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J Cancer 2026; 17(10):1808-1820. doi:10.7150/jca.140132 This issue Cite

Review

Molecular mechanism and potential role of mitophagy in breast cancer

Xin Yang^1,2,#, Youqin Zeng^1,2,#, Ling Zhang^1,2, Yuting Ye^1,2, Siyu Chen³, Changyou Wei^4,*, , Ping Leng^1,2,*,

1. College of Medical Technology, Chengdu University of Traditional Chinese Medicine, China.
2. Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, China.
3. Department of Clinical Laboratory, Pengzhou Hospital of Traditional Chinese Medicine, China.
4. School of Public Health, Chengdu Medical College, China.
^#Denotes co-first authorship.
^*Equally contributing.

✉ Corresponding authors: Professor Ping Leng, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, Sichuan 611100, China. Email: lengpingedu.cn. Professor Changyou Wei, School of Public Health, Chengdu Medical College, No. 783 Xindu Avenue, Xindu District, Chengdu, Sichuan 610500, China. Email: 2830297980com. More

Received 2026-6-30; Accepted 2026-9-18; Published 2026-9-24

Abstract

Breast cancer remains the most commonly diagnosed malignancy among women worldwide and a leading cause of cancer related mortality in this population. Mitochondrial dysfunction is increasingly recognized as a hallmark of breast cancer, contributing to tumor initiation, progression, and therapeutic resistance. Mitophagy, a selective form of autophagy that eliminates damaged or dysfunctional mitochondria, is essential for maintaining cellular and mitochondrial homeostasis. Accumulating evidence indicates that mitophagy plays a context dependent role in breast cancer. Impaired mitophagy permits the accumulation of damaged mitochondria and promotes tumor growth, migration, and invasion, whereas appropriately activated mitophagy removes damaged mitochondria and suppresses tumor progression. This review synthesizes the molecular mechanisms of mitophagy, its crosstalk with ferroptosis, and its context dependent roles in breast cancer development, with the aim of offering therapeutic insights that may inform breast cancer treatment.

Keywords: mitophagy, breast cancer, cell death, therapy

1. Introduction

Breast cancer exhibits a rising global incidence [1]. Despite advances in early detection and treatment, breast cancer remains the most commonly diagnosed malignancy in women globally and the second leading cause of cancer-related death, accounting for approximately 2.3 million new cases and 670,000 deaths in 2022 [2]. The advent of novel breast cancer therapies has been tempered by the occurrence of adverse effects [3], notably organ damage, drug resistance, and an elevated risk of disease recurrence [4-6]. Therefore, identifying effective therapeutic targets and developing novel treatment strategies remain a current priority.

Regulated cell death (RCD) refers to a type of cell death that is controlled by defined molecular pathways [7]. Cell death may occur through genetically programmed suicide mechanisms such as apoptosis, or be triggered by dysregulated metabolic processes such as ferroptosis [8]. Various cell death modalities play significant roles in regulating tumor development, progression and drug resistance through different signaling pathways. Autophagy is a cellular process that promotes the degradation of intracellular macromolecules or damaged organelles [9]. Autophagy can be subdivided into nonselective forms (e.g., microautophagy and macroautophagy) or selective forms (including mitophagy, endoplasmic reticulum autophagy (ER-autophagy), and ribosomal autophagy) [10,11]. By identifying and eliminating damaged or excess mitochondria, the selective autophagic process known as mitophagy regulates mitochondrial number and function to maintain cellular balance [12]. Accumulating evidence implicates mitophagy in cancer pathogenesis, particularly in breast cancer [13]. Mitochondrial dysfunction underpins key aspects of tumorigenesis, including cancer cell survival and drug resistance [14,15]. Due to a dual role and dynamic participation in the inhibitory and promoting processes of tumors, the mechanism of mitophagy in the occurrence and development of breast cancer is rather complex. Furthermore, the therapeutic potential of targeting this process remains to be fully elucidated [16]. Therefore, by investigating the role and molecular processes of mitophagy in breast cancer progression, this review aims to summarize the role and molecular mechanisms of mitophagy in breast cancer progression and to highlight potential therapeutic strategies.

