Apoptosis is a form of PCD in multicellular organisms. The process can be divided into two main stages: the formation of apoptotic bodies and their subsequent recognition, phagocytosis and degradation by neighboring cells. The signal transduction mechanism of apoptosis mainly includes the triggeringof endogenous and exogenous pathways (Elliott and Ravichandran, 2010; Galluzzi et al., 2018). When DNA damage, hypoxia and metabolic stress occur, the endogenous pathway of apoptosis, also known as mitochondrial pathway, will be triggered by the decrease of mitochondrial membrane potential and the increase of membrane permeability (Nossing and Ryan, 2023). Bcl-2 family members, including anti-apoptotic proteins such as Bcl-2 and Bcl-xl, pro-apoptotic proteins such as Bax and Bak, and BH3-only proteins such as Bad and Bid, are key mediators in regulating mitochondrial membrane permeability (Czabotar et al., 2014). Under the action of various pro-apoptotic signals, pro-apoptotic proteins such as Bax and Bak are no longer inhibited, and extend to the mitochondrial outer membrane and promote mitochondrial outer membrane permeability (MOMP), leading to the increase of mitochondrial membrane permeability (Wei et al., 2001; Tait and Green, 2010; Bock and Tait, 2020). Cytochrome C (Cytc) is transferred from the mitochondria to the cytoplasm and binds to apoptosis protease-activating factor-1 (Apaf-1) to form a multimercomplex to activate Pro-Caspase 9, which then activates downstream apoptotic effector proteins to lead to apoptosis (Cain et al., 2002). When the extracellular environment is disturbed, death receptors on the membrane surface receive the death signal transmitted by extracellular ligands and activate the extrinsic apoptotic pathway (Tenev et al., 2011). There are at least eight apoptosis-related death receptor protein family members on the surface of mammalian cells, among which Fas (APO-1/CD95), TNFR1, TRAILR1 (DR4) and TRAILR2 (DR5) are the most common (Suliman et al., 2001; Peter and Krammer, 1998; Ashkenazi and Dixit, 1998). The cytoplasmic portion of these receptors contains the Death Domain (DD), which is used to recruit key molecules (Han Y. H. et al., 2023). After binding to their ligands, the receptors form death-inducing signaling complex (DISC) to initiate the extrinsic apoptotic pathway (Yang et al., 2024). Fas and TNFR1 are typical representatives. Upon binding to FasL and TNF, respectively, it triggers trimerization of intracellular receptors and exposure of death domains to recruit adaptor proteins FADD and TRADD (Macewan, 2002; Guicciardi and Gores, 2009). FADD recruits and activates the precursor Caspase-8, which converts to the apoptosis-initiating protein Caspase-8. Subsequently, the activated Caspase-8 activates the apoptotic effector protein Caspase-3, leading to PCD (Dickens et al., 2012). In contrast, TRADD activates TNFR-related factor TRAF-2 upon binding to RIP1. TRAF-2 interacts with TRAF-1 to recruit cIAPs to form a complex that inhibits Caspase-8 activity and its release to prevent apoptosis and promote survival (Hsu et al., 1996a; Hsu et al., 1996b). In addition, the endogenous and exogenous pathways of apoptosis are not completely independent, but can interact together to regulate the apoptotic process under specific conditions. For example, activated Caspase-8 can cleave Bid to produce t-Bid, which is transported to mitochondria to promote the release of Cytc and ultimately induce apoptosis (Zhang et al., 2021; Perez and White, 2000) (Figure 2a).

