Metabolic reprogramming represents a fundamental characteristic of cancer biology, with tumor-associated metabolic alterations manifesting through multiple interconnected pathways. The hallmarks of cancer metabolism reprogramming include enhanced glycolysis, altered redox status, changes in lipid metabolism, and modified amino acid metabolism. As central hubs for cellular energetics, mitochondria occupy a pivotal position in mediating these cancer-specific metabolic adaptations. Under aerobic conditions, normal cells primarily utilize mitochondrial oxidative phosphorylation for energy production, while cancer cells display a preference for glycolysis, even in the presence of oxygen, a phenomenon famously termed the Warburg effect. According to reports, treatment of glioma cells with RSL3 resulted in the downregulation of key rate-limiting enzymes in glycolysis, including hexokinase II (HKII), platelet-type phosphofructokinase (PFKP), and pyruvate kinase M2 (PKM2), leading to impaired glycolytic function. Mitochondria metabolic kinase PCK2 phosphorylates and activates ACSL4 to drive ferroptosis-associated phospholipid remodeling. Tumor-repopulating cells (TRCs) downregulate the PCK2 expression to confer themselves on a structural ferroptosis-resistant state [69].

Glutaminolysis and tricarboxylic acid (TCA) cycle are involved in ferroptosis, but the underlying metabolic process remains unclear. Various TCA metabolites and enzymes have close relations with ferroptosis, the expression level of these key enzymes determines the sensitivity of cancer cells to ferroptosis. Glutamine is essential for ferroptosis, and glutaminase can hydrolyze glutamine to generate glutamate, providing fuel for the TCA cycle. Glutaminase 2 (GLS2), a key regulator of glutamine hydrolysis, has been demonstrated to promote ferroptosis [70]. Alpha-ketoglutarate (α-KG) can mimic the role of glutamine in ferroptosis. α-KG and its downstream products, such as succinate and fumarate, enhance ferroptosis induced by cysteine depletion [71] (Fig. 2). The degradation of glutamine required GLS, glutamate dehydrogenase (GDH) and GOT2 to provide fuel for TCA cycle and lipid biosynthesis. TCA cycle metabolites such as α-KG mimic the function of glutamine in ferroptosis. α-KG and its downstream products such as succinic acid and fumaric acid, all enhance ferroptosis induced by cysteine depletion [71]. IDH1 and IDH2 facilitate the transformation of isocitrate into α-ketoglutarate. However, mutations in these enzymes result in the conversion of α-ketoglutarate into D-2-hydroxyglutarate (D-2-HG). In tumors, mutated IDH1 reduces GPX4 protein levels, enhances glutathione consumption, and induces ferroptosis. However, D-2-hydroxyglutarate (D-2-HG) confers resistance to ferroptosis in cells [72]. Mitochondrial NADP+-dependent IDH2 is a major enzyme that produces NADPH, which is a crucial driver of mitochondrial GSH turnover, and downregulation of IDH2 sensitizes cancer cells to erastin-induced ferroptosis [73]. Fumarate hydratase (FH) is a TCA cycle enzyme. The inactivation of FH is induced and leads to cell death via ferroptosis because of the dysfunction [74]. In renal cancer cells, FH mutations inhibit ferroptosis due to cysteine starvation [71], but knockdown of the FH gene makes cells more sensitive to erastin-induced ferroptosis [74].

