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Potential role of AhR in ischemia‑reperfusion injury and cancers: Focus on ferroptosis and lipid peroxidation signaling pathways (Review)

  • Authors:
    • Zhihong Liao
    • Mingzhang Huang
    • Yuanqi Zhang
    • Siqi Huang
    • Wei Lei
    • Xiaorong Shui
  • View Affiliations / Copyright

    Affiliations: Laboratory of Vascular Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China, Department of Breast Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China, Guangdong Provincial Engineering Technology Research Center for Molecular Diagnosis and Innovative Drugs Translation of Cardiopulmonary Vascular Diseases, University Joint Laboratory of Guangdong Province and Macao Region on Molecular Targets and Intervention of Cardiovascular Diseases, Department of Precision Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
    Copyright: © Liao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 156
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    Published online on: July 25, 2025
       https://doi.org/10.3892/ijmm.2025.5597
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Abstract

The aryl hydrocarbon receptor (AhR) is a pivotal ligand‑activated transcription factor that plays a crucial role in maintaining cellular redox homeostasis. The disruption of redox homeostasis in the etiology of numerous diseases primarily manifests as the accumulation of reactive species and the attenuation of the antioxidant defenses, leading to the progressive buildup of lipid peroxides. This phenomenon significantly contributes to the initiation and progression of diseases, such as atherosclerosis, cancer, diabetes and ischemia‑reperfusion injury. Ferroptosis is a form of cell death characterized by iron dependency and lipid peroxidation. The regulation of ferroptosis presents a promising therapeutic target for anticancer therapy and the prevention of neurodegenerative and cardiovascular diseases. AhR transcriptionally regulates downstream target genes, thereby modulating the biosynthesis and accumulation of bioactive compounds and the antioxidant defense mechanism. This process is intricately linked to lipid peroxide accumulation and subsequent ferroptosis. The present review provides an overview of the influence of AhR on lipid peroxidation and ferroptosis, the potential therapeutic targets, and the prospective application value of targeting the AhR to influence lipid peroxidation‑ferroptosis processes in tumor cells and ischemia‑reperfusion injury.
View Figures

Figure 1

Molecular mechanisms and key
regulators of lipid peroxidation and ferroptosis. The initiation of
ferroptosis is primarily driven by the accumulation of labile iron
pools within cells, which originates from two main sources: Iron
uptake mediated by transferrin receptor 1 and free iron release
during heme metabolism catalyzed by heme oxygenase 1. In normal
cells, free iron, polyunsaturated fatty acids, and ROS generate
lipid hydroperoxides via the Fenton reaction. This process is
predominantly modulated by GSH-dependent and non-GSH-dependent
intracellular antioxidant systems. The GSH-dependent system
facilitates the uptake of cystine, an essential precursor for
reduced glutathione, through the SLC7A11/SLC3A2 isodimer, and
subsequently consumes reduced GSH via GPX to detoxify lipid
peroxides. FSP1, also known as AIFM2 or AMID, represents a recently
identified core inhibitor of ferroptosis. It regulates the redox
cycle of coenzyme Q10 through pathways independent of GSH and GPX4,
thereby forming a secondary defense mechanism against lipid
peroxidation. ATF4 and NRF2 function as the core transcription
factors enabling cells to respond to oxidative stress and metabolic
imbalance. Both ATF4 and NRF2 inhibit lipid peroxidation and confer
resistance to ferroptosis by regulating distinct target gene
networks. ROS, reactive oxygen species; GSH, glutathione; SLC7A11,
solute carrier family 7 member 11; GPX, glutathione peroxidase;
FSP1, ferroptosis suppressor protein 1; ATF4, activating
transcription factor 4; NRF2, nuclear factor erythroid 2-related
factor 2; CoQ10, coenzyme Q10; NADP+, nicotinamide
adenine dinucleotide phosphate; PUFA, polyunsaturated fatty acid;
MDA, malondialdehyde; 4-HNE, 4-hydroxynonenal; ARE, antioxidant
response element.