Necroptosis is a form of PCD between apoptosis and necrosis. Since the concept of PCD was proposed in the 20th century, apoptosis has been regarded as the main form of PCD, and it is generally believed that it is closely related to the activation of Caspase family (Grootjans et al., 2017). However, with the development of research, scientists have found that death receptor-induced cell death still occurs even when Caspase family is inhibited. This mode of death shows typical necrosis-like morphological features such as cell swelling and deformation, cell membrane rupture. This suggests that Caspase activation is not the only mechanism that determines cell fate during PCD and that there are other possible cell death pathways (Weinlich et al., 2017; Galluzzi et al., 2017). This novel mode of cell death, necroptosis, was first reported by Degterev et al., in 2005 (Degterev et al., 2005). The activation of necroptosis is an active and dependent process of intracellular signal transduction, and its regulatory mechanism is similar to that of apoptosis. Among them, TNF-α is the most important upstream signaling molecule of necroptosis, and its receptor TNFR1 can recruit a variety of proteins, including TRADD, RIPK1, CIAP1, CIAP2 and LUBAC, which together form a signaling complex named “complex Ⅰ” (Annibaldi and Meier, 2018). In most cases, CIAP and LUBAC in complex I promote the ubiquitination of RIPK1 through K63 linkage and linear ubiquitin chains, which further recruit TAK and IKK complexes to activate NF-κB and MAPK signaling pathways, thereby promoting the production of inflammatory factors and maintaining cell survival (Annibaldi and Meier, 2018). In addition, the K63-linked ubiquitin chain on RIPK1 is hydrolyzed under the action of two deubiquitinating enzymes, CYLD and A20, thereby promoting the formation of complex II (Priem et al., 2020; Lork et al., 2017; Chen, 2012). The dissociated RIPK1 forms complex Ⅱb together with FADD and Caspase-8. When Caspase-8 activity is inhibited, RIPK1 further recruits and phosphorylates RIPK3 to form a RIPK1-RIPK3 necrosome (Li et al., 2012; Cho et al., 2009). RIPK1 and RIPK3 activate MLKL through autophosphorylation and cross-phosphorylation via homotypic interaction in the RHIM domain. Subsequently, RIPK3 catalyzes the phosphorylation of MLKL at Thr357 and Ser358 in its pseudokinase domain. After MLKL phosphorylation, its conformation changes, exposing the four-helix bundle (4HB) domain, which promotes MLKL oligomerization (Murphy et al., 2013). Oligomerization of MLKL migrates to the plasma membrane, where it forms a permeable pore, destroying the integrity of the membrane, and eventually causing programmed necrosis (Chen et al., 2014; Wang et al., 2014; Kaczmarek et al., 2013). In addition to TNF, other stimulating factors such as Fas, DR3, DR4, DR5 and DR6 can also trigger this process (Bi et al., 2017; Strilic et al., 2016) (Figure 2b).

Pyroptosis, also known as inflammatory necrosis of cells, is characterized by the continuous expansion of cells until cell membrane rupture, resulting in the release of cell contents and triggering an intense inflammatory response. Pyroptosis is an important part of the body’s innate immune response and plays a key role in the pathological process of immune system and nervous system diseases. The process is usually induced and executed by members of the Gasdermin (GSDM) protein family. The GSDM family of proteins contains six members, Five of them are Gasdermin A (GSDMA), Gasdermin B (GSDMB), Gasdermin C (GSDMC), Gasdermin D (GSDMD) and Gasdermin E (GSDME) -- each plays a unique rolein pore formation and pyroptosis-induced cell death (Yang F. et al., 2022). The GSDM-mediated pyroptosis pathway can proceed in either an inflammasome-dependent or an inflammasome-independent manner. The canonical inflammasome pathway is mediated by Caspase-1, while the non-canonical inflammasome pathway is mediated by Caspase-11 (mouse) and Caspase-4/5 (human), respectively. Both pathways eventually lead to the cleavage of GSDMD to generate its N-terminal and C-terminal fragments, of which the N-terminal fragment (GSDMD-N, or pore-forming domain PFD) is further oligomerized to form holes in the cell membrane (Toldo and Abbate, 2024). In the classical inflammasome pathway, GSDMD cleavage activates Pro-IL-1β and Pro-IL-18 to form mature inflammatory factors IL-1β and IL-18, which are released to the outside of the cell, followed by pyroptosis and lytic death of the cell (Rathinam and Fitzgerald, 2016; Broz and Dixit, 2016). In the non-canonical pathway, when stimulated by Gram-negative bacteria and their lipopolysaccharide (LPS), Caspase-4, Caspase-5 and Caspase-11 can directly bind to and be activated by LPS to cleave GSDMD protein. The N-terminus of GSDMD protein can not only mediate cell membrane lysis and pyroptosis, but also activate NLRP3 inflammasome to activate Caspase-1, and finally produce and release IL-1β (Hagar et al., 2013; Shi et al., 2014). In addition to the above two modes of pyroptosis, Caspase-3/8-mediated pathway and GSDM protein-related induction pathway can also trigger pyroptosis (Toldo and Abbate, 2024). Specifically, Caspase-3 can be activated by a variety of stimulants such as drugs and viruses, and specifically cleave GSDME protein to mediate the pyroptosis process (Liu et al., 2022). However, the mechanism of caspase-8-mediated pyroptosis is more complex: first, after the tumor necrosis factor (TNF) -mediated death receptor signaling is activated, GSDMC can be cleaved by Caspase-8, and then apoptosis converts to pyroptosis in GSDMc-expressing cells (Qin et al., 2025). Second, when YopJ, a Yersinia effector protein, inhibited the activity of TGF-β-activated kinase-1 (TAK1) or IKK kinase, it activated the RIPK1-Caspase-8 pathway, leading to the cleavage of GSDMD and accelerated the occurrence of pyroptosis (Orning et al., 2018; Sarhan et al., 2018). Studies have shown that GSDM mediated pyroptosis plays an important role in pathological processes such as neuroinflammation and mental diseases. As a defense mechanism, pyroptosis not only helps to remove pathogens and restore the stability of the intracellular environment, but also enhances the recognition and clearance efficiency of phagocytes such as neutrophils by encapsulating toxic substances. However, if the regulation is not balanced, it may lead to excessive tissue inflammation, which is closely related to a variety of nervous system diseases such as AD and Parkinson’s disease (Zhang S. et al., 2022) (Figure 2c).

