Biliary tract cancer (BTC) includes a spectrum of
invasive malignancies that arise from the bile duct epithelium. It
is relatively uncommon but highly heterogeneous, comprising
gallbladder cancer (GBC; which arises from the gallbladder or
cystic duct) and cholangiocarcinoma (CCA; which arises from the
intrahepatic, perihilar or distal biliary tree). BTC accounts for
<1% of all human types of cancer and ~3% of digestive system
tumors globally (1,2). In recent years, the incidence of BTC
has been increasing globally, particularly in Asian countries,
where it represents an important health problem (3,4).
Globally, adenocarcinoma accounts for ~90% of all BTC cases
(5,6). BTC is usually diagnosed at advanced
stage. The majority of patients with symptomatic BTC, such as those
presenting with biliary obstruction, have incurable tumors with
invasion of the surrounding organs, lymph nodes and distant
metastases, which results in poor prognoses (2,7).
At present, surgery remains the gold standard for treating
early-stage tumors; however, only a limited number of patients have
this opportunity (8,9). The 5-year overall survival rate of
BTC is <20% for patients from the United States of America and
Europe (10). Furthermore,
despite undergoing curative resection with a negative margin (R0),
BTC still have a high recurrence rate of >50% (8,9,11).
Gemcitabine-platinum chemotherapy is a recommended first-line
treatment for advanced BTC; however, its efficacy is not
satisfactory (12). The emergence
of targeted therapies and immunotherapies, such as Durvalumab and
Pembrolizumab, has revolutionized the treatment paradigm of
malignant tumors. Immunotherapy plus chemotherapy has been verified
to be effective in treating BTC (13-15). Investigating the key molecular
mechanisms and identifying novel therapeutic targets for BTC is
imperative.
Cell death can occur either due to unregulated
causes or following a regulated process (Fig. 1) (16). Unregulated cell death is the
instantaneous demise of cells due to severe physical, chemical or
mechanical causes. Unlike unregulated cell death, regulated cell
death (RCD) is characterized by organized signaling cascades and
specific molecular mechanisms, suggesting that it can be controlled
(17). The process of RCD can be
influenced, either delayed or accelerated, through pharmacological
or genetic interventions. A study by Dixon et al (18) first proposed the notion of
'ferroptosis' in 2012 (19).
Ferroptosis is a new type of RCD, differing from necroptosis
(Fig. 1A) (20), apoptosis (Fig. 1B) (21), pyroptosis (Fig. 1C) (22) and autophagy (Fig. 1D) (23) in morphology, genetics and
biochemistry (24,25). As its name implies, ferroptosis is
an iron-dependent mechanism of cell death (26). Ferroptosis is triggered by lipid
peroxidation (LPO), which results from an imbalanced cellular
metabolism and redox homeostasis. The morphological evidence of
ferroptosis includes the presence of small mitochondria with
increased mitochondrial membrane densities, reduced or missing
mitochondrial crista, outer mitochondrial membrane rupture and a
normal nucleus (Fig. 1E)
(27,28). Ferroptosis is indicated to serve
an important pathophysiological role in the development and
occurrence of numerous diseases, such as ischemic heart disease and
acute kidney injury, but particularly in cancer (19,29). Non-small cell lung cancer,
hepatocellular carcinoma, pancreatic cancer, breast cancer and
renal cell carcinoma are reported to be sensitive to ferroptosis
(30-34). Additionally, various ferroptosis
inducers, such as sorafenib, sulfasalazine and artemisinin,
demonstrate a mitigation of tumor progression (35). Due to the issue of drug
resistance, there is a growing interest regarding the potential of
targeting ferroptosis as a therapeutic strategy for malignancies
(36-38).
The present review aimed to provide a comprehensive
overview of the signaling pathways and molecular mechanisms of
ferroptosis, the research progress on ferroptosis in the occurrence
and development of BTC, and the potential application of
ferroptosis as a targeted therapy for BTC.
Following the first description of ferroptosis, a
form of non-apoptosis and iron-dependent RCD, in 2012, there has
been an increasing interest to investigate the process and
regulation of ferroptosis (39).
Previously, several studies investigated the mechanisms involved in
ferroptosis (40-42). The present study aimed to review
the core mechanisms of ferroptosis based on three aspects, namely
iron metabolism, lipid metabolism and antioxidant defense
systems.
