Advances in mitophagy research in hepatocellular carcinoma: mechanisms and therapeutic implications

Introduction

Mitochondria, indispensable organelles within eukaryotic cells, comprise the inner mitochondrial membrane (IMM), outer mitochondrial membrane (OMM), intermembrane space, and mitochondrial matrix. These dynamic structures govern vital cellular functions including biosynthesis, bioenergetics, and signaling—through perpetual cycles of fusion and fission, thereby safeguarding mitochondrial quality and integrity (1,2). Under cellular stress, such as nutrient deprivation, hypoxia, deoxyribonucleic acid (DNA) damage, or reactive oxygen species (ROS) assault, mitochondria suffer depolarization and functional decline. Such mitochondrial dysfunction critically undermines cellular homeostasis, bioenergetics, and redox balance, ultimately fueling the pathogenesis of diverse diseases (3). Consequently, the timely elimination of these dysfunctional organelles is imperative for preserving robust mitochondrial and cellular homeostasis.

Autophagy stands as a highly conserved metabolic process, a vigilant guardian of cellular homeostasis. It achieves this by degrading dysfunctional cytoplasmic components and invading pathogens through the powerful lysosomal system (4). Based on substrate specificity, autophagy manifests as either non-selective or exquisitely selective. Mitophagy, a specialized form of selective autophagy, acts as a dedicated quality control mechanism. It specifically targets damaged mitochondria for destruction, thereby preventing the dangerous accumulation of deleterious mitochondrial DNA (mtDNA) mutations and rigorously ensuring mitochondrial integrity (5). This crucial process unfolds through a precise cascade of four sequential stages (6) (Figure 1): (I) depolarization of damaged mitochondria: loss of the vital mitochondrial membrane potential, serving as the fundamental trigger initiating mitophagy. (II) Engulfment by autophagosomes: the compromised mitochondria become engulfed by autophagosomes, forming distinct mitophagosomes. (III) Fusion with lysosomes: these mitophagosomes then fuse seamlessly with lysosomes, creating autolysosomes. (IV) Degradation and recycling: finally, potent lysosomal acid hydrolases dismantle the mitochondrial contents, liberating essential nutrients for cellular rescue.

Figure 1 The key processes in mitophagy. Under cellular stress, damaged mitochondria undergo depolarization and loss of membrane potential, triggering mitophagy initiation. Subsequently, selective engulfment of impaired mitochondria occurs via autophagosome, forming mitophagosome. lysosomes fuse with mitophagosomes, mediating enzymatic degradation of mitochondrial components. OMM, outer mitochondrial membrane; ROS, reactive oxygen species.

Liver cancer ranks as the sixth most frequently diagnosed malignancy globally and stands as the third leading cause of cancer-related deaths (7). Hepatocellular carcinoma (HCC), the predominant histological form of primary liver cancer, accounts for a staggering 75–85% of all cases (8). Major risk factors encompass cirrhosis, metabolic disorders, and chronic infections with hepatitis B virus (HBV) or hepatitis C virus (HCV) (9). Due to its highly aggressive behavior and the insidious onset of symptoms, the majority of HCC patients receive their diagnosis at an advanced stage, resulting in a median survival of merely 1–3 years (10-12). Thus, HCC imposes a substantial global public health burden. This reality underscores the urgent imperative to elucidate the precise molecular mechanisms underlying HCC progression.

Mitophagy exhibits a complex, context-dependent role in cancer, varying significantly by cancer type, stage, and genetic background (13). Mounting evidence underscores its dualistic impact during tumorigenesis and malignant progression (14,15). mitophagy can function as a tumor-suppressive mechanism, selectively eliminating dysfunctional mitochondria to maintain stringent mitochondrial quality control and cellular homeostasis. Conversely, it paradoxically bolsters tumor cell survival under stress by mitigating mitochondrial damage-induced apoptosis, thereby fueling therapeutic resistance across multiple cancer types. Perturbations in mitophagy machinery and mitochondrial dynamics are deeply implicated in HCC pathogenesis. Initial observations in the 1950s first associated alterations in mitochondrial homeostasis with liver cancer (16,17). Subsequent transmission electron microscopy (TEM) analysis of HCC patient specimens and subcellular compartments from liver tissue from safrole-induced HCC mice reveals a clear association between loss of mitochondrial integrity and the onset of hepatocarcinogenesis (18,19). Recent investigations further demonstrate mitophagy’s critical function in purging damaged or dysfunctional mitochondria to sustain homeostasis within HCC cells (20). Moreover, mitophagy proves essential for robust tumor growth and metastasis (21). Consequently, comprehensively elucidating mitophagy’s role in HCC and strategically inhibiting tumor progression by regulating mitophagy are crucial objectives.