Ferroptosis is a non-apoptotic cell death mode dependent on iron, which was first proposed by Dixon et al., in 2012 (Dixon et al., 2012). As an essential trace element for cells to maintain their morphology and function, iron plays an important role in oxygen transport, ATP synthesis, and DNA biosynthesis. Under normal physiological conditions, divalent iron (Fe²⁺) from food is transported to intestinal epithelial cells for absorption through divalent metal transporter 1 (DMT1). The absorbed Fe²⁺ is oxidized to Fe³⁺ in the intestinal mucosal epithelial cells, which is bound to transferrin (TF) and transported to the cells (Outten and Theil, 2009). The transferrin receptor (TFR1) on the cell surface recognizes and binds to a complex carrying trivalent iron (Tf-Fe³⁺) (Frazer and Anderson, 2014). It endocytoses into the cell interior. Once inside the cell, prostate transmembrane epithelial 3 antigen (STEAP3) reduces Fe³⁺ to Fe²⁺. Some Fe²⁺ is stored in the available LIP, while excess Fe²⁺ is stored in ferritin (Bogdan et al., 2016). Ferritin is an important iron storage protein, which can dynamically regulate the oxidation of ferrous ions (Fe²⁺) to ferric iron (Fe³⁺) for intracellular enzymatic reactions or storage. When the Fe²⁺ stored in the LIP binds to nuclear receptor coactivator 4 (NCOA4), it will trigger ferroautophagy and form autolysosome, leading to the degradation of ferritin and the release of large amounts of Fe²⁺ to complete the iron metabolism process (Hou et al., 2016). However, excessive iron uptake, decreased iron storage, or blocked iron removal due to a variety of factors may lead to intracellular Fe²⁺ overload. Excess Fe²⁺ undergoes the Fenton reaction with hydrogen peroxide (H₂O₂) to generate strongly oxidizing hydroxyl radicals (·OH). These free radicals can directly attack polyunsaturated fatty acids (such as arachidonic acid AA and adrenal acid AdA) in the cell membrane, trigger lipid peroxidation, accelerate the occurrence of lipid peroxidation, produce a large number of reactive oxygen species (ROS), and then promote ferroptosis (Chen et al., 2023). Lipid peroxidation triggered by iron metabolism disorder is a key mechanism leading to cell damage and ferroptosis. In addition, the imbalance of the antioxidant system of amino acids can also trigger the accumulation of lipid peroxides, which in turn promotes the occurrence of ferroptosis. A variety of antioxidant pathways have been evolved to resist oxidative stress damage, including cystine glutamate antitransporter receptor (system XC⁻) pathway, glutathione peroxidase 4 (GPX4) pathway, inhibitor of ferroptosis protein 1-Coenzyme Q10 (FSP1-CoQ10) pathway and P53 pathway (Zheng and Conrad, 2020; Bersuker et al., 2019). System XC⁻ is an important amino acid transport system, which consists of a heterodimer of solute transport family 7A11 (SLC7A11) and SLC3A2 subunits. The main function of this system is to transport cystine, the precursor of the major intracellular antioxidant glutathione (GSH), into the cell. During ferroptosis, GSH reduces lipid peroxides to normal lipids through GPX4 to prevent their accumulation, thereby inhibiting the occurrence of ferroptosis. When system XC⁻ is inhibited or its function is reduced, the intracellular cystine uptake is reduced, resulting in decreased GSH synthesis, which in turn reduces the antioxidant capacity of cells, increases the accumulation of lipid peroxides, and ultimately promotes ferroptosis (Jiang et al., 2015). P53 can inhibit the uptake of cystine by system XC- by down-regulating the expression of cystine, affect the activity of GPX4, reduce the antioxidant capacity of cells, and accelerate the occurrence (Xie et al., 2017) of ferroptosis. Coenzyme Q10 (CoQ10), as an important lipid-soluble antioxidant in vivo, can effectively capture free radicals generated during lipid peroxidation and inhibit the accumulation of lipid peroxides. In addition, CoQ10 is able to regenerate other antioxidants such as α-tocopherol (vitamin E), thereby indirectly inhibiting lipid peroxidation. Ferroptosis inhibitor protein 1 (FSP1) is a key protein in the regulation of ferroptosis. It catalyzes the REDOX cycle of CoQ10 to generate ubiquinol, which further reduces the accumulation of lipid peroxides and prevents the occurrenceof ferroptosis (Bersuker et al., 2019; Kuang et al., 2020) (Figure 2d).