2. Two Pathways of Mitophagy: Ubiquitin-dependent Pathways and Ubiquitin-independent Pathways

2.1 Ubiquitin-dependent pathways

The PTEN-induced putative kinase 1-Parkin RBR E3 ubiquitin-protein ligase (PINK1-Parkin) pathway is the most extensively studied mechanism of mitophagy [17]. The N-terminus of PINK1 contains the mitochondrial outer membrane localization signal, which is responsible for maintaining the localization of PINK1 during depolarization of the outer mitochondrial membrane (OMM). The C-terminus of PINK1 is involved in the regulation of its kinase activity [18]. Under conditions of mitochondrial damage or depolarization, PINK1 import into the inner mitochondrial membrane is impaired, leading to its accumulation on the OMM [14]. There, PINK1 phosphorylates ubiquitin at Ser65 to generate phospho Ser65 ubiquitin and subsequently phosphorylates Parkin at Ser65 within its Ubl domain [19-21]. Phospho Ser65 ubiquitin acts as both an allosteric activator and a membrane receptor for Parkin, accelerating UBCH7 ubiquitin thioester discharge, relieving autoinhibition of the catalytic cysteine, and recruiting Parkin to depolarized mitochondria to establish a feed forward amplification loop [20-22]. Binding of phospho Ser65 ubiquitin to Parkin also induces a conformational change that enhances Parkin Ser65 accessibility, promoting optimal phosphorylation by PINK1 [23]. This dual phosphorylation mechanism ultimately triggers autophagic lysosomal degradation of damaged mitochondria. In addition to Parkin, several ubiquitin E3 ligases such as SMURF1 [24], Gp78 [25], SIAH1 [26], and ARIH1 [27] are involved in the ubiquitination of mitochondrial proteins and the induction of mitophagy [28-30]. In contrast, mitochondrial E3 ubiquitin protein ligase 1 (MUL1) restrains Parkin-mediated mitophagy by maintaining ER-mitochondrial contacts [31]. Upon Parkin activation, the E3 ubiquitin ligase conjugates polyubiquitin chains to outer mitochondrial membrane proteins, including voltage dependent anion channels (VDACs) and mitofusins (MFN1 and MFN2) [31]. This ubiquitinated surface is recognized by cytosolic autophagy adaptors, such as optineurin (OPTN) [32], nuclear dot protein 52 kDa/CALCOCO2 (NDP52) [33], sequestosome 1 (SQSTM1/p62), Tax1 binding protein 1 (TAX1BP1) [34], and neighbor of BRCA1 gene 1 (NBR1) [35], each of which contains ubiquitin-binding domains (UBDs) that engage the polyubiquitin moieties on the mitochondrial outer membrane. These adaptors simultaneously use their LC3-interacting region (LIR) motifs to associate with autophagy-related protein 8 (ATG8) family proteins on the nascent autophagosomal membrane [36]. Through this dual engagement, the adaptors serve as molecular bridges that couple the ubiquitinated mitochondrion to the autophagosome, facilitating encapsulation and subsequent lysosomal delivery of the damaged organelle for degradation. Table 1 provides a detailed comparison of the two modes of mitophagy.

2.2 Non-ubiquitin dependent pathways mediated by mitophagic receptors

Certain proteins on the mitochondrial surface can function directly as mitophagy receptors, enabling ubiquitin-independent mitophagy [37]. Owing to their intrinsic LIR domains, these proteins can directly bind microtubule-associated protein 1A/1B-light chain 3 (LC3) and/or GABA receptor-associated protein (GABARAP), thereby initiating mitophagy independently of ubiquitination [38].

2.2.1 The BNIP3/NIX receptor

The BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) and BCL2 interacting protein 3 like (BNIP3L/NIX) receptor-mediated pathways are important and widely regulated under many physiological conditions. The single-channel C-terminal transmembrane (TM) structural domain of the transmembrane proteins BNIP3L/NIX, which are autophagy receptors, serves as an anchor for the proteins to the OMM [39]. The majority of BNIP3 and BNIP3L/NIX are directed to the cytoplasm by the TM structural domain, where these receptors use their LIR and/or microtubule-binding domains to recruit the cellular autophagy machinery to the mitochondria [19]. Phosphorylation of Ser17, which is adjacent to the BNIP3 LIR motif, is required for its binding to LC3B, whereas synergistic phosphorylation at both Ser17 and Ser24 enhances BNIP3's affinity for GABARAPL2 and subsequently augments mitophagy [40,41]. Mitophagy induction leads to the dephosphorylation of BNIP3L/NIX, which facilitates its dimerization. The resulting dimer then undergoes dual phosphorylation on its LIR domain, a critical step for its full activation. Dimerization thereby enhances autophagosome recruitment and mitophagy efficiency [42]. Previous studies have demonstrated that the SCFFBXL4 family localizes to the mitochondrial outer membrane of non-stressed cells and mediates the ubiquitination and degradation of the mitophagy receptors BNIP3 and BNIP3L/NIX to inhibit mitophagy [43]. In addition, accumulating evidence has documented that JNK1/2 phosphorylates BNIP3 at the Ser60/Thr66 location during hypoxia, preventing BNIP3 from being degraded by proteases and encouraging mitophagy by enabling BNIP3 to directly bind to LC3 [44].

2.2.2 FUNDC1 receptor

FUN14 domain containing 1 (FUNDC1) is an OMM localized protein that binds to LC3 and promotes mitophagy under hypoxic conditions [45]. High expression of FUNDC1 enhances mitophagy and cell proliferation, while low expression of FUNDC1 inhibits hypoxia-induced mitophagy and cell proliferation [46,47]. The 155-amino-acid human FUNDC1 protein is composed of an N-terminal cytoplasmic domain, a C-terminal domain, and an intermembrane space segment [48]. Mutations or deletions in the conserved LIR sequence of FUNDC1 inhibit its interaction with LC3 and subsequent mitophagy [49].

