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Ferroptosis in biliary tract cancer: Molecular mechanisms and therapeutic applications (Review)

  • Authors:
    • Ruiqi Zou
    • Yushi Dai
    • Siqi Yang
    • Haijie Hu
    • Fuyu Li
    • Fei Liu
  • View Affiliations / Copyright

    Affiliations: Department of General Surgery, Division of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
    Copyright: © Zou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 6
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    Published online on: November 14, 2025
       https://doi.org/10.3892/ijo.2025.5819
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Abstract

Biliary tract cancer (BTC) encompasses a group of aggressive malignancies arising from the bile duct epithelium, including gallbladder cancer and cholangiocarcinoma, which are characterized by aggressive progression, frequent metastases and poor prognoses. BTC accounts for ~3% of all digestive system tumors, with a 5‑year overall survival rate of <20%. BTC presents a clinical challenge. Despite multidisciplinary therapeutic approaches incorporating surgery, chemotherapy and radiotherapy, persistent obstacles, including high tumor recurrence rates (>50%) and the development of treatment resistance remains, underscoring the urgent need for novel treatment strategies such as targeted therapies and immunotherapies. Ferroptosis, a distinct mechanism of regulated cell death triggered by lipid peroxidation, serves critical roles in disease occurrence and progression. Increasing evidence supports the potential of ferroptosis as a targeted therapy in malignancies, with emerging implications for personalized BTC treatment. The present review investigated the molecular mechanisms and signaling pathways that govern ferroptosis, the advances in the understanding of ferroptosis during the initiation and progression of BTC, and the translation potential of ferroptosis for precision therapeutics. By integrating current knowledge, the present study aimed to provide theoretical suggestions for future mechanistic investigations and clinical studies of ferroptosis‑based interventions for patients with BTC.
View Figures

Figure 1

Main molecular mechanisms of
different types of cell death. Cell death includes unregulated cell
death and RCD. (A) Necroptosis is a form of RCD that is dependent
on the RIPK1/RIPK3/mixed lineage kinase domain like pseudokinase
signaling pathway. It is characterized by cell swelling, plasma
membrane rupture and the release of damage-associated molecular
patterns. (B) Apoptosis is a non-inflammatory form of RCD initiated
by perturbations of the extra- or intracellular microenvironment.
It is characterized by cell shrinkage, chromatin condensation,
apoptotic body formation and phagocytic clearance. (C) Pyroptosis
is a form of RCD activated by inflammasomes and caspases, which is
characterized by plasma membrane pore formation, cell lysis and the
release of proinflammatory cytokines (such as IL-1β and IL-18). (D)
Autophagy is a conserved cellular self-degradation process that
maintains homeostasis by sequestering damaged organelles or
misfolded proteins into autophagosomes, which then fuse with
lysosomes for degradation. (E) Ferroptosis is an iron-dependent RCD
induced by glutathione depletion and glutathione peroxidase 4
inactivation, which leads to excessive lipid peroxidation. It is
characterized by lipid oxidative damage to the plasma membrane and
cell swelling and is inhibited by iron chelators and lipophilic
antioxidants. Compared with necroptosis, apoptosis, pyroptosis and
autophagy, ferroptosis is a new type of RCD and presents distinct
morphological, genetic and biochemical characteristics. RCD,
regulated cell death; RIPK, receptor-interacting protein
kinase.

Figure 2

Antioxidant systems that suppress
ferroptosis. Pathways of the antioxidant system include the
SLC7A11-GSH-GPX4, FSP1-CoQ-NAD(P)H, GCH1-BH4,
DHODH-CoQH2 and MBOAT1/2-MUFA pathways. The
SLC7A11-GSH-GPX4 axis transports cystine into cells via SLC7A11 (a
component of system Xc−) for GSH synthesis.
Subsequently, GPX4 uses GSH to scavenge lipid peroxides, which
serves as the core antioxidant defense axis for ferroptosis
inhibition. In the FSP1-CoQ-NAD(P)H pathway, NAD(P)H serves as the
energy source, FSP1 reduces CoQ to CoQH2 and
CoQH2 directly binds lipid free radicals and inhibits
lipid peroxidation. Therefore, the FSP1-CoQ-NAD(P)H pathway acts as
a ferroptosis defense pathway independent of GSH. In the GCH1-BH4
system, GCH1 catalyzes the production of BH4, which reduces lipid
peroxidation by stabilizing the lipid bilayer structure, chelating
free iron or directly scavenging free radicals. Therefore, the
GCH1-BH4 system exerts antioxidant and ferroptosis-inhibiting
effects. In the DHODH-CoQH2 system, DHODH participates
in pyrimidine synthesis in mitochondria using CoQ as an electron
acceptor, while reducing CoQ to CoQH2. Subsequently,
CoQH2 inhibits lipid peroxidation, forming a
mitochondrial-level antioxidant defense mechanism. In the
MBOAT1/2-MUFA system, MBOAT1/2 catalyzes the combination of MUFA
with phospholipids to form MUFA-containing phospholipids, which can
resist lipid peroxidation and enhance the cell anti-ferroptosis
capabilities at the membrane structure level. SLC7A11, solute
carrier family 7 member 11; System Xc−,
cystine/glutamate antiporter; GSH, glutathione; GPX4, glutathione
peroxidase 4; FSP1, ferroptosis inhibitory protein 1; CoQ,
ubiquinone; GCH1, GTP cyclic hydrolase 1; BH4, tetrahydrobiopterin;
DHODH, dihydroorotate dehydrogenase; CoQH2, ubiquinol;
MBOAT1/2, membrane-bound O-acyltransferase domain-containing 1/2;
TXNRD1, thioredoxin reductase 1; ER, estrogen receptor; AR,
androgen receptor; FOXA1, forkhead box protein A1; GS, glutathione
synthetase; GSR, glutathione reductase; GSSG, glutathione
disulfide; γ-GCS, γ-glutamylcysteine synthetase; MUFA,
monounsaturated fatty acid.