Metabolism of mitochondria in ferroptosis. (1) Regulation of mitochondrial energy metabolism in ferroptosis. Cells whose metabolism has shifted from glycolysis to OXPHOS are susceptible to ferroptosis. FSP1 is an oxidoreductase that reduces CoQ to CoQH2, thereby inhibiting lipid peroxidation. GLS converts glutamine to glutamate, and glutamate is finally converted to α-KG in the TCA cycle. DHODH reduces CoQ to CoQH2 in mitochondria, detoxifying lipid peroxidation and protecting cells from ferroptosis. The mitochondrial TCA cycle and ETC are the main sources of lipid peroxide production. (2) Regulation of mitochondrial iron metabolism in ferroptosis. Mitochondria are pivotal in cellular iron metabolism, serving as the primary site for heme and Fe-S cluster synthesis. They are involved in the cellular import of iron through the heme pathway. Iron enters the mitochondria via VDAC or Mfn1/2. ROS in the mitochondria interact with free iron to catalyse the Fenton reaction in the mitochondria, allowing more ROS to be produced. Excess iron can be stored in FtMts to protect mitochondria from damage induced by free iron. CISD1 inhibits mitochondrial iron accumulation. The enzyme NFSI facilitates the biosynthesis of iron-sulfur clusters by acquiring sulfur from cysteine. These clusters are then transported to the CIA via the protein ABCB7

Mitochondrial electron transport chain (ETC) activity is not only necessary for ATP production but also essential for the generation of an adequate amount of lipid ROS, which is crucial for triggering ferroptosis. Most ROS are generated by the ETC during electron transfer processes. When any key ETC gene is missing or ETC function is inhibited, the quantity of ROS increases, and high levels of ROS accumulation may lead to ferroptosis. Inhibitors of mitochondrial ETC complexes can suppress ferroptosis [75], and erastin has been shown to target the voltage-dependent anion channel (VDAC) in mitochondria [76]. Moreover, enhanced ETC activity also affects cancer cell sensitivity to ferroptosis [77]; for example, a subunit of cytochrome c oxidase, COX7A1, enhances sensitivity of non-small cell lung cancer cells to cysteine deprivation-induced ferroptosis by blocking autophagic flux, inhibiting mitochondrial dynamics, and impairing mitochondrial biogenesis and mitosis. Additionally, the ATP release pathway protein, Panx1, plays a pro-apoptotic role in kidney injury cells. Panx1 deficiency has been shown to provide protection against renal ischemia/reperfusion injury (IRI) by modulating cellular ferroptosis [78]. The mitochondrial NEET protein family plays a crucial role in maintaining the delicate balance of ROS and the storage of labile iron within mitochondria. NEET proteins carry unstable 2Fe-2 S clusters that can transfer to apo-receptor proteins [79]. CISD3, a member of the NEET protein family, is universally upregulated in various human cancers and is associated with poor prognosis. The depletion of CISD3 results in a metabolic shift in glutamine metabolism, necessary for mitochondrial OXPHOS. Knocking out CISD3 significantly accelerates lipid peroxidation and the initial accumulation of free iron induced by Xc- inhibition or cysteine deprivation, resulting in cell ferroptosis [80].

The maintenance of cellular energy homeostasis is essential for organismal survival. Under conditions of glucose deficiency, cells experience metabolic stress, triggering compensatory mechanisms to reestablish energy equilibrium. Energy stress, characterized by the depletion of intracellular ATP and a corresponding increase in intracellular AMP levels, inhibits ferroptosis. As a central regulator of energy metabolism, AMP-activated protein kinase (AMPK)is activated in response to this stress [81]. Cancer cells with high AMPK activation are resistant to ferroptosis, while AMPK inactivation sensitizes these cells to ferroptosis [21]. AMPK activation leads to phosphorylation of two key AMPK targets: FoxO3a and acetyl-CoA carboxylase (ACC). Through AMPK-dependent ACC phosphorylation, cells suppress lipid biosynthesis, conferring protection against ferroptosis during glucose limitation [21]. Glucose deprivation can lead to energy stress and markedly increase the intracellular level of ROS [82, 83]. AMPK regulates ferroptosis through ACC and polyunsaturated fatty acid (PUFA) biosynthesis [84]. Alternative to the impact on lipid synthesis, the energy stress-activated AMPK could also compensate the pentose phosphate pathway (PPP)‐suppression‐induced reduction of cellular NADPH and enhance ferroptosis resistance. The underlying mechanism is that AMPK phosphorylate and inhibit ACC1 and ACC2 to suppress the NADPH‐consuming synthesis of fatty acids, meanwhile enhancing the oxidization of fatty acids to replenish the NADPH supply[21]. The LKB1-AMPK pathway negatively regulates ferroptosis by inhibiting ACC1-mediated fatty acid synthesis [85]. For example, the loss of function of tumor suppressor LKB1 enhances human non-small cell lung cancer cells sensitivity to ferroptosis [85].