Copper is an indispensable trace element in the physiological processes of all types of cells in the human body. It is widely involved in mitochondrial respiration, antioxidant reactions, biosynthesis of biological compounds, and energy metabolism. Therefore, the uptake, distribution and metabolism of copper are strictly regulated (Tang et al., 2022; Maung et al., 2021). The imbalance of copper homeostasis in the body will trigger a form of cell death caused by excessive copper, namely, Cuproptosis (Tsvetkov et al., 2022). The basic metabolic process of copper relies on three key copper transporters: SLC31A1 is responsible for copper uptake, while ATP7A and ATP7B are responsible for copper efflux. Prostate six-transmembrane epidermal antigen (STEAP), a metalloreductase located on the surface of small intestinal epithelial cells, reduces Cu²⁺ to Cu⁺ and subsequently enters the cell through the high-affinity transmembrane transporter copper transporter 1 (CTR1). Once inside the cell, Cu⁺ binds to copper chaperones through the cytoplasmic, mitochondrial and Golgi pathways, and is targeted for delivery to different copper proteins (Galler et al., 2020). For example, in the cytoplasm, superoxide dismutase copper chaperones (CCS) activate superoxide dismutase 1 (SOD1), which plays an important antioxidant role by regulating the distribution of SOD1 in the cell, ensuring the balance of ROS in the body, and preventing oxidative damage caused by copper overload (Wang et al., 2024). In mitochondria, Cytc oxidase copper chaperone 17 (Cox17) mediates the transport of copper from the cytoplasm to the mitochondria and participates in the respiratory chain and REDOX pathway. In addition, most of the Cu⁺ entering hepatocytes is transported to the trans-Golgi network (TGN) through the antioxidant protein 1 (ATOX1), and copper is excreted by the major transporter ATP7A/B. Together, they maintain the body’s copper homeostasis (Da et al., 2022). When copper homeostasis is disrupted for various reasons, the intracellular copper concentration increases. Copper ionophores such as elesclomol (ES) and disulfiram (DSF) can directly bind to extracellular Cu²⁺ and actively enter the cell, where they are targeted and enriched inmitochondria through the mitochondrial membrane (Tsvetkov et al., 2022; Lutsenko et al., 2010). On the one hand, Cu²⁺ is reduced to more toxic Cu⁺ under the action of ferredoxin 1 (FDX1), which inhibits the synthesis of Fe-S Cluster proteins related to mitochondrial respiration and triggers a proteotoxic stress response that eventually leads to cell death (Tsvetkov et al., 2019). On the other hand, FDX1, as an upstream regulator of protein lipoacylation, participates in the tricarboxylic acid cycle and binds to lipoacylated mitochondrial proteins (such as DLAT), causing protein oligomerization and producing ROS to induce oxidative stress. These abnormal processes together eventually lead to cuproptosis of cells (Sun et al., 2023). Therefore, the accumulation of intracellular copper exceeding the limit is the direct cause of cuproptosis. Cu death can be induced by directly delivering Cu²⁺ into cells using copper ionophore, over-expressing the copper transporter SLC31A1/CTR1, or down-regulating the expression of ATP7A/B protein to increase the intracellular Cu+ concentration (Xie J. et al., 2023) (Figure 2e).