Iron is one of the crucial minor elements for human
health, and the correct intracellular level of iron is
indispensable for a well-functioning metabolic balance (43). Iron is mainly obtained from
dietary intake, existing in two distinct oxidation states. These
are the divalent (Fe2+) and trivalent (Fe3+)
ions (44). The continuous
interconversion of Fe2+ and Fe3+ allows
iron-dependent cofactors, such as cytochrome P450s, to effectively
carry out their catalytic functions in various biological
processes, including nucleic acid synthesis as well as repair,
epigenetic regulation and cellular respiration (45). While in the Fe2+ state
or combined with a transporter protein, iron is primarily absorbed
in the duodenum and upper jejunum epithelial cells. The less
soluble Fe3+ ion must first be reduced to absorbable
ferrous Fe2+ and is then transported via divalent metal
transporter 1 (DMT1) into epithelial cells (46). Absorbed iron then either enters
the blood circulation via ferroportin (FPN) or is stored as
ferritin. Fe3+ is the primary form of iron in blood
circulation. FPN, encoded by the transporter solute carrier family
40 member 1 gene, is the only known iron-exporting protein in
mammalian cells. It is responsible for exporting Fe3+ to
the extracellular space (47).
Subsequently, multi-copper ferroxidases on the epithelial cell
membrane re-oxidize Fe2+ to Fe3+, which is
then bound by transferrin (TF) and transported in the plasma
(44). Lactotransferrin also
contributes positively to the regulation of iron absorption by
enhancing iron uptake, similar to TF (48). The majority of cells mainly obtain
non-heme iron through two primary pathways that involve TF-bound
iron uptake and non-TF-bound iron (NTBI) uptake. TF binds to
transferrin receptor (TFR)1 and forms endosomes through
clathrin-dependent endocytosis. Within cells, TF-bound iron
separates, and six-transmembrane epithelial antigen of prostate 3
reduces Fe3+ to Fe2+, which then enters the
cytoplasm via DMT1 for subsequent use or storage as ferritin
(49,50). When there is an iron overload,
such as in hemochromatosis, excess iron surpasses the capacity of
TF, resulting in the increased circulation and uptake of NTBI
(forming an unstable iron pool) through transporters such as solute
carrier family 39 member 14 (51). The main repository for
intracellular iron is the ferritin dimer, consisting of ferritin
heavy and light chains. Nuclear receptor coactivator 4 (NCOA4)
increases iron levels by facilitating ferritin degradation
(52-54).
Ferroptosis relies on iron, as suggested by its
name. An elevated iron level in the body has a direct association
with the onset of ferroptosis (18). Excessive iron levels increase the
production of reactive oxygen species (ROS), leading to cell
dysfunction or death, tissue damage and diseases, such as human
leukocyte antigen-linked hemochromatosis and Friedreich ataxia
(44). An excessive accumulation
of iron can result in ferroptosis either through Fenton reactions
or by activating arachidonate lipoxygenases and cytochrome P450
oxidoreductase-mediated phospholipid peroxidation metabolism
(55,56). As an important step in
ferroptosis, the Fenton reaction involves the non-enzymatic
oxidation of organic compounds, such as polyunsaturated fatty acids
(PUFAs), into inorganic states by a mixture of hydrogen peroxide
(H2O2) and Fe2+ (37). Glutathione peroxidase 4 (GPX4) is
the major neutralizing enzyme of phospholipid (PL) hydroperoxides
(OOHs; PLOOHs). GPX4 knockdown results in an accumulation of
PLOOHs, which induces an increase in lipid peroxidation and
ferroptosis (57).
Uncontrolled LPO represents a key hallmark of
ferroptosis. A key initiation step of ferroptosis involves an
excessive oxidation of PUFA-PLs (19). The susceptibility of PUFAs to
peroxidation is attributed to their diallyl moieties (55). The magnitude of LPO is influenced
by both the abundance and distribution of PUFAs within
phospholipids (28). Arachidonic
acid (AA) and adrenic acid (AdA) serve as the primary LPO
substrates in ferroptosis. Acyl-CoA synthetase long-chain family
member 4 (ACSL4) catalyzes the esterification of AA or AdA with
CoA, generating oxidizable AA- or AdA-CoA. Subsequently,
lysophosphatidylcholine acyltransferase 3 (LPCAT3) facilitates the
PL remodeling of AA- or AdA-CoA and membrane
phosphatidylethanolamine (PE) into AA- or AdA-PE, anchoring it to
the cell or mitochondrial membranes (58). Conversely, acyl-CoA synthetase
long-chain family member 3 (ACSL3) and stearoyl-CoA desaturase 1
(SCD1) confer cellular resistance to ferroptosis by catalyzing the
synthesis of monounsaturated fatty acid (MUFA) and the displacement
of PUFAs from plasma membrane phospholipids (55,59,60). Subsequently, 15-lipoxygenase (LOX)
then oxidizes AA-PE or AdA-PE to PL-PUFA-OOHs, which acts as a
ferroptosis signal (58).
However, 12-LOX can mediate the ACSL4-independent pathway of LPO
production via the p53/solute carrier family 7 member 11
(SLC7A11)/12-LOX axis (61).