Coenzyme Q (CoQ) serves dual functions within cells: it functions as an electron carrier within the mitochondrial ETC and serves as an endogenous lipophilic antioxidant. The compound FIN56, identified as a specific inducer of ferroptosis, activates squalene synthase to inhibit CoQ, thereby enhancing sensitivity to ferroptosis triggered by FIN56 [22]. Additionally, dihydroorotate dehydrogenase (DHODH) is pivotal in the mitochondrial de novo pyrimidine synthesis pathway, facilitating the conversion of dihydroorotate to orotate. This enzymatic step is crucial for pyrimidine biosynthesis, which is necessary to support cellular proliferation. Utilizing the CoQ pool, DHODH integrates with the ETC and relies on CoQ/ubiquinone as an electron acceptor [86]. In mitochondria, DHODH reduces CoQ to CoQH2, thereby detoxifying lipid peroxides and safeguard cells against ferroptosis. This pathway operates independently of mitochondrial GPX4, providing an alternative route to inhibit ferroptosis, distinct from the cytosolic GPX4 or FSP1 pathways [87, 88].

Treatment with targeted mitochondrial antioxidants can rescue cells from damage caused by lipid peroxidation. For instance, MitoTEMPO has been reported to rescue doxorubicin (DOX)-induced ferroptosis in myocardial diseases, suggesting that mitochondria may be a critical factor in DOX-induced ferroptosis in the heart [89]. Another mitochondrial-targeted antioxidant, nitroxide XJB-5-131, can inhibit ferroptosis induced by erastin or RSL3, indicating the crucial role of mitochondrial ROS in ferroptosis [90]. It has been reported that P53 positively regulates ferroptosis by promoting ROS production [8]. However, under certain conditions, P53 can also protect cells by clearing ROS. Further research is needed to elucidate the relationship between P53 and ferroptosis.

Apart from their function as the primary energy generators in cells, mitochondria also play a crucial part in cellular iron metabolism. Within the mitochondrial matrix, iron metabolism occurs, requiring the transfer of iron across both the outer and inner mitochondrial membranes. VDACs present in the outer mitochondrial membrane (OMM) facilitate the transport of iron and other metabolites across this barrier [91]. Erastin induces the opening of VDAC2/3, mediating iron uptake and thereby accelerating ferroptosis [92, 93]. BDNF-AS/WDR5/FBXW7 axis regulates ferroptosis in GC by affecting VDAC3 ubiquitination [94]. Mitochondrial iron transport across the inner mitochondrial membrane (IMM) is mediated by two proteins: mitoferrin-1 and mitoferrin-2. These proteins, encoded by the SLC25A37 and SLC25A28 gene respectively, function as mitochondrial iron importers and facilitate this process without requiring ATP. Disorders like Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease, characterized by ferroptosis, have been linked to the imbalanced expression of mitoferrin-1 and mitoferrin-2 [95]. In vitro and in vivo evidence suggest that Mfrn1 acts as a tumor suppressor to regulate mitochondrial iron-induced ferroptosis in HCC [96]. A previously study revealed the Mfrn2-dependent mitochondrial iron uptake induced iron-dependent mitochondrial dysfunction and the subsequent killing of human head and neck squamous carcinoma cells [97]. However, Mfrn1/2-mediated mitochondrial iron accumulation promotes osteosarcoma carcinogenesis, and high expression of Mfrn1 in GBM tumor tissues increases the level of mitochondrial iron and is associated with a poor prognosis [98, 99]. Overall, the expression and function of Mfrn1/2 may vary depending on the cell types and conditions (Fig. 2).