This review summarizes current insights into the dual role of mitophagy in the development and progression of HCC. Additionally, we critically evaluate emerging therapeutic strategies targeting mitophagy to improve HCC treatment outcomes.

The pivotal role of mitophagy in the emergence and progression of HCC

Mitophagy suppresses the onset of HCC

During early carcinogenesis, autophagy exerts a protective role by inhibiting cell necrosis and suppressing the expression of inflammatory factors, thereby attenuating tumor progression. Accumulating evidence indicates that defects in mitophagy are associated with diverse pathologies, including cancer (22). Functional loss of specific genes can impair mitophagy, leading to the accumulation of damaged mitochondria and subsequent tumorigenesis. For instance, in a diethylnitrosamine (DEN)-induced HCC mouse model, FUN14 domain containing 1 (FUNDC1) knockout resulted in the retention of dysfunctional mitochondria, mtDNA release, and caspase-1 activation (23). These cascading events triggered excessive secretion of pro-inflammatory cytokines, thereby accelerating HCC initiation and progression. Conversely, in wild-type HCC mouse models, FUNDC1-mediated mitophagy suppressed inflammasome activation and inhibited hepatocarcinogenesis. Similarly, Parkin-deficient mouse models demonstrated that hepatocytes promoted cell proliferation and apoptosis resistance in a follistatin-dependent manner, ultimately driving hepatic tumorigenesis (24). These examples illustrate how mitophagy can inhibit HCC onset by curbing inflammation or unchecked proliferation. Furthermore, mitophagy may also suppress HCC development by promoting apoptosis. For example, in starvation-treated HCC cells, the DNA damage-regulated autophagy modulator (DRAM) translocates to mitochondria to mediate mitophagy, thereby promoting apoptosis (25). Additionally, the plant lectin concanavalin A (ConA) induces apoptosis in HCC cells in vitro via BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3)-dependent mitophagy and inhibits hepatic tumor nodule formation in vivo (26,27). While mitophagy is recognized to exhibit dual roles in tumor biology, its contribution to HCC progression remains debated. The question of whether mitophagy facilitates HCC development under certain contexts will be further explored in subsequent sections.

Mitophagy fuels HCC progression

A key mechanism by which mitophagy promotes HCC is by protecting cancer cells from mitochondrial apoptosis (28). Studies have demonstrated that apoptotic stimuli in HCC cells can elevate ROS levels, thereby activating the mitochondrial apoptosis pathway and inducing cell death. However, to counteract mitochondrial damage, apoptin induces mitophagy via the PTEN-induced putative kinase1 (PINK1)/Parkin pathway, establishing a cytoprotective mechanism that suppresses apoptosis (29). This finding is supported by additional evidence. For example, Zheng et al. revealed that stomatin-like protein 2 (STOML2) promotes Parkin-mediated mitophagy by stabilizing PINK1 on mitochondrial membranes in HCC cells (30). This process eliminates damaged mitochondria, inhibits apoptosis, and enhances HCC cell proliferation and migration. Thioredoxin-related transmembrane protein 2 (TMX2), identified as an independent prognostic marker in HCC patients, interacts with voltage-dependent anion channel 2 (VDAC2) and voltage-dependent anion channel 3 (VDAC3) to facilitate Parkin recruitment to defective mitochondria (31). This interaction promotes cytoprotective mitophagy during oxidative stress, thereby increasing liver cancer cell viability. Additionally, staphylococcal nuclease domain-containing protein 1 (SND1), localized to mitochondria in HCC cells and mouse models, enhances mitophagy by mediating the interaction between phosphoglycerate mutase 5 (PGAM5) and dynamin-related protein 1 (DRP1) (32). Under carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment or glucose deprivation, SND1 or PGAM5 deletion suppresses mitophagy, subsequently inhibiting tumor progression. Therefore, mitophagy drives HCC development by blocking apoptosis, maintaining cellular homeostasis, and enhancing cancer cell proliferation and migration.