FSP1 is a GSH-independent ferroptosis suppressor,
acting in parallel to GPX4. When GPX4 is knocked out, FSP1 (also
known as apoptosis-inducing factor mitochondrial-associated protein
2) is activated as a compensatory antioxidant system. FSP1 is
located on the plasma membrane and uses NAD(P)H to reduce CoQ to
ubiquinol (CoQH2), which acts as an antioxidant by
binding to radicals. This neutralizes lipid peroxide free radicals
and blocks the propagation of LPO (66,67) (Fig.
2).
The GCH1-BH4 system is another important
GPX4-independent ferroptosis inhibitor. GCH1 prevents ferroptosis
via the synthesis of its metabolic derivatives, BH4 and
dihydrobiopterin (BH2), and lipid remodeling. GCH1 overexpression
selectively protects those PLs containing two PUFA chains from
degradation, which potentially has two simultaneous mechanisms: i)
Acting as an antioxidant that directly binds to radicals; and ii)
contributing to the synthesis of CoQ (68,69) (Fig.
2).
As PL-modifying enzymes, MBOAT1 and MBOAT2 function
as GPX4/FSP1-independent ferroptosis suppressors. MBOAT1 and 2
inhibit ferroptosis by remodeling PLs by selectively incorporating
MUFAs into lyso-PE. This increases the cellular MUFA-PE levels and
decreases the PUFA-PE levels (71). However, MBOAT1 and 2 function as
sex hormone-dependent regulators, and their transcription is
upregulated by androgen and estrogen receptors (71) (Fig.
2).
The TME serves pivotal roles in the initiation,
progression, metastasis and therapeutic resistance of tumors
(72-75). It is a dynamic interacting network
that is comprised of diverse cellular components, including
malignant cells, immune cells, cancer-associated fibroblasts and
endothelial cells, alongside acellular elements such as the
extracellular matrix, cytokines and metabolites (76). Ferroptosis engages in a complex
bidirectional crosstalk with the TME, particularly through
metabolic reprogramming and immunomodulation, which regulates BTC
malignancy and treatment responses (77,78).
Ferroptosis in malignant cells modulates antitumor
immunity within the TME through immunogenic signaling (79,80). Previous evidence indicates that
ferroptotic cancer cells release damage-associated molecular
patterns (DAMPs), a hallmark of immunogenic cell death (ICD), which
function as endogenous adjuvants to potentiate antitumor immunity
(81,82). As well as the classic DAMPs, such
as high mobility group protein 1 (83-85), adenosine triphosphate (86,87), calcium reticulum protein (84,86) and the recently identified
proteoglycan decorin (88),
ferroptotic cancer cells release immunomodulatory cytokines such as
C-X-C motif chemokine ligand 1 (CXCL1), tumor necrosis factor (TNF)
and interferon (IFN)-β, that contribute to the remodeling of the
TME (89). However, whether
ferroptosis is a classic form of ICD is still an ongoing scientific
debate (89). In addition, the
specific role of ferroptotic cancer cells in antitumor immunity is
also contradictory. A previous study demonstrates that tumor cell
competition for cystine compromises the function of CD8+ T cells
within the TME. Cystine deprivation triggers glutamate
accumulation, which potentiates CD36-mediated LPO (90). However, ferroptotic cells can
activate antitumor immunity by expressing
1-steaoryl-2-15-HpETE-sn-glycero-3-PE. This serves as a signal that
mediates phagocytosis by engaging Toll-like receptor 2 on
macrophages (91) and enhancing
the activities of natural killer cells (92).
Immune cells exhibit differential susceptibility to
ferroptosis within the TME, and their functional heterogeneity
enables distinct populations to either potentiate or suppress
ferroptosis in malignant cells (80). CD8+ T cells exhibit an increased
sensitivity to GPX4 inhibition compared with malignant cells,
resulting in a premature impairment of antitumor immunity prior to
notable tumor cell death (93).
However, these effector lymphocytes demonstrate relative resistance
to system Xc− inhibitors, such as sulfasalazine, as
inhibition of system Xc− did not affect T cell
proliferation and antitumor immune responses (94). Activated CD8+ T cells with high
expression levels of fatty acid transporter CD36 increases the risk
of LPO and ferroptosis (95).
Compared with tumor-derived CD8+ T cells, tumor-infiltrating
regulatory T cells (Tregs) typically have reduced levels of LPO,
suggesting that they are less prone to ferroptosis in the TME
(93). However, system
Xc− inhibitors rarely impair the viability of Tregs
(96). Tumor-associated
macrophages (TAMs) are one of the most abundant types of immune
cells in the TME and include the proinflammatory antitumor M1 and
anti-inflammatory protumor M2 types (97,98). The sensitivity of these two types
of cells to ferroptosis is different due to the high levels of
inducible nitric oxide synthase and nitric oxide-free radicals in
M1 type compared with M2 type TAMs (99). Another group of immune-suppressive
cells, namely myeloid-derived suppressor cells (MDSCs), exhibit
notable resistance to ferroptosis, which is associated with the
upregulation of system Xc− and neutral ceramidase
N-acylsphingosine amidohydrolase expression levels (100).