Autophagy is a process of engulfing damaged or aged organelles and proteins, encapsulating them into vesicles to form autolysosomes for degradation, and ultimately achieving cell self-renewal. This process can be divided into two types: selective and non-selective (Gatica et al., 2018; Nakatogawa, 2020). In view of the important role of selective autophagy in maintaining body homeostasis and its ability to target the removal of damaged mitochondria, mitophagy, as an important branch of selective autophagy, has become a hot research field (Vargas et al., 2023). In mammals, the regulatory pathways of mitophagy can be classified into two categories (Khaminets et al., 2016): Ubiquitin-dependent and independent.

PINK1/Parkin signaling, which is dependent on extensive ubiquitylation of mitochondrial surface proteins, is the classical pathway to mediate mitophagy. Pten-induced kinase 1 (PINK1) plays a key role in this process (Harper et al., 2018). Under normal physiological conditions, PINK1 is transported to the inner mitochondrial membrane through the mitochondrial outer membrane translocase complex (TOM) and is rapidly degraded to maintain mitochondrial quality control (Bausewein et al., 2020; Ruth et al., 2014; Sekine et al., 2019). When Mitochondrial damage results in loss of Mitochondrial Membrane Potential (MMP), PINK1 is unable to enter the inner Membrane and accumulates steadily on the Outer Mitochondrial Membrane (OMM). It undergoes rapid autophosphorylation and undergoes a series of modifications on Parkin, such as binding to Ser 65 phosphorylated ubiquitin (pSer 65-Ub) to activate E3 ubiquitin ligase activity. In addition, PINK1 interacts with microtubule-associated protein 1A/1B light chain 3 (LC3) to initiate autophagosome formation and fusion with lysosomes, ultimately promoting the degradationof damaged mitochondria (Koyano et al., 2014; Rasool et al., 2018).

In addition to participating in ubiquitin-dependent mitophagy, some mitochondrial proteins also act as mitophagy receptors, directly mediating the targeted binding and degradation process of dysfunctional mitochondria to autophagosomes (Palikaras et al., 2018). For example, autophagy receptor proteins such as BNIP3, NIX/BNIP3L, FUNDC1 and AMBRA1 interact with LC3 and GABARAP through their LIR domains to efficiently mediate mitochondrial clearance (Gatica et al., 2018; Marinkovic et al., 2021; Hanna et al., 2012) (Figure 2f) (Table 1).

Aβ can bind to Fas and TNF-α receptors on the cell membrane of neurons and activate the endogenous apoptosis signaling pathway. For example, after binding to Fas receptor, Aβ induces the expression and release of Fas ligand (FasL), forming Fas-fasl complex and activating caspase-8 to initiate apoptosis. Studies have shown that in AD model mice, the expression of Fas receptor in hippocampal neurons is upregulated, which is positively correlated with the degree of Aβ deposition. Meanwhile, administration of FasL antagonist can reduce neuronal apoptosis and improve cognitive function. In addition, Aβ deposition directly acts on mitochondria, increasing membrane permeability and releasing pro-apoptotic factors such as Cytc. Cytc binds to Apaf-1 and activates caspase-9 to initiate the mitochondria-mediated apoptotic pathway (Kumari et al., 2023). At the same time, Aβ deposition can also induce the production of A large number of ROS, which triggers oxidative stress. It attacks DNA, proteins and lipids, causing oxidative damage. It further activates the apoptotic signaling pathway in the cell, which eventually leads to apoptosis. Tau binds to Thr212/Thr231/Ser262 and other sites, which will dissociate from microtubules and lead to hyperphosphorylation. With the release of Cytc, Tau binds to Apaf-1 to form apoptotic bodies and activate the cascade of Caspase-9/3 (Alonso et al., 2010). In addition, phosphorylated Tau protein decreased the activity of PI3K/Akt pathway, increased the expression of pro-apoptotic factor Bax, and decreased the expression of anti-apoptotic factor Bcl-2 by competitively inhibiting the regulation of β-catenin by GSK-3β (Ulamek-Koziol et al., 2020). Notably, Caspase-3 can cleave Asp421 site of Tau protein to generate truncated Tau protein, which further aggravates the apoptotic process (Alonso et al., 2010).