Mitochondria are central to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), processes responsible for adenosine triphosphate (ATP) generation (33). They play a critical role in the metabolism of major nutrients. In tumor metabolism, cancer cells preferentially utilize glycolysis to rapidly generate ATP, supporting their rapid growth. Mitochondrial integrity critically determines respiratory and metabolic efficiency, which regulates tumor growth and metastasis (34-36). Therefore, mitophagy is essential for modulating energy metabolism in cancer cells and may influence HCC progression through metabolic regulation. For instance, optineurin (OPTN), highly expressed in HCC cells, accelerates mitophagy to boost ATP production and β-oxidation, thereby fueling HCC cell proliferation and migration (37). Similarly, in HCC cells expressing the hepatitis B virus X protein (HBx), HBx induces BCL2/adenovirus E1B 19-kDa interacting protein 3-like (BNIP3L)-dependent mitophagy to upregulate glycolytic metabolism, enhancing cancer stemness both in vitro and in vivo (38). These findings underscore that mitophagy drives HCC progression by reprogramming mitochondrial metabolism to meet the bioenergetic and biosynthetic demands of tumor cells.

Cancer stem cells (CSCs), also known as tumor-initiating cells, are a functionally distinct subpopulation within tumors. These cells exhibit stem cell-like properties, including self-renewal capacity and differentiation potential, which drive the formation of heterogeneous tumor cell populations (39). Distinct from non-stem tumor cells, CSCs employ multifaceted self-protective mechanisms—such as enhanced DNA damage repair, suppression of apoptotic pathways, and upregulation of drug-resistance proteins—to sustain survival and promote tumor aggressiveness. In the context of HCC, mitophagy, a selective autophagy process targeting damaged mitochondria, regulates critical aspects of the CSC phenotype, including self-renewal, proliferation, and tumorigenicity (40).

Emerging evidence highlights the role of mitophagy in maintaining CSC properties. In liver cancer stem cells (LCSCs), enhanced mitophagy facilitates the co-localization of the tumor suppressor p53 (p53) with mitochondria, leading to its autophagic degradation (41). Conversely, mitophagy inhibition induces PINK1-mediated phosphorylation of p53 at serine-392, which suppresses the expression of Nanog homeobox (NANOG)—a key pluripotency marker. This reduction in NANOG levels diminishes the LCSCs population, thereby attenuating HCC progression. These findings suggest that mitophagy modulates p53 activity to sustain LCSCs maintenance and promote hepatocarcinogenesis. Further supporting this mechanism, Luo et al. demonstrated that adenosine deaminase acting on RNA 1 (ADAR1) in LCSCs activates PINK1-dependent mitophagy through GLI1 RNA editing, thereby enhancing CSC self-renewal and driving HCC tumor growth and metastasis (42). Collectively, these studies establish mitophagy as a central regulator of LCSC maintenance and a driver of HCC.

In summary, mitophagy promotes HCC cell survival, proliferation, and metastasis by inhibiting apoptosis and regulating mitochondrial metabolism. As a subset of HCC cells with stem-like properties, LCSCs leverage mitophagy to maintain their self-renewal capacity, thereby driving tumor growth and dissemination. Targeting mitophagy in HCC and LCSCs thus represents a promising therapeutic strategy for liver cancer treatment.

Taken together, mitophagy plays a dual role in the pathogenesis and progression of HCC (Figure 2). Elucidating the mechanisms underlying this duality is crucial for understanding the disease’s development and for designing effective therapeutic strategies.

Figure 2 The dual role of mitophagy during the development of hepatocellular carcinoma. HCC, hepatocellular carcinoma; LCSC, liver cancer stem cell.

Mechanisms and pathways of mitophagy in HCC

The execution of mitophagy is orchestrated by a complex molecular machinery, which can be broadly categorized into two primary pathways: a ubiquitin-dependent pathway and a ubiquitin-independent, receptor-mediated pathway (43). As the aforementioned studies indicate, mitophagy plays a dual role in the initiation and progression of HCC. Understanding these pathways is fundamental to deciphering the specific role of mitophagy in HCC.