Metabolic reprogramming is a defining hallmark of
malignancy, triggering cancer metastasis, aggressiveness and
therapeutic resistance (101).
Remodeled metabolic environments and immunosuppressive environments
enable cancer cells to evade RCD (78). This metabolic reprogramming
extends beyond canonical adaptations such as the Warburg effect (in
which preferential glycolysis reduces mitochondrial ROS
generation), and includes the suppression of pyruvate
dehydrogenase, limiting the acetyl-CoA flux for PUFA biosynthesis,
which is critical for ferroptosis (102-104). Within the TME, MDSCs increase
immunosuppression through IL-6/JAK2/STAT3-mediated SLC7A11
upregulation, which depletes the extracellular cystine pools
(105). This metabolic
competition induces a GSH deprivation-induced ferroptosis in CD8+ T
cells, further inactivating antitumor immunity (90).
To resist ferroptosis, cancer cells use lipid
metabolic reprogramming as a defense strategy via two primary
mechanisms: i) PL membrane restructuring via the activation of the
sterol regulatory element-binding protein-1-SCD1 axis, replacing
oxidation-vulnerable PUFAs with MUFAs (106); and ii) mevalonate
pathway-derived antioxidant production, such as isopentenyl
pyrophosphate from cholesterol metabolism, which neutralizes lipid
peroxides (107,108). Iron homeostasis is also
inhibited through TFR1-mediated uptake and ferritin heavy chain
(FTH)-dependent storage, which reduces the levels of cytotoxic free
Fe2+ (109,110). Furthermore, gut
microbiota-derived metabolites, such as short-chain fatty acids
(such as butyrate) and tryptophan metabolites (such as
indole-acrylic acid), also affect the TME and influence the
resistance of cancer cells to ferroptosis (111,112).
Epigenetic regulation is a heritable mechanism that
regulates the expression of genes through chemical modifications
without altering the DNA sequence. It primarily involves DNA
methylation, histone modifications, non-coding RNA (ncRNA)-mediated
regulation and RNA methylation (113).
Several key genes are dynamically controlled by DNA
methylation. For example, in normal tissues, the core enzyme GPX4,
which is essential for eliminating lipid peroxides, has notably
reduced expression levels due to transcriptional repression caused
by the hypermethylation of CpG islands within its promoter region
compared with cancer tissues. This suppression increases cellular
susceptibility to ferroptosis (114-117). By contrast, the promoter of the
system Xc− light chain subunit SLC7A11 is frequently
hypomethylated, leading to its elevated expression levels (118,119). This enhances cystine uptake and
GSH synthesis, which inhibits ferroptosis. Furthermore,
hypermethylation of the FSP1 promoter results in a reduction to its
expression levels, which sensitizes cells to ferroptosis (120,121).
RNA methylation, the most abundant
post-transcriptional modification in eukaryotic mRNA, also
contributes to ferroptosis regulation. AlkB homolog 5 regulates
glutamate-cysteine ligase modifier subunit (GCLM) mRNA levels
though N6-methyladenosine (m6A) modification
of GCLM and YTH m6A RNA binding protein-mediated decay
of GCLM, which regulates ferroptosis (122). Additionally,
methyltransferase-like protein 16 (METTL16) serves a role in
ferroptosis and tumorigenesis by catalyzing the m6A
modification of Sentrin/small ubiquitin-like modifier-specific
protease 3 mRNA and regulating the stability of lactotransferrin
(123).
Histone modifications serve an important role in
shaping chromatin structure. It exerts precise transcriptional
control over ferroptosis-associated genes, such as SLC7A11 and
ACSL3, and impacts gene expression and cancer development (124-126). p53 promotes the nuclear
translocation of a histone H2B monoubiquitylation (H2Bub1)
deubiquitinase, ubiquitin-specific protease 7 (USP7), which
negatively regulates H2Bub1 levels. The interaction between p53 and
USP7 reduces the occupancy of H2Bub1 at the regulatory region of
SLC7A11, leading to transcriptional repression of SLC7A11and
enhancing the ferroptosis induction sensitivity of cells (125). Histone acetylation and
methylation also demonstrate bidirectional regulatory effects on
ferroptosis (126-129).
ncRNAs regulate the expression of
ferroptosis-associated genes via post-transcriptional regulation,
forming protein-RNA interaction networks. Specifically, microRNA
(miR)-137/miR-9 and miR-15a-5p promote ferroptosis by targeting
SLC7A11 and GPX4 mRNA, respectively (130,131), whereas miR-27a and miR-4717
exert anti-ferroptosis effects by targeting ACSL4 and NCOA4
(132,133). Long ncRNAs (lncRNAs) also
participate in ferroptosis regulation by acting as protein decoys,
chromatin modifiers or miRNA sponges (134,135).
