lipid peroxidation involves the production of hydroperoxides from PUFAs through enzymatic and iron-mediated reactions (113-115). Cytosolic phospholipase A2 (cPLA2α) is upregulated during IS, and cPLA2α promotes lipid peroxidation of arachidonic acid and ROS generation (116,117). ACSL4 is also upregulated in IS and promotes lipid peroxidation (118). In addition, arachidonic acid lipoxygenase 12/15, which promotes lipid peroxidation, is upregulated in IS (119,120).

Overaccumulation of iron is a key feature of ferroptosis, with ferric ions promoting intracellular ROS production and membrane lipid peroxidation through iron-dependent reactions that decompose H₂O₂ to ·OH (29). In vivo, divalent iron is oxidized to trivalent iron, which binds to transferrin and enters cells via transferrin receptor 1 (TfR1) (121). Inside endosomes, trivalent iron is reduced to divalent iron by six-transmembrane epithelial antigen of the prostate 3 (STEAP3), and then transported into the cytoplasm via divalent metal transporter 1 (DMT1) or zinc transporter 8/14 (121-123). Iron ions are taken up into the cell and form the labile iron pool (LIP) (123). Divalent iron forms a LIP and is packaged into ferritin by poly (rC)-binding protein 1 (123). Even before the concept of ferroptosis emerged, abnormal accumulation of iron was observed in brain tissues during IS (124,125). Injury to the blood-brain barrier facilitates iron entry from the blood into the brain tissue, promoting ferroptosis (114). In IS, NF-κB activation increases DMT1 expression, enhancing intracellular iron uptake (126,127). Hypoxia-inducible factor-1α (HIF-1α) is upregulated in IS, promoting TfR1 expression and contributing to iron overload (128,129). Ferritin regulates ferroptosis, with increased ferritin attenuating CIRI, while decreased ferritin exacerbates CIRI (130-132). Histone deacetylase 9 (HDAC9) is expressed at high levels in IS and induces TfR1 expression through HIF-1α modification (133). Nuclear receptor coactivator 4 (NCOA4) exacerbates IS-induced ferroptosis by promoting ferritinophagy, releasing iron ions (134). Additionally, during IS, hepcidin is upregulated, inhibiting divalent iron transport (135,136).

In IS-induced ferroptosis, lipid peroxidation and iron accumulation coincide with inhibition of the intracellular anti-ferroptosis system (137). The solute carrier family 7 member 11 (SLC7A11)/GSH/GPX4 system is crucial for ferroptosis resistance, and its expression is downregulated during IS, indicating the role of the SLC7A11/GSH/GPX4 system in mediating IRI (137-139). High extracellular glutamate concentrations inhibit the Xc-system, reducing GPX4 production and promoting ferroptosis (140). High HDAC9 expression downregulates GPX4 through specificity protein 1 modification (133). Conversely, nuclear factor erythroid 2-related factor 2 (Nrf2) activation enhances SLC7A11, GPX4 and heme oxygenase 1 (HO-1) expression, inhibiting ROS production and attenuating IS-induced ferroptosis (141) (Fig. 5).

Apoptosis is the earliest recognized form of PCD, and numerous studies have demonstrated that it serves a crucial role in cellular damage within brain tissues during the pathophysiological process of IS (13,143). Over the past decade, several potential drugs that inhibit IS-induced apoptosis have been identified (Table I).

Caspase-3 is the primary executor of apoptosis during IS-induced injury, and inhibiting caspase-3 can effectively reduce apoptosis (144). Chen et al (145) demonstrated that memantine, a non-competitive N-methyl-D-aspartate receptor antagonist, inhibited apoptosis by blocking the calpain/caspase-3 signaling pathway, thereby mitigating neuronal damage induced by middle cerebral artery occlusion/reperfusion (MCAO/R) in rats. Zhang et al (146) found that Pien-Tze-Huang inhibited apoptosis by reducing the levels of cytochrome c, Bax, p53, and cleaved caspase-3 and -9 after IS, leading to decreased injury in rat MCAO/R models. Additionally, Nie et al (147) reported that the Tanhuo formula also reduced neuronal apoptosis after IS by inhibiting the caspase-3 pathway. In terms of the extrinsic pathways of apoptosis, Mei et al (148) showed that Shuan-Tong-Ling inhibited apoptosis mediated by the extrinsic pathway by lowering the levels of TNF-α and IL-1β following IS. Shuan-Tong-Ling also inhibited intrinsic pathway-mediated apoptosis by upregulating sirtuin 1 (SIRT1) and Bcl-2, while downregulating p53 and Bax expression (148). Wang et al (149) demonstrated that Comp. B, a novel bicoumarin derivative, attenuated mitochondria-mediated apoptosis by decreasing the Bax/ Bcl-2 ratio, thus reducing middle cerebral artery occlusion (MCAO)-induced brain tissue injury in mice. Raghavan and Shah (150) found that Withania somnifera, also known as 'rutabaga', markedly mitigated apoptosis induced by permanent MCAO in mice through inhibition of the poly(ADP-ribose) polymerase 1-AIF pathway. Peng et al (151) showed that artemisinin could reduce IS-induced apoptosis by activating the ERK1/2/cAMP response element binding protein (CREB)/ BCL-2 signaling pathway, where CREB promoted Bcl-2 expression to prevent apoptosis. Similarly, rolipram, a phosphodiesterase-4 inhibitor, was found to diminish transient middle cerebral artery occlusion-induced apoptosis in rats by activating the cAMP/CREB signaling pathway, as reported by Hu et al (152).