In neurodegenerative diseases, necroptosis is mediated by A series of signaling pathways. Firstly, necroptosis can lead to the loss and damage of neurons, which further aggravates the deposition of Aβ and the formation of neurofibrillary tangles. Secondly, necroptosis can release inflammatory factors, such as IL-1β and TNF-α, activate microglia and astrocytes, trigger neuroinflammatory responses, and further damage the function and survival of neurons. Among them, the RIPK1/RIPK3/MLKL signaling axis is the key regulatory pathway. In the brain of AD patients, Aβ binds to the receptor on the cell membrane, activates the downstream RIPK1, and then phosphorylates RIPK3, leading to the phosphorylation and oligomerization of MLKL. Finally, Aβ inserts into the cell membrane to form holes, causing the release of cell contents and inducing the occurrence of cell necroptosis. In addition, cell necroptosis can also affect the intracellular REDOX balance, increase the production of ROS, and lead to oxidative stress damage, thereby promoting the aggregation of Aβ and neurotoxicity. Other studies have shown that p-MLKL, a necrotizing marker of apoptosis, co-localizes with Tau pathology in AD models. Inhibition of RIPK1 or MLKL can significantly reduce Tau aggregation and improve cognitive function (Balusu and De Strooper, 2024).

Aβ and neuronal pyroptosis is A two-way regulation mechanism, which depends on NLRP family proteins in cultured neurons in cortical regions. When NLRP3 inflammasome activity is inhibited, Aβ deposition is significantly reduced. Dempsey et al. found that the use of NLRP3 inhibitor MCC950 can effectively inhibit the expression of NLRP3 and its downstream Caspase-1, thereby inhibiting pyroptosis and reducing Aβ accumulation (Dempsey et al., 2017). In addition to inhibiting NLRP3, pyroptosis can also be inhibited by inhibiting other inflammasomes such as NLRP1, NLRC4 and AIM2, which in turn reduces Aβ deposition (Tan et al., 2014). During the progression of AD, pyroptosis of microglia promotes the formation of ASC-Aβ complexes, not only exacerbating the accumulation of Aβ but also leading to the assembly of NLRP3 inflammasomes, activation of caspase-1, maturation of IL-1β, and cleavage of GSDMD, and further promoting pyroptosis of adjacent microglia. Tau protein showed similar to amyloid Aβ activation mechanism of NLRP3 inflammatory corpuscle. Specifically, phagocytosis of Tau by microglia disrupts lysosomal stability, leading to the release of cathepsin B and its binding to the NLRP3 inflammasome, thereby participating in its activation. This process induces the secretion of interleukin-1β (IL-1β) in an ASC-dependent manner (Stancu et al., 2019). When NLRP3 or ASC is deficient, Tau phosphorylation is significantly inhibited, and key kinases that induce Tau phosphorylation, such as CaMKII-α and GSK-3β, are significantly downregulated, while PP2A, a phosphatase that promotes Tau dephosphorylation, is significantly upregulated. This suggests that NLRP3 inflammasome can promote the pathological process of Tau by regulating the phosphorylation level of tau protein (Wang et al., 2020).