Ferroptosis induction has emerged as a novel
strategy to overcome tumor therapy resistance (35,36). However, tumor cells establish
complex ferroptosis defense networks by remodeling immune-metabolic
environments, notably elevating the threshold for ferroptosis
initiation (78). The development
of this resistance limits the clinical application of
ferroptosis-inducing therapies (78). However, a series of innovative
strategies have been developed, providing a theoretical foundation
for designing effective treatments to circumvent resistance.
Recently identified, reversible palmitoylation modification of GPX4
is a key regulator of ferroptosis. The palmitoylation inhibitor
2-bromopalmitate notably enhances the antitumor efficacy of
ferroptosis inducers by inhibiting GPX4 palmitoylation (136). Furthermore, targeted protein
degradation represents an emerging therapeutic paradigm. The
GPX4-targeted autophagy-targeting chimera (GPX4-AUTAC), based on
selective autophagic degradation, induces ferroptosis and
demonstrates antitumor activity in vitro, in vivo and
in patient-derived organoids (137). In addition,
proteolysis-targeting chimeras that target GPX4/DHODH have also
been designed (138,139). The use of combination strategies
that target immune checkpoints alongside ferroptosis inducers are
also gaining attention (140).
Furthermore, the development of novel nanodrug delivery systems
offers additional approaches to overcome chemoresistance, such as
high-density lipoprotein nanoparticles with dual metabolic
disruption (selenium deprivation and LPO) (141) and antibody-targeted
nanoplatforms (such as Fe-MOF@Erastin@ Herceptin), which deliver
ferroptosis inducers (such as erastin) specifically to tumor cells
(142).
Ferroptosis is demonstrated to have therapeutic
potential in various types of cancer, including hepatocellular
carcinoma, lung carcinoma, lymphoma, pancreatic ductal carcinoma
and renal cell carcinoma (30-34). BTC is an uncommon type of
gastrointestinal malignancy that has a poor prognosis. In the early
stages of disease, surgical resection with negative margins can
effectively treat BTC (8,9). For unresectable and metastatic
disease, gemcitabine and cisplatin chemotherapies plus
immunotherapy (such as with Durvalumab or Pembrolizumab) are the
only preferred regimens approved by the National Comprehensive
Cancer Network (143,144). With the increasing number of
patients with BTC, investigating novel targets and alternative
options is crucial. Ferroptosis, which is considered to be one of
the most promising potential antitumor methods, can affect the
occurrence and development of BTC by regulating intracellular iron
and ROS levels, providing new treatment options for patients with
BTC (70,124,145). The following section primarily
concentrates on the advancements in ferroptosis-associated research
in BTC, including potential therapeutic targets, treatment options
and associated mechanisms (Table
I; Fig. 3).
TP53 is acknowledged as a classic tumor suppressor
gene, which serves important roles in controlling the cell cycle,
cell proliferation and cell death (146,147). TP53 serves a role in controlling
the susceptibility to ferroptosis via both transcription-dependent
and transcription-independent mechanisms (148). Shank-associated RH domain
interacting protein (SHARPIN) is a crucial part of the complex
responsible for activating the linear ubiquitin chain, which
inhibits ferroptosis through the p53/SLC7A11/GPX4 signaling pathway
and promotes cell proliferation in CCA. Silencing the SHARPIN gene
results in the suppression of p53 ubiquitination and degradation,
as well as a decreased expression of SLC7A11, GPX4, superoxide
dismutase (SOD)-1 and SOD-2. Targeting SHARPIN may serve as a
potential strategy benefiting CCA treatment (149). Human hydroxysteroid
dehydrogenase-like 2 (HSDL2) is also a regulator of cancer
progression and lipid metabolism. Knocking down HSDL2 promotes CCA
progression by inhibiting ferroptosis through the p53/SLC7A11 axis
(150). As a member of
Runt-domain family, Runt-related transcription factor 3 (RUNX3) has
a reduced expression level in GBC. This downregulation, mediated by
promoter DNA hypermethylation, is notably associated with adverse
outcomes in patients with GBC. RUNX3 activates the transcription of
inhibitor of growth protein 1, which leads to the suppression of
SLC7A11 through a p53-dependent pathway and the induction of
ferroptosis (151). Golgi
phosphoprotein 3 also promotes CCA malignancy by inhibiting
ferroptosis through SLC7A11 upregulation (152). Additionally, TP53-induced
glycolysis and apoptosis regulator (TIGAR) is associated with
adverse outcomes and ferroptosis resistance in patients with
intrahepatic CCA (iCCA). TIGAR encodes an enzyme responsible
for regulating glycolysis and scavenging ROS. Knockdown of TIGAR
reduced the expression of GPX4, a key inhibitor of ferroptosis
(153). Furthermore, combining
TIGAR knockdown with cisplatin treatment synergistically induces a
notable increase in ferroptosis (153).