Ubiquitin-dependent mitophagy pathways

The PINK1/Parkin pathway: this is the most extensively studied mitophagy pathway. Upon mitochondrial depolarization, PINK1 accumulates on the OMM and recruits the E3 ubiquitin ligase Parkin, which ubiquitinates numerous OMM proteins to trigger mitophagy. In HCC, PINK1/Parkin activation is strongly associated with tumor progression. Multiple mechanisms promote this pathway: in starved HCC cells, DRAM translocation to mitochondria activates the PINK1/Parkin pathway, inducing mitophagy and apoptosis, thereby suppressing HCC development (25). STOML2 stabilizes PINK1 to enhance pro-survival mitophagy and cell migration (30). Apoptin activates the PINK1/Parkin pathway to induce mitophagy, establishing a cytoprotective mechanism that inhibits apoptosis (29). In LCSCs, ADAR1 activates it via editing GLI1 RNA, maintaining LCSC function and promoting HCC growth and metastasis (42). Thus, the functional output of the PINK1/Parkin pathway in HCC is context-dependent. Beyond this canonical axis, other ubiquitin-dependent mechanisms also contribute to mitophagic regulation in HCC. For instance, TMX2 facilitates Parkin recruitment, increasing cell viability under oxidative stress (31).

Receptor-mediated mitophagy pathways

Mitophagy can also be executed through ubiquitin-independent mechanisms. Specific OMM proteins harboring LC3-interacting regions (LIRs) act as autophagy receptors, directly binding to LC3 on autophagosomal membranes to initiate mitophagy without the need for ubiquitination (44).

The FUNDC1 pathway: this pathway is a key sensor of hypoxia. Its activity is regulated by phosphorylation; dephosphorylation enhances its interaction with LC3 to initiate mitophagy (45). In HCC, FUNDC1-mediated mitophagy exerts a tumor-suppressive function by suppressing inflammasome activation, thereby protecting against hepatocarcinogenesis (23). Conversely, in hepatoma cells, elevated SND1 promotes HCC progression by activating FUNDC1-mediated mitophagy via PGAM5 (32).

The BNIP3/NIX pathway: in HCC, this pathway demonstrates context-dependent duality. It can mediate apoptosis-associated mitophagy, as observed with Concanavalin A treatment (26,27). However, it is more frequently co-opted to support tumor progression. For instance, HBx-induced BNIP3L-dependent mitophagy drives glycolytic reprogramming, enhancing cancer stemness (38).

Other emerging pathways and regulatory networks

These classic mitophagy pathways play pivotal roles in the initiation and progression of HCC. Evidence indicates that other mitophagic pathways also hold significant importance. For example: in cancer cells, PINK1 can activate Ariadne RBR E3 ubiquitin ligase 1 (ARIH1) to promote mitophagy independently of Parkin (46). In HeLa cells, selenite treatment induces mitophagy by triggering mitochondrial E3 ubiquitin ligase 1 (MUL1)-mediated ubiquitination of ULK1 (47). Autophagy/beclin-1 regulator-1 (AMBRA1) facilitates mitophagy by recruiting the E3 ligase HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1 (HUWE1) to ubiquitinate mitofusin 2 (MFN2), by passing PINK1/Parkin (48). Other E3 ligases, including SMAD ubiquitination regulatory factor 1 (SMURF1) (49) and glycoprotein 78 (GP780) (50), initiate mitophagy through independently of the PINK1-Parkin pathway. Additionally, prohibitin 2 (PHB2), myeloid cell leukemia-1 (MCL-1), and mitochondrial E3 ubiquitin ligase 1 (MUL-1) have also been implicated in LIR-mediated mitophagy initiation (51).

The expanding repertoire of mitophagy pathways underscores the molecular complexity of this process in HCC. Beyond the canonical PINK1/Parkin and receptor-mediated pathways, emerging regulators like MUL1, AMBRA1, and PHB2 contribute to a sophisticated network. To gain deeper insights into HCC pathogenesis, identifying and characterizing novel autophagy-related pathways is crucial for elucidating the complex mechanisms driving liver cancer development. Furthermore, it is necessary to investigate potential overlap or crosstalk between different pathways, delineate their interactions, pinpoint central hubs, and identify key molecular connectors. Deciphering this regulatory logic is not only critical for understanding HCC pathogenesis but also for developing context-specific therapeutic strategies that target mitophagy, a challenge we will address in the following sections.