Figure 3

Main regulatory network of
ferroptosis in BTC. Multiple molecules including system
Xc− and GPX4, as well as signaling pathways involving
p53, Nrf2 and NF-κB, are involved in the processes of ferroptosis
induction and inhibition. Substances such as isoliquiritigenin,
quercetin and lithocholic acid influence ferroptosis-related
processes. These regulatory mechanisms control lipid peroxidation
and ferroptosis in BTC. BTC, biliary tract cancer; SHARPIN,
shank-associated RH domain interacting protein; SLC7A11, solute
carrier family 7 member 11; GPX4, glutathione peroxidase 4; HSDL2,
hydroxysteroid dehydrogenase-like 2; DNMT1, DNA methyltransferase
1; ING1, inhibitor of growth 1; ACSL4, acyl-CoA synthetase
long-chain family member 4; ACSL3, acyl-CoA synthetase long-chain
family member 3; LPCAT3, lysophosphatidylcholine acyltransferase 3;
MUFA, monounsaturated fatty acid; IDH1, isocitrate dehydrogenase 1;
FBXO31, F-box protein 31; GOLPH3, golgi phosphoprotein 3; METTL16,
methyltransferase-like protein 16; ATF4, activating transcription
factor 4; m6A, N6-methyladenosine; STAMBPL1, signal
transducing adaptor molecule binding protein like 1; Nrf2, nuclear
factor erythroid 2-related factor 2; Keap1, Kelch-like
ECH-associated protein 1; METTL3, methyltransferase like 3; TIGAR,
TP53-induced glycolysis and apoptosis regulator; TFR, transferrin
receptor; SLC3A2, solute carrier family 3 member 2; ETV4, E26
transformation-specific variant 4; ALYREF, Aly/REF nuclear export
factor; OTUD4, OTU domain-containing protein 4; NCOA4, nuclear
receptor coactivator 4; PAX8-AS1, paired box 8-antisense RNA 1;
CYP1B1, cytochrome P450 family 1 subfamily B member 1; GS,
glutathione synthetase; GSSG, glutathione disulfide, GLS,
glutaminase; GSH, glutathione; RUNX3, runt-related transcription
factor 3; TFAP2A, transcription factor activating enhancer-binding
protein 2 α; HMOX1, haem oxygenase-1; SIRT3, sirtuin 3; STAT3,
signal transducer and activator of transcription 3; PDT,
photodynamic therapy; Ub, ubiquitin.
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Copy and paste a formatted citation
Spandidos Publications style
Zou R, Dai Y, Yang S, Hu H, Li F and Liu F: Ferroptosis in biliary tract cancer: Molecular mechanisms and therapeutic applications (Review). Int J Oncol 68: 6, 2026.
APA
Zou, R., Dai, Y., Yang, S., Hu, H., Li, F., & Liu, F. (2026). Ferroptosis in biliary tract cancer: Molecular mechanisms and therapeutic applications (Review). International Journal of Oncology, 68, 6. https://doi.org/10.3892/ijo.2025.5819
MLA
Zou, R., Dai, Y., Yang, S., Hu, H., Li, F., Liu, F."Ferroptosis in biliary tract cancer: Molecular mechanisms and therapeutic applications (Review)". International Journal of Oncology 68.1 (2026): 6.
Chicago
Zou, R., Dai, Y., Yang, S., Hu, H., Li, F., Liu, F."Ferroptosis in biliary tract cancer: Molecular mechanisms and therapeutic applications (Review)". International Journal of Oncology 68, no. 1 (2026): 6. https://doi.org/10.3892/ijo.2025.5819
Copy and paste a formatted citation
x
Spandidos Publications style
Zou R, Dai Y, Yang S, Hu H, Li F and Liu F: Ferroptosis in biliary tract cancer: Molecular mechanisms and therapeutic applications (Review). Int J Oncol 68: 6, 2026.
APA
Zou, R., Dai, Y., Yang, S., Hu, H., Li, F., & Liu, F. (2026). Ferroptosis in biliary tract cancer: Molecular mechanisms and therapeutic applications (Review). International Journal of Oncology, 68, 6. https://doi.org/10.3892/ijo.2025.5819
MLA
Zou, R., Dai, Y., Yang, S., Hu, H., Li, F., Liu, F."Ferroptosis in biliary tract cancer: Molecular mechanisms and therapeutic applications (Review)". International Journal of Oncology 68.1 (2026): 6.
Chicago
Zou, R., Dai, Y., Yang, S., Hu, H., Li, F., Liu, F."Ferroptosis in biliary tract cancer: Molecular mechanisms and therapeutic applications (Review)". International Journal of Oncology 68, no. 1 (2026): 6. https://doi.org/10.3892/ijo.2025.5819
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