The transcription factor Nrf2 controls the
expression of genes involved in counteracting oxidative and
electrophilic stresses, which serves a role in regulating the
cellular antioxidant response (154,155). A study by Huang et al
(156) reports that
transcription factor activating enhancer-binding protein 2 α
(TFAP2A) may serve a role as a regulator of ferroptosis in GBC via
the Nrf2 signaling pathway. GBC cells exhibit elevated levels of
TFAP2A, compared with non-tumorigenic human intrahepatic bile duct
cells (H69), and knocking down TFAP2A lead to a decrease in GBC
cell proliferation, migration and invasion, as well as a decreased
expression of oxidative stress-associated genes, such as heme
oxygenase 1 and Nrf2. A study by Zheng et al (157) demonstrates high
methyltransferase-like 3 expression levels in cisplatin-resistant
iCCA cells compared with parental cells. This upregulation enhances
m6A modifications, leading to the inhibition of
ferroptosis and a resistance to cisplatin through the stabilization
of Nrf2 mRNA and an increase in the Nrf2 protein expression levels.
Additionally, overexpression of METTL16 in patients with CCA is
associated with poor prognosis. Mechanistically, METTL16 increases
the m6A modifications of activating transcription factor
4 (ATF4) mRNA, which increases the expression of ATF4 and
subsequently results in the suppression of ferroptosis (158).
At present, GPX4 is recognized as the only enzyme
with the ability to directly reduce complex phospholipid
hydroperoxide (159). Therefore,
GPX4, which is responsible for the efficient removal of
phospholipid hydroperoxides, is critical for cell survival
(160). When GPX4 fails to
effectively remove PLOOHs, there is an increase in LPO and
ferroptosis (57,161). GPX4 is also one of the important
adverse prognostic indicators in iCCA (162). A study by Lei et al
(163) demonstrates that JUND
enhances the transcription of linc00976, which promotes the
development of CCA and prevents ferroptosis by regulating the
miR-3202/GPX4 axis. F-box protein 31 (FBXO31) stimulates the
ubiquitination process of GPX4 and consequently promotes the
degradation of the GPX4 proteasome, which enhances the occurrence
of ferroptosis. Additionally, FBXO31-upregulated cancer stem
cell-like cells present enhanced sensitivity to cisplatin compared
with control cells (164). In
addition, lncRNA paired box 8-antisense RNA 1 binds to p62 and
activates Nrf2, which promotes GPX4 transcription and stabilizes
GPX4 mRNA by interacting with insulin-like growth factor 2 mRNA
binding protein 3. This inhibits ferroptosis and promotes
resistance to gemcitabine and cisplatin. Treatment with JKE-1674 (1
μM), a GPX4 inhibitor, combined with gemcitabine (5
μM) and cisplatin (10 μM) exhibits an improved
antitumor potential in preclinical models of both subcutaneous
tumor and orthotopic mice models, compared with gemcitabine and
cisplatin therapy (165).
Previous studies reveal ACSL4 promotes ferroptosis
by catalyzing the esterification of long-chain PUFAs into PUFA-CoA,
which serve as substrates for LPO (166,167). Data from the Gene Expression
Omnibus and The Cancer Genome Atlas databases demonstrates that
there is a higher level of ACSL4 in CCA compared with normal
adjacent tissues. Additionally, ACSL4 levels are associated with
the prognosis of patients with CCA as well as the immune
infiltration in CCA (168).
Targeting the ACSL4 pathway may be an anti-cancer approach. A study
by Liao et al (169)
reveals that, via ACSL4-dependent lipid reprogramming, IFNγ from
cytotoxic T lymphocytes and AA from the TME induce tumor cell
ferroptosis. Furthermore, cancer cells that derive from migration
exhibit a higher ferroptosis sensitivity and PUFA lipid contents
compared with primary-tumor-derived cells. This supports the
possibility of targeting ferroptosis in the treatment of cancer
(170). Specific and targeted
inhibitors of ACSL4 with anti-ferroptosis function such as
AS-252424 have been screened and identified (171). In GBC, sirtuin 3 has tumor
suppressive effects through the induction of the expression of
ACSL4 and AKT-dependent ferroptosis, and inhibition of the
epithelial-mesenchymal transition (172). Another member of the acyl-CoA
synthetase long chain family, ACSL3, synthesizes MUFAs that
suppress PUFAs peroxidation, which confers ferroptosis protection.
Furthermore, ACSL3 is an unfavorable prognostic biomarker in
patients with CCA and a mediator of ferroptosis resistance in CCA
cells. Therefore, ACSL3 may be a potential therapeutic target
(173).