The treatment of liver cancer

Current status of liver cancer treatment

Surgical resection and liver transplantation remain the primary therapeutic options for HCC patients. However, due to the aggressive growth pattern and late clinical manifestation of HCC, the majority of patients are diagnosed at an unresectable advanced stage (52). Consequently, the management of these patients relies on locoregional and systemic therapies, including transcatheter arterial chemoembolization (TACE), radiotherapy, and systemic therapies such as tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (53). Despite these approaches, the asymptomatic nature of early-stage HCC, combined with high rates of tumor recurrence and acquired drug resistance in advanced stages, results in suboptimal therapeutic outcomes (54-56). Therefore, elucidating the molecular mechanisms underlying treatment resistance and recurrence is critical for developing innovative therapeutic approaches to improve clinical outcomes.

Mitophagy and drug resistance in HCC

Drug resistance persists as a formidable barrier in cancer therapeutics. Tumor cells deftly evade therapeutic stress by dynamically remodeling mitochondrial processes, notably enhancing mitochondrial fission and mitophagy-mechanisms that collectively fuel treatment resistance (57,58). In HCC, mitophagy is mechanistically entrenched in drug resistance. For instance, within hypoxia-induced sorafenib-resistant (SR) HCC models, miR-210-5p downregulates ATPase family AAA domain-containing protein 3A (ATAD3A), resulting in PINK1 accumulation on the mitochondrial outer membrane. This activation of mitophagy directly promotes sorafenib resistance and propels HCC growth (59). Similarly, in lenvatinib-resistant HCC cells, the long non-coding RNA LINC01607 upregulates p62/sequestosome 1 (SQSTM1), initiating protective mitophagy (60). This critical mechanism reduces ROS levels, alleviates oxidative stress-induced apoptosis, and fosters chemoresistance. Furthermore, BNIP3-mediated mitophagy in these lenvatinib-resistant cells diverts energy production from oxidative phosphorylation to glycolysis via the AMP-activated protein kinase (AMPK)-enolase 2 (ENO2) axis, sustaining glycolytic flux and bolstering tumor cell survival (61). These compelling findings indicate that TKIs may paradoxically accelerate HCC progression by mitigating mitochondrial damage-induced apoptosis and fundamentally reprogramming tumor metabolism.

Crucially, mitophagy-associated resistance extends beyond TKI therapies to other treatment modalities. For instance, the limited efficacy of systemic chemotherapy in advanced HCC stems partially from activated mitophagy (62-64). During radiotherapy, the long non-coding RNA nuclear enriched abundant transcript 1 (NEAT1) robustly promotes PINK1/Parkin-dependent mitophagy via gamma-aminobutyric acid receptor-associated protein (GABARAP) and superoxide dismutase 2 (SOD2), facilitating the clearance of radiation-damaged mitochondria and significantly enhancing HCC cell radioresistance (64). Similarly, following radiofrequency ablation (RFA), sublethal hyperthermia induces NADPH oxidase NOX4 (NOX4)-dependent mitochondrial ROS (mtROS) production in residual HCC cells. This surge activates nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, which in turn triggers PINK1-mediated mitophagy to eliminate heat-stressed mitochondria, thereby enabling tumor cell survival and driving post-RFA recurrence (65). In summary, mitophagy emerges as a pivotal mediator of treatment resistance in HCC. By counteracting the cytotoxic onslaught of diverse therapies and maintaining tumor cell viability, mitophagy is a key driver of both chemoresistance and relentless disease progression.

Mitophagy and HCC treatment

Given the dual role of mitophagy in HCC pathogenesis and its close association with drug resistance, it represents a highly attractive yet complex therapeutic target. The central paradox lies in the fact that both inhibiting and inducing mitophagy can exert anti-tumor effects, depending on the context. Therapeutic strategies must therefore precisely discern whether the goal is to dismantle the pro-survival, “protective” mitophagy or to push it into overdrive, triggering “excessive” or lethal mitophagy that culminates in cell death. Current research is actively exploring pharmacological agents that target mitophagy, either as monotherapy or in combination regimens, for HCC management (Figure 3). The following sections detail these strategic approaches.