The structural features of FUNDC1 allow it to regulate mitophagy through phosphorylation and dephosphorylation in response to changes in intracellular signaling. FUNDC1 is normally stabilized on the OMM, and phosphorylation of Ser13 and Tyr18 by SRC kinase and casein kinase 2 (CK2) adversely influences the interaction between FUNDC1 and ATG8 proteins [50]. The dephosphorylation of FUNDC1, together with the inactivation of Src and CK2, enables FUNDC1 to bind LC3 and trigger mitophagy under hypoxia [51,52]. Figure 1 briefly summarizes the two pathways of mitophagy and the related molecules involved.

 Figure 1 

Two mechanisms of mitophagy. When mitochondria are damaged by external stimuli, two distinct pathways are activated to remove the damaged organelles. On the one hand, PINK1 is stabilized on OMM, where it phosphorylates ubiquitin at Ser65 and Parkin at Ser65, leading to Parkin activation and polyubiquitin chain formation on OMM proteins. Parkin-coupled polyubiquitin chains recruit autophagy adaptor proteins, such as OPTN, NDP52, TAX1BP1, and NBR1, which serve as molecular bridges that deliver the ubiquitinated mitochondrion to the autophagosome, where it subsequently fuses with the lysosome for degradation. On the other hand, the ubiquitin-independent mitophagy pathway mainly relies on mitophagy receptor proteins, such as BNIP3L/NIX, BNIP3, and FUNDC1, which directly interact with LC3 to initiate mitophagy without ubiquitination, followed by autophagosome-lysosome fusion and degradation of the damaged mitochondria.

3. The Role of Mitophagy-Related Molecules in Breast Cancer

3.1 PINK1/Parkin in breast cancer

The mRNA expression of PINK1 is downregulated in most tumors. Despite the significant prognostic value of PINK1 expression in cancer, PINK1 plays a protective or deleterious role in different types of cancer [53]. However, PINK1 exerts opposing effects on breast cancer cells depending on the cellular context. Mechanistically, PINK1 activation promotes Parkin-mediated ubiquitination and degradation of breast cancer susceptibility gene 1 (BRCA1), whereas PINK1 inhibition stabilizes BRCA1 expression [54]. Elevated BRCA1 levels, in turn, correlate with enhanced proliferative activity in breast cancer cells, as demonstrated by both in vitro assays and clinical transcriptomic analyses linking high BRCA1 mRNA to increased proliferation scores [55]. Consequently, in contexts wherein PINK1 inhibition gives rise to BRCA1 accumulation, PINK1 may exert a suppressive rather than promotive influence on breast cancer cell proliferation, thereby underscoring the context-dependent nature of its biological function. According to another study, PINK1 deficiency can inhibit breast cancer cells from growing [56]. As a tumor suppressor, Parkin is a crucial protein in the regulation of mitophagy [57,58]. Parkin expression is frequently dysregulated across diverse human malignancies. In breast cancer, compared with adjacent normal tissues, the mRNA and protein levels of Parkin are down-regulated [59]. These findings emphasize the importance of mitophagy in the pathophysiology of breast cancer and the function of PINK1 and Parkin in controlling cellular metabolism.

3.2 FUNDC1 and BNIP3 in breast cancer

High levels of FUNDC1 enhance oxidative phosphorylation and facilitate the proliferation and growth of tumor cells [60]. Compared with normal breast tissues, FUNDC1 expression is significantly upregulated in breast cancer tissues. Moreover, elevated FUNDC1 protein levels are associated with a more aggressive disease phenotype in breast cancer patients [61]. Additionally, FUNDC1 is essential for encouraging breast cancer cells to proliferate, migrate, and invade [62]. Furthermore, the overexpression of BNIP3 occurs in the early stage of breast cancer [63]. Functionally, breast cancer cells with high expression of BNIP3 exhibit enhanced metabolism, proliferation, migration, and drug resistance, along with higher antioxidant capacity [64].

4. The Role of Mitophagy in the Development of Breast Cancer

The functional significance of mitophagy in breast cancer is context-dependent, governed by three interrelated variables: tumor subtype, metabolic phenotype, and the intensity of mitochondrial stress. Mitochondria generate adenosine triphosphate (ATP) primarily through oxidative phosphorylation, which is fueled by the tricarboxylic acid cycle (TCA). When damaged, ATP synthesis declines and reactive oxygen species (ROS) accumulate, prompting the selective removal of dysfunctional mitochondria through mitophagy to maintain cellular homeostasis [65]. Mitophagy is triggered by hypoxia, nutrient deprivation, oxidative stress, and pharmacological agents, primarily through hypoxia-inducible factor 1 subunit alpha (HIF1α) and NF-κB signaling [66]. The regulation and consequences of mitophagy in breast cancer vary considerably according to the molecular and metabolic context [67].