Furthermore, several other factors potentially
regulate ferroptosis sensitivity. For example, circular
(circ)forkhead box protein P1 and Homo sapiens_circ_0050900
affect ferroptosis by interacting with OTU domain-containing
protein 4 and regulating SLC3A2, respectively (174,175). TFR modulates the ferroptosis
sensitivity of cells by regulating intracellular iron levels.
Additionally, TFR is also an adverse prognostic factor in patients
with iCCA (176). The regulatory
importance of the E26 transformation-specific variant 4-ALY/REF
export factor-pyruvate kinase M2 and Aldo-keto reductase family 1
member C1-cytochrome P450 family 1 subfamily B member 1-cAMP axes
also warrant attention (177,178). Additionally, gut microbiotas
inhibit ferroptosis in iCCA by altering glutamine metabolism
through the regulation of the activin receptor-like kinase 5/NADPH
oxidase 1 axis (179).
Ferroptosis serves a role in the pathogenesis,
progression and treatment resistance of BTC. Furthermore,
accumulating evidence demonstrates that ferroptosis-associated
indicators are notably associated with patient prognosis and
represent potential prognostic biomarkers (Table II). Techniques such as RNA
sequencing and immunohistochemistry reveal elevated expression of
ferroptosis-associated markers, including ACSL3/4, SLC7A11 and
GPX4, in BTC tumor tissues compared with normal adjacent tissues,
which is notably associated with poorer clinical outcomes (168,173,176,180-183). By contrast, isocitrate
dehydrogenase 1 (IDH1) mutations are associated with a more
favorable prognosis in BTC (183,184). In addition, other key
ferroptosis-associated markers, such as LPCAT3 and FSP1, are also
associated with prognosis in various solid tumors including ovarian
cancer and lung adenocarcinoma; however, their clinical validation
in BTC requires further investigation (185-192). Taken together, these
ferroptosis-associated indicators may serve as novel prognostic
markers for BTC, potentially offering a new perspective for precise
prognosis assessment and individualized treatment strategies.
Furthermore, integrating these indicators to establish
multi-parameter prognostic models may enhance the accuracy of
existing BTC prognostic assessment systems.
Traditional Chinese medicine (TCM) is currently
recognized as a viable complementary treatment in malignancies
(196). Accumulating evidence
demonstrates that TCM can notably enhance the chemosensitivity of a
patient, potentiate the antitumor efficacy of therapeutic agents
and mitigate treatment-associated adverse effects in cancer
management (197,198). Quercetin (QE), a flavonoid in
flowers, stems and leaves of various plants, possesses the ability
to impede the progression of breast and colon cancer by
interrupting the cell cycle (199,200). Previous studies demonstrate that
QE induces ferroptosis in iCCA cells by inhibiting the NF-κB
signaling pathway, which inhibits iCCA cell invasion (201,202). Isoliquiritigenin (ISL), also
known as 2',4',4-trihydroxychalcone, is also a type of flavonoid
and is extracted from the root of the liquorice plant. ISL induces
apoptosis and inhibits proliferation in tumors (203,204). A study by Wang et al
(205) reveals that ISL triggers
ferroptosis in GBC by activating the p62-Kelch-like ECH-associated
protein 1-Nrf2-haem oxygenase-1 (HMOX1) signaling pathway and
reducing the expression of GPX4. Silencing HMOX1 or increasing GPX4
expression levels decreases the susceptibility of GBC cells to
ISL-induced ferroptosis and enhances the survival of GBC cells
(205). Another naturally
occurring triterpenoid compound named liquidambaric acid (LCD) also
exhibits notable therapeutic potential. LCD can bind to and inhibit
signal transducing adaptor molecule binding protein like 1, which
stabilizes Nrf2 through de-ubiquitination, and notably enhances CCA
cell proliferation and migration while impeding ferroptosis
(206). Wu-Mei-Wan, a
long-utilized TCM formula, demonstrates potential efficacy as a
second-line GBC therapy. It enhances gemcitabine chemosensitivity
and induces ferroptosis through phosphorylated (p)-STAT3-mediated
transcriptional regulation of ferroptosis-associated targets,
downregulating GPX4, HIF-1α and FTH1, while upregulating ACSL4
(207).
At present, chemoimmunotherapy is the first-line
treatment option for BTC due to the durvalumab plus gemcitabine and
cisplatin in advanced BTC and KEYNOTE-966 studies (143,144). A study by Zhu et al
(208) reveals that, in
AKT-hyperactivated iCCA, the p-AKT-p-phosphoenolpyruvate
carboxykinase 1 (PCK1)-p-lactate dehydrogenase A-SPRINGlac axis is
a driver of ferroptosis resistance. This combines p-PCK1-mediated
glycolytic activation and mevalonate flux reprogramming. However,
simvastatin treatment effectively reverses this resistance,
underscoring its therapeutic potential for improving the
chemoimmunotherapy efficacy through ferroptosis sensitivity
(208).