Figure 3 Targeting mitophagy in HCC treatment. In the treatment of HCC, mitophagy has emerged as a therapeutic target. On one hand, inhibition of mitophagy suppresses the protective mitophagic response in HCC cells, promoting their apoptosis. On the other hand, induction of excessive mitophagy via specific inducers facilitates mitochondrial autophagy-mediated cell death. HCC, hepatocellular carcinoma.

Targeting protective mitophagy: inhibition strategies

Given that mitophagy drives HCC progression and mediates chemoresistance, its suppression represents a promising therapeutic strategy. To overcome treatment failure, particularly in the context of TKI resistance, innovative combination therapies are being developed to disrupt mitophagy in resistant cells. Canagliflozin, a type II diabetes medication, enhances sorafenib’s efficacy by crippling ATP production via potent inhibition of both the electron transport chain (ETC) and glycolysis (66). This dual metabolic blockade disrupts survival-promoting mitophagy, exacerbates mitochondrial damage, and powerfully suppresses HCC progression in both in vitro and in vivo. Similarly, melatonin potently downregulates hypoxia-inducible factor-1α (HIF-1α) protein synthesis by inhibiting the mechanistic target of rapamycin complex1 (mTORC1)/p70 ribosomal protein S6 kinase (p70S6K) pathway, thereby decisively blocking hypoxia-induced protective mitophagy and significantly potentiating sorafenib’s anti-tumor effects in HCC cells (67). These findings validate combination therapies targeting TKI-associated mitophagy as feasible and potent strategies to overcome entrenched chemoresistance.

Given the dose-limiting toxicities linked to TKIs, natural mitophagy inhibitors offer attractive alternatives. Oroxylin A (OA), a potent bioactive flavonoid derived from Scutellaria baicalensis, suppresses PINK1/Parkin-dependent mitophagy initiation by inhibiting cyclin-dependent kinase 9 (CDK9) and inactivating the sirtuin 1 (SIRT1)-forkhead box O3 (FOXO3)-BNIP3 axis. This dual action effectively induces profound mitochondrial dysfunction and triggers apoptosis in HCC cells (68). Sesamol, a potent phenolic antioxidant, collapses mitochondrial membrane potential (ΔΨm) while directly blocking class III phosphatidylinositol 3-kinase (PI3K class III)/Beclin-1-mediated mitophagy, promoting selective apoptosis of damaged HCC mitochondria (69). Collectively, these natural compounds exert a dual-pronged mechanisms: inflicting direct mitochondrial damage while inhibiting compensatory mitophagy, overwhelming cellular repair and triggering apoptosis.

Mitophagy encompasses multiple critical stages, and disruption at any single phase can halt the entire process. In HCC, sanguinarine induces significant ROS accumulation, activating PINK1/Parkin-mediated mitophagy initiation. Yet, it concurrently inhibits autophagosome degradation by directly interfering with autophagosome-lysosome fusion. This blockade of late-stage mitophagy triggers the release of apoptotic proteins and caspase activation, driving mitochondrial apoptosis and subsequent cell death, thereby powerfully suppressing HCC cell growth (28,70). Similarly, Li et al. demonstrated that deapioplatycodin D (DPD), a triterpene saponin isolated from Platycodon grandiflorum roots, robustly promotes BNIP3L-mediated mitophagy initiation. However, it simultaneously inhibits the expression of syntaxin17, synaptosome-associated protein, 29 kDa (SNAP29), and vesicle-associated membrane protein 8 (VAMP8), thereby blocking lysosomal fusion. This disruption of autophagosome-lysosome fusion effectively inhibits HCC proliferation (71).

In summary, strategically inhibiting mitophagy—whether through combination therapies, natural compounds, or stage-specific disruption—effectively suppresses HCC progression by disabling this critical pro-survival mechanism.