While investigating therapeutic drugs for IS, researchers have identified that targeting various intracellular signaling mechanisms can enhance resistance to IS-induced apoptosis, particularly through the PI3K/AKT pathway, which serves a critical role in cell survival (153). Hafeez et al (154) demonstrated that ethanol protected against IRI in rats by inhibiting protein kinase C δ (PKC-δ) and enhancing Akt expression. Fan et al (155) showed that S-oxiracetam mitigated MCAO/R-induced brain damage and apoptosis via α7 nicotinic acetylcholine receptor activation of the PI3K/AKT/GSK3β pathway. Xu et al (156) found that Xiaoyao San reduced oxygen glucose deprivation/reoxygenation (OGD/R)-induced apoptosis in PC12 cells via the PI3K/AKT pathway. Furthermore, Wang et al (157) reported that total flavonoids of Chuju activated the PI3K/AKT pathway to reduce IS-induced apoptosis. Zhang et al (158) suggested that kaempferol may exert anti-apoptotic effects in IS via the brain-derived neurotrophic factor-tropomyosin receptor kinase B-PI3K/AKT pathway. Luo et al (159) showed that D-allose inhibited IS-induced apoptosis and neuroinflammation by blocking the galectin-3/toll like receptor 4 (TLR4)/PI3K/AKT pathway. Qi et al (160) confirmed that Chuanzhitongluo reduced IS-induced apoptosis via PI3K/AKT activation. Lastly, Xu et al (161) indicated that Brassaiopsis glomerulata mitigated MCAO/R and oxygen-glucose deprivation-induced apoptosis by activating the PI3K/AKT/mTOR pathway. These findings emphasize the role of PI3K/AKT signaling in reducing IS-induced apoptosis.

NF-κB, first identified by Meffert and Baltimore (162), serves a crucial role in inflammatory and immune responses (163,164). Studies have indicated that targeting NF-κB signaling can also help reduce IS-induced apoptosis (165,166). Zhou et al (167) found that oleoylethanolamide mitigated MCAO/R-induced apoptosis in mice by activating peroxisome proliferator-activated receptor α (PPARα) and inhibiting the TLR4/NF-κB and ERK1/2 pathways. Yan and Zhu (168) demonstrated that rosuvastatin reduced apoptosis and brain injury after IS by inhibiting the Sirt1/NF-κB pathway. Li et al (169) showed that anifibatide attenuated MCAO/R and OGD/R-induced apoptosis in rat brain tissues and primary neuronal cells by inhibiting the NF-κB/NLRP3 pathway. Additionally, Wang et al (170) reported that Guhong injection reduced IS-induced injury by targeting both mitochondria- and NF-κB-mediated apoptosis and inflammation.

Interfering with cell-intrinsic signals is crucial for reducing IS-induced apoptosis (13). Zheng et al (171) found that carvedilol protected against OGD/R-induced PC12 cell injury by inhibiting activating transcription factor 3 (ATF3), thereby mitigating mitochondria-mediated apoptosis. Xu et al (172) demonstrated that YiQiFuMai alleviated IS-induced neuronal apoptosis by preventing mitochondrial dysfunction and overfission mediated by PKC-δ/dynamin-related protein 1. Qiu et al (173) showed that Apelin-36 decreased cerebral I/R-induced infarction and apoptosis by reducing ER stress. Wu et al (174) indicated that Apelin-13 mitigated neuronal apoptosis via G protein α inhibitory subunit/G protein αq subunit-casein kinase 2 signaling. Li et al (175) reported that Xuesaitong promoted recovery in MCAO/R mice by downregulating the STAT3 pathway, thus reducing neuronal apoptosis and enhancing M2 microglial polarization. Li et al (176) found that γ-glutamylcysteine alleviated OGD/R-induced neuronal apoptosis by activating PERK and IRE1α. Joshi et al (177) showed that tideglusib reduced IS-induced apoptosis and neuroinflammation by inhibiting phosphorylated GSK-3β S9. Ding et al (178) reported that candesartan inhibited IS-induced apoptosis via the free fatty acid receptor 1/integrin subunit α4 axis. Li et al (179) demonstrated that darutoside or oridonin reduced IS-induced neuronal apoptosis by inhibiting RIPK3. Zhang et al (180) showed that myricetin attenuated apoptosis via the MAPK-ERK pathway.