Subtype specificity and metabolic phenotype determine the baseline dependency on mitophagy. In triple negative breast cancer (TNBC), a subtype marked by high metabolic plasticity, mitophagy predominantly acts as a pro-survival mechanism. Divalent metal transporter 1 (DMT1) inhibition triggers PINK1/Parkin-dependent mitophagy and promotes pulmonary metastasis [68]. Conversely, NLRX1 deficiency impairs proliferation and migration in oxidative phosphorylation-dependent TNBC cells, revealing their reliance on intact mitophagy [69]. In luminal and HER2-positive subtypes, however, PINK1 inhibition increases BRCA1 expression and promotes proliferation, suggesting a tumor-suppressive role for mitophagy in these contexts [54,55]. The PINK1-PGK2 axis connects mitophagy to glycolytic reprogramming, with PINK1 overexpression directly enhancing mitophagy and inducing a glycolytic phenotype that promotes breast cancer proliferation [14]. FUNDC1 further illustrates this complexity: it activates the calcium-NFATC1-BMI1 axis to drive migration and proliferation, while also suppressing epithelial-mesenchymal transition via ROS reduction, a duality that underscores the context-dependent nature of mitophagy in breast cancer [62].

The intensity and duration of mitochondrial damage represent a second critical determinant. Mild, transient stress elicits a homeostatic response that restores mitochondrial integrity and supports cell survival. In contrast, sustained or hyperactivated mitophagy leads to excessive mitochondrial depletion and bioenergetic failure. This threshold effect is exemplified by Unc-51 like autophagy activating kinase 1 (ULK1) deficiency under hypoxia, which suppresses mitophagy, promotes dysfunctional mitochondrial accumulation, and enhances invasive potential and osteolytic bone metastasis [70]. Similarly, HIF-1-induced MRPL52 activates PINK1/Parkin-dependent mitophagy under hypoxia, suppressing apoptosis and promoting metastasis via the ROS-Notch1-Snail axis [71]. BRCA1 loss impedes stress-induced mitophagy by blocking ATM-AMPK-DRP1-dependent fission while activating the NLR family pyrin domain containing 3 (NLRP3) inflammasome, thereby creating a tumor-permissive microenvironment that favours metastasis [72]. Thus, the same pathway that preserves cellular integrity under acute stress can, when chronically overstimulated, trigger cell death.

Metabolic phenotype further modulates this duality. Cells heavily reliant on oxidative phosphorylation (OXPHOS) are particularly vulnerable to mitophagy inhibition, which compromises mitochondrial function and viability. In contrast, glycolytic cells exhibit relative resistance, suggesting that the therapeutic window for mitophagy-targeted interventions is contingent upon the tumor's metabolic state, a stratification that may facilitate the identification of responsive tumors.

Recent studies have substantiated this paradigm by positioning mitophagy as a mechanistic hub linking metabolic reprogramming to therapeutic resistance in TNBC. Epigenetic reactivation of TNFRSF19 suppresses PINK1/Parkin-mediated mitophagy by disrupting TGFBR1-SMAD3 signaling, thereby sensitizing TNBC to doxorubicin [73]. Lysyl oxidase (LOX) inhibition disrupts mitochondrial homeostasis via uncoupling glucose metabolism from Parkin-mediated mitophagy, thereby generating a targetable ferroptotic vulnerability [74]. Conversely, TBX20 drives doxorubicin resistance through ABCC1 upregulation coupled with mitophagy suppression, illustrating the paradoxical pro-resistance outcome of mitophagy inhibition in certain settings [75]. The tumor suppressor CIDEC impairs mitochondrial fitness and abrogates protective autophagy via cGMP/PKG pathway inhibition, exerting context-dependent antitumor effects [76]. Furthermore, mitochondrial PDK1 potentiates PINK1/Parkin-dependent mitophagy under hypoxia, thereby fueling bevacizumab resistance and malignant progression, with its targeting restoring chemosensitivity [77]. Collectively, these findings underscore that the therapeutic exploitation of mitophagy, whether via activation or inhibition, demands careful contextualization to tumor subtype, metabolic state, and the prevailing resistance mechanism.

5. Mitophagy and Ferroptosis in Breast Cancer

Ferroptosis is a recently identified kind of iron-dependent cell death that is different from apoptosis and other types of cell death. It is typically accompanied by severe lipid peroxidation and the accumulation of iron ions [78]. Among the identified autophagic processes, ferroptosis is regulated by nuclear receptor coactivator 4 (NCOA4)-mediated ferritin autophagy [79], BECN1-mediated inhibition of system Xc⁻ [80], and PINK1 associated mitophagy [81]. BNIP3 knockdown upregulates NCOA4 and promotes ferroptosis, suggesting a functional interplay between BNIP3-mediated mitophagy and NCOA4-mediated ferritinophagy in iron homeostasis and ferroptosis regulation [82]. A schematic overview of the molecular crosstalk between mitophagy and cell death subroutines, including pyroptosis, apoptosis, and the core autophagy and mitophagy machinery, is presented in Figure 2.