Figure 2

Oxidative and antioxidant AhR ligands
regulate lipid peroxidation and ferroptosis via an
oxidative-antioxidant bidirectional regulatory network. Exogenous
pro-oxidative AhR ligands, such as the toxins TCDD and
benzo[a]pyrene, bind to AhR, forming the AhR-ARNT complex that
translocates into the nucleus. This complex subsequently binds to
the XRE, initiating the transcription of various progenitor
enzymes, including CYP1A1, CYP1B1, CYP1A2, COX-2 and NOX, then
mediating ROS production, which in turn induces lipid peroxidation
and ferroptosis. Conversely, natural AhR ligands derived from plant
sources, such as snake tail grass, soybean, fig tree, and fish tail
grass, activate the transcription of antioxidant enzymes (e.g.,
NQO1, GST and UGT1A1) through AhR signaling. This activation
suppresses ROS production, thereby mitigating lipid peroxidation
and inhibiting ferroptosis. AhR, aryl hydrocarbon receptor; TCDD,
2,3,7,8-tetrachlorodibenzo-p-dioxin; ARNT, AhR nuclear
translocator; NOX, nitrogen oxide; ROS, reactive oxygen species;
NQO1, NAD(P) H dehydrogenase [quinone] 1; GST, glutathione
S-transferase; UGT1A1, UDP-glucuronosyltransferase 1-1; HMOX1, heme
oxygenase 1; IDO1, indoleamine 2,3-dioxygenase 1; SLC7A11, solute
carrier family 7 member 11; COX-2, cyclooxygenase-2; ALDH1A3,
aldehyde dehydrogenase 1 family, member A3.

Figure 3

The mechanism of AhR mediating lipid
peroxidation-ferroptosis via CYP1, SLC7A11/GPX4 axis, or HMOX1 heme
metabolism by different ligands in different disease states. AhR
modulates the expression of diverse target genes across various
contexts, consequently influences ferroptosis in distinct disease
processes. IS triggers ferroptosis in MC3T3-E1 cells by activating
the SLC7A11/GPX4 signaling pathway via AhR. In renal tubular
epithelial cells and liver I/R injury, suppression of the AhR
signaling pathway mitigates the extent of damage. Under the
condition of oxidative stress of intestinal epithelial lymphocytes,
inhibition of AhR signaling can alleviate intestinal epithelial
lymphocytes ferroptosis by reducing ROS production. Butylphthalide
exerts an inhibit effect on neuronal ferroptosis in traumatic brain
injury by inhibiting the AhR-CYP1A-ROS axis. AhR, aryl hydrocarbon
receptor; SLC7A11, solute carrier family 7 member 11; GPX,
glutathione peroxidase; HMOX1, heme oxygenase 1; I/R,
ischemia/reperfusion; ROS, reactive oxygen species.

Figure 4

The mechanism of AhR mediating lipid
peroxidation-ferroptosis through the SLC7A11/GPX4 axis or the
ALDH1A3/FSP1 axis under different ligand binding or cytosolic
lysosomal cystine deficiency states. AhR modulates the expression
of diverse target genes across different contexts, thereby
influencing ferroptosis in various disease states. Specifically,
lysosomal cystine deficiency triggers ATF4 expression via the AhR
signaling pathway, leading to the activation of the SLC7A11/GPX4
antioxidant system, which in turn inhibits ferroptosis in tumors.
I3P inhibits ferroptosis by activating the AhR-mediated
SLC7A11/GPX4 axis antioxidant system in bronchial epithelial cells
and non-small cell lung cancer. In colorectal cancer, intestinal
metabolites regulate the IDA-AhR-ALDH1A3 pathway and affect the
level of NADPH to promote the production of FSP1-mediated reduced
ubiquinone, thereby inhibiting tumor cell ferroptosis and promoting
tumor progression. AhR, aryl hydrocarbon receptor; SLC7A11, solute
carrier family 7 member 11; ALDH1A3, aldehyde dehydrogenase 1
family, member A3; FSP1, ferroptosis suppressor protein 1; GPX,
glutathione peroxidase; IDA, trans-3-indoleacrylic acid; ATF4,
activating transcription factor 4; CoQ10, coenzyme Q10;
NADP+, nicotinamide adenine dinucleotide phosphate.