In the ferroptosis pathway, the 5′untranslated region of APP mrna contains an Iron Response Element (IRE) that is regulated by intracellular iron levels. The expression of APP can be regulated by post-transcriptional Iron Regulatory Protein (IRP). When intracellular iron overload occurs, iron ions bind to IRP and promote its dissociation from IRE, thereby increasing the translation efficiency of APP, leading to the increase of APP protein level and finally the production of excess Aβ (Belaidi et al., 2018). As an important proprotein convertase, Furin protease can convert a variety of precursor proteins into mature proteins. The presence of iron ions can reduce the transcription and translation level of Furin, inhibit the activity of α-secretase and activate β-secretase, thus playing a key role in the processing of APP (Guillemot et al., 2013). Studies have shown that Aβ can promote ferroptosis by activating signaling pathways such as mGLIUS and STIM proteins, and regulating the expression of ferroptosis-related genes such as FTH1 and SAT1. The interaction between ferroptosis and Tau protein also shows the characteristics of bidirectional regulation. The imbalance of iron metabolism activates glycogen synthase kinase-3β (GSK-3β), promotes abnormal phosphorylation of Tau protein, inhibits the ubiquitin-proteasome system, and hinders the degradation of Tau protein, thereby accelerating its pathological aggregation (Wang et al., 2022a). In addition, ferroptosis-inducing agents further aggravate the toxic effects of Tau by inhibiting System Xc- and GPX4 (Wang et al., 2022b).

Cuproptosis is a novel form of cell death, which is associated with the abnormal accumulation of intracellular copper ions. Studies have shown that copper content is significantly increasedin peripheral blood and brain tissue of AD patients (Zhou et al., 2022). Excessive copper ions can bind to lipoic acid esterified proteins in mitochondria, leading to mitochondrial dysfunction and the loss of iron-sulfur cluster proteins, which in turn induces proteotoxic stress and further promotes the deposition and aggregation of Aβ. Aβ deposition is not only one of the pathological features of AD, but also may affect the occurrence of cuproptosis through A variety of mechanisms. On the one hand, Aβ deposition can lead to increased levels of oxidative stress in cells, and oxidative stress is one of the important factors inducing the death of copper. On the other hand, Aβ deposition may interfere with the distribution and metabolism of intracellular copper, increase the accumulation of copper ions in cells, and thus promote the occurrence of cuproptosis. Studies have shown that Aβ peptide and APP bind to copper through specific amino acid residues (such as histidine His13, His14, His6 and tyrosine Tyr10), and reduce Cu²⁺ to Cu⁺ through CTR1. This process generates ROS, which in turn leads to oxidative damage of Aβ peptide, intracellular proteins and lipids. And aggravate neurotoxicity (Multha et al., 1996). Knockout of CTR1 can significantly reduce the accumulation of copper in the brain, thereby alleviating Aβ42-induced neurodegeneration and enhancing the resistance to oxidative damage. Inhibition of CTR1 can effectively regulate the accumulation of copper in the brain and improve Aβ-induced neurotoxicity (Lang et al., 2013).

In recent years, autophagy has become A hot spot in AD research. In AD, autophagy participates in the clearance of Aβ and promotes the degradation of p-tau, which is of greatsignificance for the improvement of AD (Weller and Budson, 2018). Specifically, the autophagy-lysosome pathway plays an important role in the metabolism of Aβ, and intracellular Aβ is mainly degraded by lysosomal metabolism. Under normal circumstances, Aβ produced by autophagosomes is transported to lysosomes and degraded by A variety of hydrolases. Therefore, the amount of Aβ in neuronal lysosomes is very small. However, under pathological conditions, the content of Aβ in lysosomes increases significantly due to the blockage of this pathway, and the excessive deposition of Aβ and APP will lead to autophagy dysfunction, and the clearance of Aβ by autophagy will fall into A decompensated stage. With the continuous exploration of the pathogenesis of AD, it has been found that inducing autophagy in the early stage of AD can switch a large number of APP-rich metabolic substrates to the autophagy-lysosome system metabolic pathway, accelerate the clearance of misfolded proteins and damaged organelles, and thus improve AD (Whyte et al., 2017). Autophagy is also one of the key mechanisms to clear phosphorylated tau protein from neurons. Studies have shown that the damage of autophagy-lysosome system can lead to the formation of tau oligomers and insoluble aggregates. Autophagy dysfunction is closely related to the excessive accumulation of p-tau in the brain, which can be significantly alleviated by inducing autophagy (Zhang J. et al., 2024; Silva et al., 2019). Studies have found that activation of AMPK-mTOR pathway can enhance the autophagy pathway to reduce the content of tau protein, thereby improving the cognitive impairmentof AD mice (Malampati et al., 2020). In addition, some studies have suggested that activating the Nrf2/Keap1/NQO-1 pathway can increase autophagy flux and promote the clearance of P-tau, thus playing a therapeutic rolein AD (Ma et al., 2024).