Inducing lethal mitophagy: activation strategies

Researchers have actively explored autophagy inducers as promising therapeutic candidates for HCC. While mitophagy inhibitors disrupt mitochondrial homeostasis and suppress tumor growth under drug-resistant conditions (detailed in “Targeting protective mitophagy: inhibition strategies” section), an alternative clinical approach combines molecular targeted drugs with mitophagy inducers to trigger excessive mitophagy and overcome chemoresistance. For instance, melatonin enhances sorafenib’s cytotoxic effects in Hep3B cells by inducing mitophagy, thereby promoting mitochondrial apoptosis and cell death (72). Artesunate (ART), a semi-synthetic water-soluble artemisinin derivative, reduces sorafenib resistance in HCC by augmenting mitophagy dependent on the actin filament-associated protein 1-like 2 (AFAP1L2)-SRC-FUNDC1 axis (73). Furthermore, combining human menstrual blood-derived stem cells (MenSCs) with sorafenib in resistant HCC cells elevates BNIP3 and BNIP3L levels, disrupting balanced autophagy; this hyperactivation of mitophagy causes severe mitochondrial dysfunction, ultimately inducing autophagic death in HCC-SR cells (74). Collectively, these findings demonstrate that combining sorafenib with mitophagy inducers exacerbates HCC cell death. This combination therapy effectively overcomes drug resistance, yielding superior therapeutic outcomes.

Given the significant adverse effects of conventional therapies like sorafenib, researchers have investigated natural compounds to directly induce excessive mitophagy in HCC. Ketoconazole, traditionally an antifungal agent, downregulates prostaglandin-endoperoxide synthase 2 (PTGS2) and activates the PINK1/Parkin axis to induce excessive mitophagy, accelerating apoptosis and inhibiting HCC growth (75). Mallotucin D (MLD), a bioactive chlorane diterpene isolated from Croton crassifolius, induces severe mitochondrial damage, marked by decreased translocase of outer mitochondrial membrane 20 (TOM20) expression, loss of ΔΨm, and massive ROS overproduction. Crucially, MLD promotes autophagic cell death through PI3K/AKT/mTOR inhibition and subsequent mitophagy hyperactivation (76). Moracin, a prenylated flavonoid from mulberry root bark, inhibits ATP-citrate lyase (ACLY), causing ROS accumulation in HCC cells. This damage triggers PINK1/Parkin-dependent mitophagy, ultimately inducing apoptosis (77). Similarly, polycystine D (PGD), a triterpenoid saponin, suppresses hepatoma growth through BNIP3L-mediated crosstalk between mitophagy and intrinsic apoptosis pathways (78). Collectively, these studies underscore the potential of natural compounds to suppress HCC by inducing excessive mitophagy, which converges on the activation of apoptotic cell death through distinct upstream mechanisms.

A comprehensive summary of the drugs and candidate molecules discussed in this section, including their targets, mechanisms of action, and research stages, is provided in Table 1.

Novel and future therapeutic strategies targeting mitophagy

Beyond direct inhibition or induction, next-generation strategies aim to exploit the crosstalk between mitophagy and other cancer hallmarks, including immune evasion, metabolic reprogramming, and tumor microenvironment (TME) remodeling.

Advances in immunotherapy have expanded the therapeutic relevance of mitophagy. For example, the natural compound icariin induces immunogenic cell death (ICD) in HCC by activating mitophagy, thereby reshaping the immunosuppressive TME (79). In murine liver cancer models, nanoparticle-mediated co-delivery of icariin and doxorubicin enhances early anti-tumor efficacy by promoting immune memory responses. suggesting mitophagy modulation can act as a potent immunomodulatory adjuvant. A critical future frontier is to investigate mitophagy’s role in tumor immune evasion—a mechanism established in other cancers but underexplored in HCC. For instance, in glioblastoma multiforme (GBM), mitophagy activation leads to mtDNA release, which activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and upregulates programmed cell death-ligand 1 (PD-L1) expression, facilitating immune escape (81). Determining if this axis operates in HCC is a priority, as it could reveal strategies to enhance immunotherapy efficacy.

Targeting mitophagy-associated metabolic vulnerabilities represents another promising direction. Synthetic agents such as the mitochondria-targeting copper (II) complex CTB promote drp1-dependent mitochondrial fission, dissociate hexokinase 2 (HK2) from mitochondria, suppress glycolysis, and ultimately inhibit tumor growth (80). This strategy highlights the potential of dual disruption of mitochondrial quality control and cancer cell metabolic adaptation.