Autophagy serves a dual role in IS pathology, with both excessive and insufficient autophagy exacerbating injury (181). Studies have indicated that modulating autophagy after IS can effectively reduce IS-induced damage (61,181). The present review summarizes potential protective drugs that attenuate IS-induced injury by targeting autophagy disruption (Table II).

Excessive autophagy can worsen IS injury, and some drugs exert protective effects by inhibiting autophagy (61). mTOR is a key regulator of autophagy, and targeting it can alleviate autophagy disorders associated with IS (61). Jiang et al (182) showed that vitexin reduced MCAO/R-induced brain injury by inhibiting autophagy through the mTOR/Ulk1 pathway. Tang et al (183) found that exogenous netrin-1 protected against IS injury by inhibiting autophagy via the PI3K/mTOR pathway. Zhang et al (184) reported that the dichloromethane fraction (DF) of Piper nigrum and P. longum reduced IS damage by activating the AKT-mTOR signaling pathway. Other mechanisms also help inhibit excessive autophagy. Liu et al (185) suggested that activin A reduced IS injury by inhibiting cyclic GMP-AMP synthase-stimulator of interferon genes-mediated autophagy. Lv et al (186) showed that phenothiazines mitigated IS injury by reducing ER stress-mediated autophagy via the PERK-eukaryotic initiation factor-2α pathway. Yuan et al (187) reported that DF inhibited the expression of autophagy-related proteins such as LC3 and Beclin1 to attenuate IS-induced autophagy. Zhu et al (188) found that the protein tyrosine phosphatase 1B inhibitor sc-222227 regulated ER stress-induced autophagy in microglia, reducing IS injury. Wang et al (189) demonstrated that medioresinol inhibited autophagy after IS via the PPARα/glutamic-oxaloacetic transaminase 1 pathway, protecting endothelial cells. Xia et al (190) revealed that extracellular vesicles from induced pluripotent stem cell-derived mesenchymal stem cells inhibited autophagy and promoted angiogenesis via STAT3 activation. Zhang et al (191) showed that hydroxysafflor yellow A reduced IS-induced autophagy by inhibiting HIF-1, BNIP3 and Notch1.

A lack of autophagy hampers the removal of damaged organelles, harmful proteins and nucleic acids, exacerbating IS-induced cellular damage (192). The AMPK pathway has been widely studied due to its role in developing protective drugs that enhance autophagy and mitigate IS injury (193,194). Li et al (193) demonstrated that stilbene glycoside protected against IS injury by promoting mitophagy and inhibiting apoptosis through the SIRT3/AMPK pathway. Ao et al (194) showed that the newly synthesized cyclovirobuxine D analog, JLX-001, enhanced autophagy and reduced IS damage via the AMPK/ULK1 signaling pathway. Li et al (195) found that ginaton attenuated MCAO-induced brain injury in rats by activating autophagy via the AMPK pathway. Additionally, Zhou et al (196) reported that oxymatrine promoted autophagy and reduced IS-induced damage by activating SIRT1.

Necroptosis differs from ordinary necrosis primarily due to its regulatory role in intracellular signaling, with the RIPK3/MLKL pathway being central to IS-induced necroptosis (197). Deng et al (198) first highlighted the protective effect of inhibiting necroptosis in IS, showing that the necrosis inhibitor necrostatin-1 mitigated IS injury by blocking the RIPK3/MLKL signaling pathway. Subsequently, Zhang et al (199) made significant contributions to identifying protective drugs against IS-induced necroptosis. The authors found that ligustroflavone inhibited necroptosis by targeting the RIPK1/RIPK3/MLKL pathway, providing protective effects in IS (199). Additionally, caspofungin was shown to inhibit necroptosis by upregulating Pellino3 and ubiquitinating RIPK1, thereby reducing IS-induced damage (200). Telaprevir also mitigated IS-induced brain injury by inhibiting necroptosis through the RIPK1/RIPK3/MLKL pathway (201) (Table III).

Pyroptosis is a key type of PCD that triggers inflammatory responses, notably contributing to IS-induced injury (202). Studies have identified protective drugs that inhibit pyroptosis as promising treatments for IS (Table III).