Autophagy has been confirmed as an important physiological protective mechanism in cells. In the early stage of disease, the body actively activates autophagy pathway to prevent cell apoptosis. However, with the progression of the disease, when autophagy function is impaired, it may lead to a significant increase in neuronal apoptosis. In recent years, more and more studies have shown that the excitability and toxicity of glutamate play a key role in neurodegenerative diseases. It has been reported that the activation of autophagy is closely related to the level of glutamate. For example, in a cell model of glutamate-induced AD, glutamate stimulation significantly upregulated the expression of autophagy-related proteins Beclin-1 and LC3-II, decreased the Bax/Bcl-2 ratio and P62 protein level, and restored mitochondrial membrane potential. These results indicate that the increased level of autophagy can effectively inhibit the expression of apoptosis-related proteins and reduce the deposition of β-amyloid (Aβ), Tau protein phosphorylation and the formation of neurofibrillary tangles (NFTs), which provides A new theoretical basis (Xie D. et al., 2023). In addition, IKKβ-activating enzyme has been shown to inhibit the occurrence of necroptosis by enhancing autophagy activity in Aβ-induced neuroblastoma cell model. Specifically, when autophagy-related proteins were silenced, the expression of necrotizing effectors in cells was significantly increased, further exacerbating the necrotizing process. These results indicated that autophagy could effectively inhibit RIPK-mediated necroptosis in Aβ-induced neuroblastoma cells. Further studies have found that IKKβ is an upstream signaling molecule of autophagy, and its activation can significantly improve necroptosis caused by impaired autophagy and reduce Aβ deposition, which has potential value for the treatment of AD (Wang W. et al., 2022).

Previous studies have found that necroptosis in rats with Aβ-induced AD can increase the expression of SLC7A11, the key factor of ferroptosis, and decrease the level of TFR, leading to the decrease of RIPK1 and RIPK3 expression, and thus improve the pathological process of AD mediated by necroptosis. Further studies have found that necrospot-1, an inhibitor of necroptosis, has no effect on ferroptosis, but Aβ induced necroptosis is inhibited by ferrostatin, indicating that ferroptosis pathway may act as an upstream signal of necroptosis to regulate Aβ neurotoxicity in AD (Tang et al., 2021).

Autophagy plays a key role in the regulation of ferroptosis. Excess iron interacts with ferritin and binds to NCOA4 to induce selective autophagy and release more free iron. At the same time, P62 can lead to abnormal expression of ferritin autophagy, resulting in large iron accumulation and iron overload (Quiles and Mancias, 2019). At the same time, there is crosstalk between mitophagy and ferroptosis in the process of AD. By establishing A cell model of Aβ-induced AD damage, we found that there was a crosstalk between CD36/PINK/Parkin-mediated mitophagy and ferroptosis. This ferroptosis pathway could be exacerbated by mitophagy inhibitors. These results indicate that CD36/PINK/Parkin-mediated mitophagy plays an important role in regulating ferroptosis and inhibiting the deposition of Aβ in AD (Li et al., 2022). Therefore, dysregulation of the autophagy system may directly lead to the abnormal accumulation of iron in the brain of AD, which in turn triggers ferroptosis. Notably, SLC7A11, a key inhibitor of ferroptosis, is also closely related to cuproptosis. Studies have found that when the expression level of SLC7A11 is upregulated, it can promote the synthesis of glutathione from cysteine, which in turn chelates copper ions, reduce the level of intracellular copper ions, and inhibit the occurrence of cuproptosis (Zhang P. et al., 2024). Although there are few reports on the crosstalk relationship among autophagy, ferroptosis and cuproptosis in AD, using SLC7A11 as a cross point to link autophagy, ferroptosis and cuproptosis can provide clues for future research on the pathogenesis of AD (Figure 3).