Beyond cell-intrinsic mechanisms, modulating the TME through mitophagy presents another therapeutic frontier. For instance, peritumoral monocytes in HCC suppress mitophagy via intracellular interleukin-1α (IL-1α), driving excessive interleukin-8 (IL-8) secretion. IL-8 upregulates stemness-related transcription factors in HCC cells, enhancing their self-renewal, drug resistance, and tumor-initiating capacity (82). Additionally, IL-8 activates cancer-associated fibroblasts (CAFs) to further amplify IL-8 production, promoting epithelial-mesenchymal transition (EMT) and metastatic potential in HCC cells. Thus, targeting mitophagy in peritumoral immune cells may offer a novel stromal-based therapeutic avenue. Similarly, emerging evidence from other cancers indicates that CAFs can support tumor progression through mitophagy-mediated metabolic coupling, exporting nutrients to fuel cancer cells (83,84). Disrupting CAF-specific mitophagy could therefore represent a strategy to “starve” HCC tumors.

Finally, given the crucial role of mitophagy in maintaining LCSC stemness (41,42), developing agents that selectively disrupt mitophagy in this resilient subpopulation may be key to preventing tumor recurrence and metastasis.

Conclusions

Mitophagy, a fundamental cellular quality-control mechanism, plays a context-dependent dual role in HCC, functioning as both a tumor suppressor and a promoter of malignancy. This review has synthesized evidence underscoring its intricate involvement in hepatocarcinogenesis, tumor progression, metabolic reprogramming, stemness maintenance, and therapy resistance. The functional outcome of mitophagy is dictated by specific molecular pathways—primarily the ubiquitin-dependent (e.g., PINK1/Parkin) and receptor-mediated (e.g., FUNDC1, BNIP3/NIX) axes—and is profoundly influenced by the dynamic TME.

This mechanistic understanding positions mitophagy as a compelling yet complex therapeutic target. Current therapeutic strategies thus diverge into two main avenues: inhibiting pro-survival, protective mitophagy to sensitize tumors to cell death, and inducing excessive, lethal mitophagy to directly eradicate cancer cells. Promising preclinical evidence supports the efficacy of various pharmacological agents, including natural compounds and synthetic molecules, within these paradigms. Furthermore, cutting-edge approaches are exploring the convergence of mitophagy modulation with immunotherapy, metabolic intervention, and stromal reprogramming, highlighting its potential as a multimodal therapeutic node.

Despite significant progress, critical challenges and knowledge gaps remain. Future research should prioritize the following directions to advance the field: first, mitophagy pathways are diverse and may not function independently during tumorigenesis and progression. Further elucidation of the specific contributions and crosstalk among distinct mitophagy pathways across different HCC subtypes and disease stages is essential. Identifying and validating HCC-specific mitophagy regulators or synthetic lethal targets will be key to enhancing therapeutic selectivity. Second, tumor development is closely linked to intricate interactions within the TME. Investigating the context-specific regulatory mechanisms and functions of mitophagy in LCSCs, immune cells, and other stromal components (e.g., CAFs) will provide novel insights for developing precise targeting strategies. Third, a deeper exploration of how mitophagy influences and is modulated by the broader TME—including metabolic, immune, and physical properties—is crucial for understanding therapy resistance and devising effective combination treatments. Finally, translating preclinical findings into clinical practice remains a major challenge. This includes developing reliable biomarkers to identify patients likely to benefit from mitophagy-targeted therapies, designing intelligent drug delivery systems for tumor-specific regulation, and rationally combining mitophagy modulators with other agents (e.g., immune checkpoint inhibitors, metabolism-targeting drugs) to maximize efficacy and overcome resistance.

In summary, mitophagy occupies a central yet nuanced role in HCC. A deeper understanding of its dual functions is driving a shift from conventional inhibition or activation toward context-dependent modulation. Deciphering this complex regulatory network through integrated multi-omics, high-resolution imaging, and advanced disease models will be essential to pave the way for personalized and effective therapeutic strategies targeting mitophagy in liver cancer.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-709/prf

Funding: This work was supported by the Chengdu Municipal Bureau of Science and Technology (No. YF05-02191-SN) and the Chengdu Seventh People’s Hospital-Chengdu Medical College (No. 2022LHTD-01).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-709/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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