 Figure 2 

Molecular crosstalk between mitophagy and cell death subroutines. A. Pyroptosis. Damage-associated molecular patterns (DAMPs) and mitochondrial DNA (mtDNA) released from damaged mitochondria promote the formation of NLRP3 inflammasomes and trigger caspase-1. Gasdermin D (GSDMD) is cleaved by active caspase-1, which simultaneously cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into their mature forms. Pyroptosis results from the oligomerization of the N-terminal fragment of GSDMD, which creates a pore in the plasma membrane. Mitophagy limits NLRP3 inflammasome activation by removing damaged mitochondria and reducing mtDNA release. B. Apoptosis. Mitochondrial outer membrane permeabilization (MOMP) occurs in severely damaged mitochondria and promotes apoptosis by releasing cytochrome C, which triggers apoptosome formation. MOMP is regulated by the B-cell lymphoma 2 (BCL-2) family of proteins, which includes the anti-apoptotic BCL-2 and B-cell lymphoma-extra large (BCL-xL), and the pro-apoptotic BCL-2-associated X protein (BAX) and BCL-2 antagonist/killer (BAK). BCL-xL inhibits Parkin recruitment to the outer mitochondrial membrane, thereby inhibiting mitophagy. C. Core autophagy/mitophagy machinery. Autophagy is initiated by phagophore formation, which sequesters cytoplasmic components for degradation. The mechanistic target of rapamycin (mTOR) pathway controls the ULK1 complex, which is essential for this process. Phagophores expand and mature into autophagosomes, which fuse with lysosomes to form autolysosomes for degradation. The ATG family, Beclin-1, and LC3 coordinate vesicle nucleation, elongation, and autophagosome maturation. Mitophagy is a selective form of autophagy in which damaged mitochondria are engulfed by autophagosomes. BID: BH3-interacting domain death agonist; BAD: BCL-2-associated agonist of cell death; BIM: BCL-2-interacting mediator of cell death; PI3K: phosphoinositide 3-kinase; VPS34: vacuolar protein sorting 34.

Ferritin autophagy plays an important role in ferroptosis, and this process is further enhanced by interactions between mitophagy and the ferritinophagy pathway [83]. Singh et al. attribute high glucose induced ferroptosis to the upregulation of thioredoxin-interacting protein, which promotes redox stress, ferritinophagy, mitochondrial damage, and lysosomal instability, thereby enabling the iron-dependent Fenton reaction and ∙OH generation [84]. Moreover, ferroptosis in turn stimulates autophagy. O-linked β-N-acetylglucosamine (O-GlcNAc) transferase inactivation occurs concurrently with ferroptosis induction, resulting in ferritin de-O-GlcNAc and NCOA4-mediated activation of ferritin autophagy and mitophagy [85,86]. Together, ferroptosis and ferritin autophagy provide an unstable iron substrate for the Fenton reaction, which accelerates the production of ROS and lipid peroxidation, both of which in turn trigger mitophagy [87].

Although mitophagy and ferroptosis are broadly interconnected through the feed forward loop described above, the net outcome of this interaction depends on which mitophagy receptor is engaged. Several mitochondrial molecules regulate ferroptosis through their effects on mitophagy, and the direction of regulation varies with the receptor and cellular context. For example, BNIP3- and BNIP3L/NIX-mediated mitophagy plays a role in regulating mitochondrial ROS (mtROS) levels and preventing ferroptosis [88]. BNIP3L/NIX releases Beclin-1 to induce mitophagy, and the released Beclin-1 binds to solute carrier family7 member 11 (SLC7A11), thereby inhibiting the cystine glutamate antiporter system Xc⁻, reducing cystine uptake and glutathione (GSH) synthesis, and consequently promoting ferroptosis through GSH depletion, GPX4 inactivation, and accumulation of ROS and lipid peroxides [80,89]. Through the stimulation of the P62-KEAP1-NRF2 pathway, BNIP3-mediated mitophagy prevents ferroptosis and preserves iron and redox balance [90]. The mitophagy receptor FUNDC1 has also been implicated in ferroptosis. FUNDC1 induces ferroptosis by binding to GPX4, facilitating its own mitochondrial transport via the TOM/TIM complex, and promoting the mitophagy dependent degradation of GPX4 [91]. FUNDC1 can also regulate ferroptosis via Acyl-CoA synthetase long-chain family member 4 (ACSL4) although the direction of this regulation requires further investigation [92]. It should be noted that these receptor specific mechanisms have been characterized largely in nonmammary models, and their relevance to breast cancer remains to be determined. Direct evidence for mitophagy and ferroptosis crosstalk in breast cancer is now beginning to emerge. Xanthatin targets CDGSH iron sulfur domain 1 (CISD1) to trigger ferroptosis and PINK1/Parkin-dependent mitophagy in TNBC, establishing a dual anticancer mechanism [93]. Platycodin D2 induces mitochondrial reactive oxygen species dependent ferroptosis and inhibits autophagic flux in breast cancer cells, with the two processes mutually reinforcing each other [94]. In addition, LOX inhibition disrupts mitochondrial homeostasis and activates PINK1/Parkin-dependent mitophagy, generating ferroptotic vulnerability in TNBC [74].