The TLR4/NF-κB signaling pathway and inflammasomes are central to mediating pyroptosis in IS (203). Wang et al (203) showed that Taohong Siwu decoction reduced MCAO/R-induced pyroptosis and inflammation by inhibiting the HMGB1/TLR4/NF-κB and MAPK pathways. Curcumin mitigated IS-induced pyroptosis via the NF-κB/NLRP3 pathway (204). Li et al (205) found that indobufen or aspirin, combined with clopidogrel or ticagrelor, reduced pyroptosis via the NF-κB/NLRP3 pathway. Ge et al (206) reported that exogenous recombinant C-X3-C motif chemokine ligand 1 inhibited NLRP3-mediated pyroptosis. Hu et al (207) demonstrated that edaravone dexborneol inhibited the NF-κB/NLRP3/GSDMD pathway. Long et al (208) found that ginsenoside Rg1 reduced pyroptosis by inhibiting the chemokine like factor pathway. Zhou et al (209) showed that tetrahedral framework nucleic acids blocked the TLR2-MyD88-NF-κB pathway, mitigating brain injury. Wang et al (210) reported that artemisinin reduced pyroptosis by inhibiting the ROS/thioredoxin interacting protein/NLRP3/caspase-1 pathway. Furthermore, Alattar et al (211) found that quercetin, by activating Nrf2, attenuated MCAO-induced pyroptosis via the Nrf2/HO-1 signaling pathway.

Ferroptosis, a novel type of PCD, serves a notable regulatory role in IS-induced injury (5). There has been increased attention on the development of ferroptosis-targeted drugs, with researchers actively exploring potential protective agents to inhibit IS-induced ferroptosis, yielding promising results (Table IV).

Iron-dependent lipid peroxidation is central to ferroptosis, and managing iron metabolism can reduce IS-induced ferroptosis (212). Yu et al (212) showed that melatonin inhibited ferritinophagy by disrupting the NCOA4-ferritin heavy chain 1 interaction. Rosmarinic acid liposomes also regulated iron metabolism by inhibiting TfR1, as demonstrated by Jia et al (213).

Excess lipid peroxidation exacerbates ferroptosis, but lipid-regulating drugs offer protection (214). Sun et al (214) found that ecdysterone mitigated ferroptosis by inhibiting ACSL4. Sun et al (215) reported that melatonin targeted the ACSL4/cytochrome P450 family 1 subfamily B member 1 pathway to protect against IS-induced ferroptosis. Jin et al (216) indicated that astragaloside IV reduced ferroptosis by upregulating ATF3 and enhancing m6A methylation of ACSL4.

Phospholipid peroxidation is critical in ferroptosis, and enhancing antioxidants such as Nrf2, SLC7A11 and GPX4 can counteract phospholipid peroxidation (217). The Danlou tablet boosted SLC7A11 and GPX4 expression to inhibit ferroptosis (218). Angong Niuhuang Wan activated the PPARγ/AKT/GPX4 pathway for similar effects (219). Danhong injection activated the SATB homeobox 1/SLC7A11/HO-1 pathway to mitigate ferroptosis (220). Caffeic acid and quercetin enhanced Nrf2 signaling, as shown by Li et al (221,222) and Peng et al (221,222). Mi et al (223) revealed that kellerin could attenuate IS-induced ferroptosis by promoting AKT-regulated Nrf2 transcriptional activity. Neutral polysaccharides from Gastrodia elata activated the Nrf2/HO-1 pathway to reduce ferroptosis according to Zhang et al (224). Wu et al (225) indicated that 15, 16-dihydrotanshinone I inhibited ferroptosis by activating Nrf2. Duan et al (226) revealed that the small molecule compound N6022 was able to attenuate IS-induced microglial ferroptosis by promoting the nuclear translocation of Nrf2 and inhibiting the interaction of S-nitrosoglutathione reductase with glutathione S-transferase pi 1, which in turn attenuated IS-induced injury. Ozone also activated the Nrf2/SLC7A11/GPX4 pathway to protect against IS-induced injury (227). Xiao et al (228) showed that edaravone dexborneol activated the Nrf2/HO-1/GPX4 pathway to inhibit ferroptosis. In addition, activation of the PI3K/AKT signaling pathway confers resistance to IS-induced ferroptosis (229). Hu et al (229) showed that ginsenoside Rd attenuated IS-induced ferroptosis in vascular endothelial cells by activating neuregulin 1/erb-b2 receptor tyrosine kinase 4/PI3K/Akt/mTOR signaling. Li et al (230) showed that voacangine attenuated IS-induced ferroptosis by activating the PI3K-Akt-FoxO pathway.