Cytoplasmic labile iron, upon entering the mitochondria, primarily serves as a substrate for synthesizing Fe-S clusters. Serving as an iron chaperone within the mitochondria, the protein frataxin (FXN) facilitates the initiation of Fe-S cluster biogenesis [100]. Frataxin is implicated in Friedreich’s ataxia (FRDA) pathology. In FRDA cell models, ferroptosis inhibitors can mitigate the toxicity induced by ferric citrate and BSO, rescuing frataxin knockdown-induced cell death [101]. Apart from its involvement in iron metabolism, Fe-S clusters participate in various biological processes such as mitochondrial respiration and redox reactions [102]. Fe-S cluster proteins, such as those found in NADH: ubiquinone oxidoreductase within the mitochondrial inner membrane’s ETC, have the ability to utilize iron from mitochondria as a cofactor [103]. The formation and maturation of Fe-S cluster-containing proteins rely on the cytosolic iron-sulfur protein assembly (CIA) system, which is crucial for this process. Once integrated into target proteins, Fe-S clusters either act as catalytic centers or engage in electron transfer reactions. The primary hub for Fe-S cluster synthesis is the mitochondrial iron-sulfur cluster (ISC) assembly and export system. NFS1, serving as another Fe-S cluster biosynthetic enzyme, collects sulfur from cysteine for Fe-S cluster synthesis, thereby protecting breast cells against ferroptosis [104]. Moreover, Fe-S clusters are transported from the mitochondria to the cytoplasm through the Fe-S cluster export mechanism facilitated by ABCB7.

Mitochondria contain an labile iron pool with potent redox activity [105]. The iron storage protein mitochondrial ferritin (FtMt) in mitochondria plays a pivotal role in maintaining the balance of free iron [106]. By preventing excessive mitochondrial ROS (mitoROS) accumulation [107], FtMt protects mitochondrial proteins, lipids, and DNA from oxidative damage, thereby sustaining ATP production and preventing energy deficits [108]. Conversely, reduced FtMt expression increases mitochondrial free iron levels, leading to elevated mitoROS accumulation and subsequent ferroptosis [109]. NEET proteins, newly discovered iron-sulfur proteins (2Fe-2 S), play crucial roles in regulating iron and energy metabolism, as well as iron-sulfur cluster and ROS levels. At present, three NEET proteins have been identified: CISD1 resides in the OMM; CISD2 is present in the OMM, ER, and membranes connecting mitochondria and ER; while CISD3 predominantly localizes within the mitochondria. In contrast to mitoferrin1/2, when the synthesis of Fe-S clusters is disrupted, NEET proteins mediate the export of sulfur ions and iron between the cytosol and mitochondria. Downregulation of CISD1-3 consistently results in increased accumulation of mitochondrial ferrous iron and the production of mitochondrial ROS [110, 111]. Taken together, these results emphasize the crucial function of mitochondria in preserving cellular iron balance. Perturbation of mitochondrial iron equilibrium might serve as a viable therapeutic strategy in cancer treatment by triggering ferroptosis in cells.

Mitochondria undergo fusion and fission processes in a state of constant flux, resulting in changes to the size and morphology of their offspring. This process is known as mitochondrial dynamics. Mitochondrial fusion and fission processes are intricately linked to iron metabolism and ferroptosis. An excess of iron disrupts the balance between mitochondrial fusion and fission [112]. The classical process of mitochondrial fusion entails the merging of two mitochondria end-to-end, encompassing both OMM fusion and IMM fusion.