VDACs are important proteins involved in mitophagy and ferroptosis. VDACs are targets of Parkin-mediated ubiquitination and act as mitochondrial docking sites, recruiting Parkin from the cytoplasm to damaged mitochondria and inducing mitophagy [95]. VDACs allow the movement of iron and metabolites across the outer membrane, and erastin induced opening of VDACs accelerates ferroptosis [96]. Furthermore, the redox-sensitive 2Fe-2S cluster protein, known as the OMM protein CISD1, is crucial for both iron uptake and regulation, as well as for maintaining ROS homeostasis. CISD1 oxidizes VDACs, leading to pore closure and impaired transport of mitochondrial metabolites [97]. CISD1 mediated VDAC oxidation blocks mitochondrial TCA cycling, causing electron leakage from the electron transport chain and increased mitochondrial ROS production [98,99]. The excess mitochondrial ROS then promotes extramitochondrial lipid peroxidation, ultimately contributing to ferroptosis [100,101].

Inhibition of mitophagy promotes or prevents ferroptosis. By increasing mitochondrial NAD⁺ via complex I upregulation, DMT1 deficiency promotes SIRT3-mediated deacetylation and activation of IDH2, leading to enhanced GSH-dependent antioxidant defense and ferroptosis suppression, as reported by Tan et al [102]. FMS-like tyrosine kinase 3 (FLT3) overexpression inhibits autophagy and ferroptosis in breast cancer cells, and the addition of mitophagy inducers restores this regulation. In addition, the transcription factor AP-2γ mediates FLT3 transcriptional activation, further inhibiting mitophagy-induced ferroptosis [103]. Accumulating evidence suggests that tumors with defective mitophagy are hypersensitive to ferroptosis induction, a phenomenon mechanistically linked to the unrestrained accumulation of mitochondrial ROS that relieves the suppression of lipid peroxidation [104]. Figure 3 provides a schematic overview of the molecular interplay between ferroptosis and mitophagy.

 Figure 3 

Mitophagy interacts with ferroptosis. Iron enters the cell via transferrin-mediated uptake through the transferrin receptor (TFR) on the cell membrane. Within the cell, Fe³⁺ is reduced to Fe²⁺ and stored in the labile iron pool, while excess iron is sequestered in ferritin. Inactivation of O-GlcNAc transferase reduces ferritin O-GlcNAcylation and activates NCOA4-mediated ferritinophagy, promoting ferritin degradation and increasing free iron levels. Free iron generates ROS via the Fenton reaction, leading to lipid peroxidation. ACSL4 catalyzes the conversion of polyunsaturated fatty acids (PUFAs) into PUFA-CoA, which is subsequently esterified into phospholipids by LPCAT3 to form PUFA-containing phospholipids (PUFA-PL). By promoting lipid peroxidation, LPCAT3 and ACSL4 are key mediators of ferroptosis. When the cystine/glutamate antiporter SLC7A11 (system Xc⁻) is blocked, cystine uptake decreases and intracellular cysteine levels fall, leading to decreased GSH synthesis and reduced GPX4 activity. The depletion of GPX4 and GSH results in the accumulation of ROS and lipid peroxides, leading to uncontrolled oxidative stress and ferroptosis. In addition, CISD1 oxidizes VDAC in a redox-dependent manner, leading to pore closure and impaired transport of mitochondrial metabolites. CISD1 mediated VDAC oxidation blocks mitochondrial TCA cycling, causing electron leakage from the electron transport chain and increased mitochondrial ROS production. The excess mitochondrial ROS then promotes extramitochondrial lipid peroxidation, ultimately contributing to ferroptosis. mtROS and iron overload subsequently trigger mitophagy through PINK1, Parkin, BNIP3, BNIP3L/NIX, and FUNDC1, which in turn modulates ferroptosis sensitivity depending on the receptor and cellular context.

6. Mitophagy in Breast Cancer Therapy

As a crucial mechanism for the selective elimination of damaged mitochondria, mitophagy contributes significantly to the maintenance of cellular homeostasis. However, in cancer, tumor cells frequently "take over" mitophagy to promote therapeutic resistance, metabolic adaptability, and survival. Targeting mitophagy has become a novel cancer treatment approach. Mitophagy exerts dual effects in cancer treatment. While it suppresses tumor growth by inducing metabolic dysfunction and DNA damage through mitochondrial destruction, it conversely fosters treatment resistance by enhancing tumor cell survival through the removal of therapy-damaged mitochondria [105]. Table 2 summarizes pharmacological agents that have been reported to modulate mitophagy in breast cancer.

6.1 Overactivation of mitophagy in breast cancer

The overactivation of mitophagy in breast cancer leads to the destruction of mitochondria and the depletion of energy stores. The activation of mitophagy may facilitate the clearance of damaged mitochondria, consequently inhibiting the viability and proliferation of tumor cells. Many drugs can treat breast cancer by directly activating mitophagy, for example, it was found that Cyclovirobuxine D induces mitophagy through activation of the FOXO3a/PINK1-Parkin pathway, thereby inhibiting the development of triple-negative breast cancer [106]. By altering the potential of the mitochondrial membrane and encouraging cellular autophagy through the AMPK/mTOR pathway, idebenone further suppresses the growth of TNBC cells [107]. In TNBC, Guangsangon E causes mitochondrial dysfunction, mitophagy, and non-apoptotic cell death [108]. Polyphyllin I increases mitochondrial PINK1 levels and induces mitophagic and apoptotic cell death in breast cancer [109]. In addition, Gramicidin A, an exogenous ionophoric peptide, accumulates in mitochondria, decreases ATP levels, and induces mitophagy, thereby inhibiting the growth of MCF-7 cells [110].