In addition, metabolic products such as lithocholic
acid (LCA) are reagents involved in inhibiting tumorigenesis. A
study by Li et al (209)
reveals that LCA induces ferroptosis in GBC by suppressing
glutaminase-mediated glutamine metabolism, which may be a
tumor-suppressive mechanism with therapeutic potential.
PDT is a treatment modality that selectively
destroys tumor tissue through the light activation of
photosensitizers and release of ROS (210). The tumor-selective destruction
capacity of PDT minimizes damage to healthy tissues, which suggests
it may be a potential antitumor therapeutic strategy (211,212). The first-generation
photosensitizer-HiPorfin-mediated PDT promotes the apoptosis and
ferroptosis of CCA cells through the activation of the
p53/SLC7A11/GPX4 signaling pathway (213). Furthermore, the
second-generation photosensitizer-Hypericin-mediated PDT induces
ferroptosis in CCA by inhibiting the AKT/mTORC1/GPX4 signaling
pathway (214). These findings
provide possible insights into individualized precision therapy for
CCA. Furthermore, combination strategies represent novel
therapeutic paradigms for BTC. Surufatinib (SUR), a multi-targeted
kinase inhibitor, has comparable clinical efficacy in patients with
advanced CCA compared with regorafenib, which is one of the
recommend regimens used for subsequent-line therapy of BTC
(12,215). Mechanistically, both SUR and PDT
induce ferroptosis through the upregulation of ACSL4 and
suppression of GPX4, and their effect is synergistically enhanced
during combination treatment (215). In addition, an integrated
nanotherapeutic platform known as CMArg@ Lip has been successfully
developed for combined PDT and gas therapy. This platform
encapsulates the photosensitizer, NO gas-generating agent and Nrf2
inhibitor with ROS-responsive liposomes, which enables it to
effectively address the challenges of tumor hypoxia and the
antioxidant microenvironment (216).
Ferroptosis, an iron-dependent, LPO-driven form of
RCD, is a research focus in BTC therapeutics. Accumulating evidence
demonstrates marked vulnerability of BTC cells to ferroptosis,
unveiling novel avenues for targeted treatment. Despite promising
advances, challenges persist. While core ferroptosis pathways, such
as the GPX4-GSH axis and system Xc− regulation, are
delineated, the integrated regulatory network, particularly
crosstalk with metabolic reprogramming and TME interactions, is yet
to be fully elucidated. At present, clinically applicable
biomarkers for predicting ferroptosis sensitivity are lacking,
which hampers patient stratification. Furthermore, current
ferroptosis inducers, such as erastin analogs and RSL3 derivatives,
have limitations in tumor specificity, systemic toxicity and
pharmacokinetic profiles.
Future studies should prioritize the following: i)
Systematic investigations of ferroptosis synergism with immune
checkpoint inhibitors and molecular-targeted agents, using
multiomics approaches to decipher resistance mechanisms; ii)
development of integrated biomarker panels incorporating genetic,
epigenetic and microenvironmental features for precision patient
stratification; iii) therapeutic validation through physiologically
relevant platforms, including patient derived organoids, orthotopic
BTC models and humanized mouse systems simulating tumor-stroma
crosstalk; and iv) engineering of tumor-targeted nano-formulations,
such as the CMArg@Lip platform, to enhance the tumor-targeted
delivery of ferroptosis inducers while mitigating off-target
effects.
In summary, bridging mechanistic insights from
laboratory studies with rationally designed clinical trials
incorporating biomarker-driven enrollment may highlight ferroptosis
modulation as a potnetial therapeutic paradigm for BTC.
Not applicable.
RZ and YD contributed to literature searching and
screening, manuscript drafting and revision of the manuscript. SY
and HH contributed to the revision of the manuscript. FLi and FLiu
contributed to the study design and revision of the manuscript.
Data authentication is not applicable. All authors read and
approved the final version of the manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
The present study was supported by 1.3.5 project for disciplines
of excellence (West China Hospital, Sichuan University; grant no.
ZYJC21046), 1.3.5 project for disciplines of excellence-Clinical
Research Incubation Project (West China Hospital, Sichuan
University; grant no. 2021HXFH001), China Telecom Sichuan Company
Biliary Tract Tumor Big Data Platform and Application Phase I
R&D Project (grant no. 312230752), National Natural Science
Foundation of China for Young Scientists Fund (grant no. 82303669),
Sichuan University-Sui Ning School-local Cooperation project (grant
no. 2022CDSN-18), and The Post-doctor Research Fund of West China
Hospital, Sichuan University (grant nos. ZYJC21046, 2021HXFH001 and
2024HXBH083).
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