Mitochondrial fusion is facilitated by OMM proteins, such as mitochondrial fusion proteins 1 and 2 (Mfn1/2), along with optic atrophy protein 1 (OPA1) on the IMM (Fig. 3b). OMM fusion comprises three distinct stages: tethering, docking, and ultimately, merger. IMM fusion presents a higher level of complexity compared to OMM fusion, necessitating swift and effective initiation after OMM fusion. Additionally, the IMM fusion protein OPA1 needs to be partially cleaved into two forms, integral (l-type) and soluble (s-type), to successfully complete the fusion reaction. OPA1 is also involved in the formation of cristae. The absence of MFN2 correlates with an accumulation of iron within mitochondria, while OPA1 experiences cleavage when cells are exposed to excessive iron levels [113]. Some studies have reported that human and mouse cells lacking OPA1 are markedly resistant to ferroptosis. Reconstitution with OPA1 mutants demonstrates that ferroptosis sensitization requires the GTPase activity but is independent of OPA1-mediated mitochondrial fusion. Mechanistically, OPA1 confers susceptibility to ferroptosis by maintaining mitochondrial homeostasis and function, which contributes both to the generation of mitochondrial lipid reactive oxygen species and suppression of an ATF4-mediated integrated stress response [114]. STING promotes ferroptosis in human pancreatic cancer cell lines by enhancing MFN1/2-dependent mitochondrial fusion rather than mitochondrial removal through autophagy. The classic ferroptosis inducer erastin can induce the accumulation of STING1 in mitochondria, where it binds with MFN1/2 to trigger mitochondrial fusion, subsequently leading to ROS generation and lipid peroxidation [115]. Deletion of MFN1/2 genes reduces the sensitivity of pancreatic cancer cells to ferroptosis [115]. The fusion state maintains the stability of Fe-S cofactors, supports ETC function, and reduces the free Fe²⁺. In contrast, fusion defects can lead to impaired Fe-S synthesis, releasing free Fe²⁺ and increasing susceptibility to ROS and ferroptosis.

The link between mitochondrial dynamics and ferroptosis. a Mitochondrial fission is regulated by DRP1, which interacts with four proteins located on the OMM: MIEF1/MiD51, Mff, MIEF2/MiD49, and FIS1. NRF2, a pivotal regulator of ferroptosis, regulates proteasomal genes involved in DRP1 degradation, consequently impeding mitochondrial division. In addition, mitochondria-localized cGAS interacts with DRP1 to promote mitochondrial fission and maintain mitochondrial membrane integrity, thereby preventing the release of iron ions to inhibit ROS production and ferroptosis. However, mitochondrial fission dysfunction disrupts the structure of the mitochondrial membrane, releasing iron ions stored in the mitochondria (such as Fe-S cofactors or Fe³⁺ bound to ferritin), which increases the labile iron pool (LIP) in the cytoplasm. Free Fe²⁺ generates hydroxyl radicals through the Fenton reaction, exacerbating ROS accumulation and lipid peroxidation, promoting ferroptosis. b OMM fusion is mediated primarily by MFN1/2, while IMM fusion is mediated by OPA1. Endoplasmic reticulum protein STING1 promoted ferroptosis by increasing mitochondrial fusion. Erastin prompts the interaction of STING1 with MFN1/2, initiating mitochondrial fusion. The fusion state maintains the stability of Fe-S cofactors, supports ETC function, and reduces the free Fe²⁺. In contrast, fusion defects can lead to impaired Fe-S synthesis, releasing free Fe²⁺ and increasing susceptibility to ROS and ferroptosis