6.2 Improving drug resistance in breast cancer through mitophagy

Senescent cells are more susceptible to the mitochondrial effects of fisetin derivatives than proliferating cells in breast cancer, an effect that leads to the removal of drug-resistant senescent breast cancer cells. This is in contrast to mitochondrial fisetin-induced cytotoxicity, which is linked to elevated levels of phosphorylated AMPK, decreased levels of AKT and HSP90, and impaired mitophagy [111]. The Pep-1-mitochondrial membrane complex potentiates doxorubicin sensitivity in breast cancer by inducing mitochondrial hyperfusion and mitophagy [112]. The miR-218-5p/ doxorubicin combination suppresses mitochondrial fusion in breast cancer cells, through the inhibition of Parkin-dependent mitophagy, leading to enhanced anticancer efficacy [113]. Programmed death ligand 1 (PD-L1) expression is independently associated with high-risk clinicopathological features, contributing to a worse prognosis in primary breast cancer patients [114]. Consequently, a crucial part of cancer treatment is immune checkpoint blockade therapy that targets PD-1/PD-L1 [115]. Although initially reported in colorectal cancer, Shen Qi Yi Chang (SQYC), a traditional Chinese medicine formula for colorectal cancer treatment, enhances PD-1 blockade via PINK1-Parkin-mediated dendritic cell mitophagy [116]. Additionally, mitochondrial redirection of PD-L1, focused on the ATAD3a-PINK1 axis, provides an effective strategy for reversing chemotherapy resistance in breast cancer [117].

6.3 Targeting novel targets associated with mitophagy in breast cancer

Multiple molecular targets associated with the mitophagy pathway are being increasingly investigated, and breast cancer therapy can also be achieved by modulating these targets. For example, mesencephalic astrocyte-derived neurotrophic factor (MANF) promotes breast cancer cell survival under glucose starvation conditions through PRKN-mediated regulation of mitophagy [118]. Early B cell factor 1 (EBF1), a key regulator of TNBC mitochondrial homeostasis, prevents widespread cell death induced by mitophagy by controlling the activity of HIF1α [119]. Mitochondrial uncoupling protein 1 (UCP1) inhibits TNBC progression through activation of mitophagy [120]. Accordingly, MANF, EBF1, and UCP1 constitute potential mitochondrial targets for therapeutic intervention in breast cancer.

6.4 Delivery systems associated with mitophagy in the treatment of breast cancer

Nanotechnology has become a viable strategy to enhance drug delivery and therapeutic results in addition to conventional targeted therapies. By encasing medications in nanoparticles, nanodelivery devices enable regulated drug release in vivo and lessen the impact of comorbidities [121,122]. The combination of hydrogel-based chimeric antigen receptor T cell (CAR-T) cell delivery and BC1618 injection improved outcomes in triple-negative breast cancer by inducing a local inflammatory microenvironment and enhanced mitophagy that promoted CAR-T cell proliferation for sustained anti-tumor activity [123]. There is also an all-in-one tumor therapy strategy that combines non-invasive sonodynamic therapy (SDT) enhanced by nanosensitizers with mitophagy inhibition. This approach combines SDT with mitophagy inhibition, thereby blocking the clearance of damaged mitochondria and ultimately inducing cell death through mitochondrial dysfunction and impaired autophagic flux [124]. Synergizing cannabidiol with carbon monoxide nanocomplexes enhances TNBC therapy through excessive autophagy [125]. TPP-SS-ATS-LS, a mitochondria-targeted artesunate smart prodrug liposome, targeting both tumor cells and mitochondria, acts by regulating PHB2 and PINK1 expression to inhibit breast cancer cell proliferation through mitophagy [126]. Beyond the delivery systems described above, several other pharmacological modulators of mitophagy in breast cancer have been reported, including chlorpromazine and luteolin [127,128]. A more comprehensive list of these agents is provided in Table 2 [127-134].

6.5 Non-pharmaceutical therapies in the treatment of breast cancer through mitophagy

Strategies that utilize non-pharmacological therapies to promote or inhibit mitophagy for the treatment of breast cancer are also beginning to emerge. In a mouse model, high-intensity interval training emerged as an effective intervention against breast cancer, reducing tumor burden through the maintenance of mitophagy, which highlights its promise as a novel therapeutic approach [135]. It has also been shown that fasting can enhance the efficacy of sorafenib in breast cancer through ROS-induced p53 pathway-mediated mitophagy [136]. While animal and cellular studies have validated mitophagy-targeting agents against breast cancer and outlined their mechanisms, clinical trials are still absent. This gap underscores the critical next step: translating these promising preclinical results into viable clinical therapies.