Mitochondrial fission relies on the participation of dynamin-related protein 1 (DRP1), which is recruited to the OMM (Fig. 3a). Upon recruitment, DRP1 initiates mitochondrial constriction, leading to subsequent division and the formation of two distinct organelles. Maintaining the equilibrium between mitochondrial fusion and fission is essential for sculpting the morphology of mitochondrial offspring. This balance facilitates the exchange of substances across mitochondrial membranes and contents, thereby playing a crucial role in preserving mitochondrial DNA (mtDNA). DRP1 interacts with four OMM proteins: mitochondrial fission factor (Mff), mitochondrial elongation factor 1 (MIEF1/MiD51), mitochondrial fission protein 1 (FIS1), and MIEF2/MiD49 [116]. Mitochondrial fission is important for mitochondrial self-regulation and maintenance of mitochondrial function. Ferroptosis is strongly linked to mitochondrial fission. NRF2 is negatively regulated by KEAP1, and increased NRF2 activity leads to increased proteasome activity, resulting in the degradation of DRP1 in a ubiquitin-independent manner [117]. The mitochondrial chaperone protein glucose-regulated protein 75 (GRP75) is sequestered outside the mitochondria under conditions of ferroptosis and competitively binds KEAP1 with NRF2. NRF2 is then stabilized and activated, leading to transcriptional activation of a set of ferroptosis resistant genes [118]. NRF2 not only inhibits mitochondrial fission by regulating proteasome genes to promote the degradation of DRP1, but also is an important factor in the regulation of ferroptosis [119, 120]. NRF2 is a major regulator of the antioxidant response and has been shown to modulate the activity of several ferroptosis and lipid peroxidation-related proteins. Some of these proteins are involved in iron/metal metabolism, some are involved in intermediary metabolism and glutathione synthesis/metabolism [121]. The relationship between iron chelation and mitochondrial elongation is revealed in the absence of FIS1, whereas cellular iron overload leads to the dephosphorylation of DRP1 at Ser637. In oral squamous cell carcinoma, DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness and driven ferroptosis [122]. In addition, mitochondria-localized cGAS interacts with DRP1 to promote its oligomerization and function, thereby preventing mitochondrial ROS accumulation and ferroptosis [123]. However, mitochondrial fission dysfunction disrupts the structure of the mitochondrial membrane, releasing iron ions stored in the mitochondria (such as Fe-S cofactors or Fe³⁺ bound to ferritin), which increases the labile iron pool (LIP) in the cytoplasm. Free Fe²⁺ generates hydroxyl radicals through the Fenton reaction, exacerbating ROS accumulation and lipid peroxidation, promoting ferroptosis. In a recent study, co-treatment with low concentrations of erastin and pentacyclic triterpenoid quinone induced significant cell death in non-small cell lung cancer (NSCLC) cells by activating the ROS-mitochondrial fission-autophagy signaling pathway [124]. This was attributed to the fact that the combined treatment led to an increase in ROS, disruption of mitochondrial membrane potential, and promotion of mitochondrial fission. SHARPIN is a tumor-associated gene, SHARPIN silencing in cholangiocarcinoma leads to an accumulation of ROS, reduction of mitochondrial fission and of mitochondrial membrane potential, which ultimately leads to ferroptosis [125]. The study found that Drp1 is phosphorylated and activated upon induction of ferroptosis, and it subsequently translocates to the mitochondria. Further activation of Drp1 via the mitochondrial phosphatase PGAM5 promotes the occurrence of ferroptosis. Remarkably, Drp1 depletion delayed mitochondrial and plasma membrane lipid peroxidation [126]. This has important implications for targeting mitochondrial dynamics in ferroptosis-based tumor therapy.

The preservation of cellular health and mitochondrial homeostasis heavily depends on the essential process of mitophagy. As cells age, encounter ROS, or experience nutrient deprivation, mitochondrial impairment ensues. In instances of mild mitochondrial damage, the mitochondrial state can be alleviated by mitochondrial fusion. However, when mitochondria endure severe damage, cells resort to autophagy mechanisms to maintain intracellular homeostasis. Here, damaged or dysfunctional mitochondria are sequestered by autophagosomes, which subsequently fuse with lysosomes for degradation. In addition, damaged mitochondria can enter the migrasome and be cleared out.