7. Conclusions and Perspectives

This review outlines the core mechanisms of the mitophagy pathway, as well as the expression patterns and roles of molecules linked to mitophagy in breast cancer. A thorough understanding of these molecules may aid in identifying new therapeutic targets for breast cancer, and may also facilitate the detection of mitophagy activity within tumors. In order to shed light on the function of mitophagy in the development of breast cancer, we also summarized the impact of this process on the growth and spread of breast tumors. A key challenge remains in translating mitophagy mechanisms into effective breast cancer treatments. The net effect of mitophagy, whether it suppresses or promotes tumorigenesis, is highly context-dependent, varying according to disease stage, molecular subtype, and the tumor microenvironment. The anti-tumor activity of a number of clinically employed anticancer agents involves the induction of various modes of RCD [8]. Currently, many studies have also found that certain drugs can be used to treat breast cancer by inducing mitophagy [118,137]. However, it is worth noting that the precise interaction between mitophagy and RCD needs further exploration. Therefore, a comprehensive and in-depth understanding of the effects of mitophagy is required to formulate effective treatment strategies for breast cancer.

Future research may prioritize several key directions. Firstly, developing subtype-specific biomarkers and mitophagy inhibitors is crucial. Subsequently, nanotechnology could enable tumor-targeted drug delivery. It is also essential to investigate the dynamic crosstalk between mitophagy and the tumor microenvironment. Finally, exploring synergies between non-pharmacological and pharmaceutical interventions could minimize side effects and improve patient survival.

Abbreviations

RCD: regulated cell death; ER-autophagy: endoplasmic reticulum autophagy; PINK1-Parkin: PTEN-induced putative kinase 1-Parkin RBR E3 ubiquitin-protein ligase; OMM: outer mitochondrial membrane; MUL1: mitochondrial E3 ubiquitin protein ligase 1; VDACs: voltage-dependent anion channels; MFN1 and MFN2: mitofusins; OPTN: optineurin; NDP52: nuclear dot protein 52 kDa/CALCOCO2; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; NBR1: neighbor of BRCA1 gene 1; UBDs: ubiquitin-binding domains; LIR: LC3-interacting region; ATG8: autophagy-related protein 8; LC3: microtubule-associated protein 1A/1B-light chain 3; GABARAP: GABA receptor-associated protein; BNIP3: BCL2/adenovirus E1B 19-kDa interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like/NIP3-like protein X; TM: single-channel C-terminal transmembrane; FUNDC1: FUN14 domain containing 1; CK2: casein kinase 2; BRCA1: breast cancer susceptibility gene 1; ATP: adenosine triphosphate; TCA: tricarboxylic acid cycle; ROS: reactive oxygen species; HIF1α: hypoxia-inducible factor 1 subunit alpha; TNBC: triple negative breast cancer; DMT1: divalent metal transporter 1; ULK1: Unc-51 like autophagy activating kinase 1; NLRP3: NLR family pyrin domain containing 3; OXPHOS: oxidative phosphorylation; LOX: Lysyl oxidase; NCOA4: nuclear receptor coactivator 4; O-GlcNAc: O-linked β-N-acetylglucosamine; SLC7A11: solute carrier family 7 member 11; GSH: glutathione; GPX4: glutathione peroxidase 4; ACSL4: acyl-CoA synthetase long-chain family member 4; CISD1: CDGSH iron sulfur domain 1; FLT3: FMS-like tyrosine kinase 3; PD-L1: programmed death ligand 1; SQYC: Shen Qi Yi Chang; MANF: mesencephalic astrocyte-derived neurotrophic factor; EBF1: early B cell factor 1; UCP1: uncoupling protein 1; CAR-T: chimeric antigen receptor T cell; SDT: sonodynamic therapy; DAMPs: damage-associated molecular patterns; mtDNA: mitochondrial DNA; GSDMD: gasdermin D; pro-IL-1β: pro-interleukin-1β; MOMP: mitochondrial outer membrane permeabilization; BCL-2: B-cell lymphoma 2; BCL-xL: B-cell lymphoma-extra large; BAX: BCL-2-associated X protein; BAK: BCL-2 antagonist/killer; mTOR: mechanistic target of rapamycin; BID: BH3-interacting domain death agonist; BAD: BCL-2-associated agonist of cell death; BIM: BCL-2-interacting mediator of cell death; PI3K: phosphoinositide 3-kinase; VPS34: vacuolar protein sorting 34; TFR: transferrin receptor; PUFAs: polyunsaturated fatty acids; PUFA-PL: PUFA-containing phospholipids; mtROS: mitochondrial ROS.

Author Contributions

XY and LZ collected literature and wrote the manuscript; XY and YTY drew the figures and tables; LZ and SYC conceived the topic area and supervised; CYW and PL reviewed and edited the manuscript drafts. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Competing Interests

The authors have declared that no competing interest exists.

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Author contact

Corresponding authors: Professor Ping Leng, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, Sichuan 611100, China. Email: lengpingedu.cn. Professor Changyou Wei, School of Public Health, Chengdu Medical College, No. 783 Xindu Avenue, Xindu District, Chengdu, Sichuan 610500, China. Email: 2830297980com.

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