One of the most extensively investigated mechanisms of mitophagy is the PINK1/Parkin pathway (Fig. 4). Under normal circumstances, PINK1 is directed to the IMM and subsequently undergoes degradation [127]. However, in the presence of damaged mitochondria, characterized by depolarization and decreased membrane potential, the translocation of PINK1 to the inner membrane is hindered. As a result, PINK1 accumulates on the OMM. Afterward, PINK1 engages with Parkin, an E3 ubiquitin ligase, to regulate mitophagy. One of the key events in this process is the phosphorylation of the Parkin substrate Ub at Ser65 (pSer65-Ub) by PINK1 [128, 129]. Following the build-up of pSer65-Ub on the OMM, autophagy receptors such as NDP52 and OPTN, along with certain autophagy initiation factors, are recruited to facilitate perimitophagy [130, 131]. OPTN and NDP52 facilitate the tethering of Ub-tagged mitochondria to the autophagosome through their interaction with microtubule-associated protein 1 light chain 3 (LC3) [132, 133]. PINK1, independent of Parkin, can directly engage OPTN and NDP52 to trigger mitophagy. The involvement of Parkin intensifies PINK1 signaling and boosts mitophagy. Acting as an autophagy-related adaptor protein, Sequestosome-1 (p62/SQSTM1) facilitates the connection between ubiquitinated cargo and autophagosomes. Throughout PINK1/Parkin-induced mitophagy, P62 relocates to mitochondria, aiding in the buildup of impaired mitochondria. Inhibition or knockout of PINK1 impairs mitophagy and enhances ROS production, leading to oxidation and oligomerization of TOMM20, followed by mitochondrial recruitment and activation of BAX. Furthermore, inhibition or deficiency of PINK1 potentiates the anti-tumor effects of the clinical ROS-inducing drug ethacrynic acid (EA) to inhibit neuroblastoma progression in vivo [134].

Two pathways of mitophagy. Cells maintain cell stability through autophagy. Damaged or dysfunctional mitochondria are sequestered by autophagosomes in this process. These autophagosomes subsequently fuse with lysosomes, facilitating the degradation of the engulfed mitochondria. One of the most extensively investigated mechanisms of mitophagy is the PINK1/Parkin pathway. PINK1 phosphorylates the Ser65 site of Ub, a substrate of Parkin, and pSer65-Ub aggregates on the OMM, facilitating the recruitment of autophagy initiators. These initiators then interact with LC3, thereby promoting mitophagy. Unlike PINK1–Parkin-mediated mitophagy ubiquitination, several proteins, such as BNIP3, NIX, and FUNDC1, contain LIR (LC3-Interacting Region) structural domains and are located on the outer or inner mitochondrial membrane. These proteins act as mitophagy receptors. They directly bind to the essential autophagy protein MAP1LC3 (LC3), without ubiquitination, thereby initiating mitophagy and selectively destroying damaged mitochondria. In mammals, these receptors include FUNDC1, BNIP3, NIX, and other receptors

Apart from the PINK1/Parkin pathway, numerous LIR domain-containing proteins reside on the mitochondrial outer membrane. These proteins include Nip3-like protein X (NIX), the FUN14 domain-containing 1 (FUNDC1) receptor, and the BCL2-interacting protein 3 (BNIP3) receptor. They are autophagy receptors that do not need to be ubiquitinated in order to bind to LC3 to induce autophagy (Fig. 4). If BNIP3 is knocked down, mitophagy will be significantly reduced, thereby aggravating cell apoptosis [135].

Recent studies have increasingly unveiled the involvement of mitophagy in regulating ferroptosis. Among various identified autophagy types such as lipophagy, clockophagy, ferritinophagy, mitophagy, play pivotal roles in driving cells towards ferroptosis. These processes include STAT3-induced lysosomal membrane permeabilization, RAB7-dependent lipophagy, NCOA4-mediated ferritinophagy, HSP90-associated chaperone-mediated autophagy, SQSTM1-dependent clockophagy, BECN1-mediated systemic Xc- inhibition, and PINK1-related mitophagy, collectively regulating the cellular ferroptosis response [136, 137]. Advancements in research have revealed that inhibitors of ferroptosis, such as certain antioxidants, can impact mitophagy, while drugs regulating mitophagy also influence ferroptosis [