Figure 5

Pharmacological targeting of AhR to
modulate ferroptosis in cancer and I/R injury. AhR ligands regulate
lipid peroxidation and ferroptosis through different molecular
axes, demonstrating environment-dependent therapeutic potential. In
parenchymal organs, such as the heart, liver and kidneys, AhR
antagonists CH223191 and SR1 alleviate I/R injury by inhibiting the
iron-stimulating pathway: CH223191 downregulates CYP1A-driven ROS
amplification and COX-2-mediated inflammatory signals, while SR1
inhibits HMOX1-dependent iron release and IDO1-induced oxidative
stress, jointly maintaining the redox balance of cells. In tumors,
AhR is pharmacologically regulated through AhR ligands, such as
aminoflavone, ITE, SR1 and CH223191, thereby influencing key
molecules in various lipid peroxidation and ferroptosis processes,
and further inducing ferroptosis in tumor cells or enhancing their
sensitivity to erastin. This is expected to eliminate tumor cells,
alleviate tumor progression and enhance the anti-tumor efficacy of
iron deposition inducers. AhR, aryl hydrocarbon receptor; HMOX1,
heme oxygenase 1; IDO1, indoleamine 2,3-dioxygenase 1; ROS,
reactive oxygen species; COX-2, cyclooxygenase-2; TCDD,
2,3,7,8-tetrachlorodibenzo-p-dioxin; NQO1, NAD(P)H dehydrogenase
[quinone] 1; GST, glutathione S-transferase; UGT1A1,
UDP-glucuronosyltransferase 1-1.
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Copy and paste a formatted citation
Spandidos Publications style
Liao Z, Huang M, Zhang Y, Huang S, Lei W and Shui X: Potential role of AhR in ischemia‑reperfusion injury and cancers: Focus on ferroptosis and lipid peroxidation signaling pathways (Review). Int J Mol Med 56: 156, 2025.
APA
Liao, Z., Huang, M., Zhang, Y., Huang, S., Lei, W., & Shui, X. (2025). Potential role of AhR in ischemia‑reperfusion injury and cancers: Focus on ferroptosis and lipid peroxidation signaling pathways (Review). International Journal of Molecular Medicine, 56, 156. https://doi.org/10.3892/ijmm.2025.5597
MLA
Liao, Z., Huang, M., Zhang, Y., Huang, S., Lei, W., Shui, X."Potential role of AhR in ischemia‑reperfusion injury and cancers: Focus on ferroptosis and lipid peroxidation signaling pathways (Review)". International Journal of Molecular Medicine 56.4 (2025): 156.
Chicago
Liao, Z., Huang, M., Zhang, Y., Huang, S., Lei, W., Shui, X."Potential role of AhR in ischemia‑reperfusion injury and cancers: Focus on ferroptosis and lipid peroxidation signaling pathways (Review)". International Journal of Molecular Medicine 56, no. 4 (2025): 156. https://doi.org/10.3892/ijmm.2025.5597
Copy and paste a formatted citation
x
Spandidos Publications style
Liao Z, Huang M, Zhang Y, Huang S, Lei W and Shui X: Potential role of AhR in ischemia‑reperfusion injury and cancers: Focus on ferroptosis and lipid peroxidation signaling pathways (Review). Int J Mol Med 56: 156, 2025.
APA
Liao, Z., Huang, M., Zhang, Y., Huang, S., Lei, W., & Shui, X. (2025). Potential role of AhR in ischemia‑reperfusion injury and cancers: Focus on ferroptosis and lipid peroxidation signaling pathways (Review). International Journal of Molecular Medicine, 56, 156. https://doi.org/10.3892/ijmm.2025.5597
MLA
Liao, Z., Huang, M., Zhang, Y., Huang, S., Lei, W., Shui, X."Potential role of AhR in ischemia‑reperfusion injury and cancers: Focus on ferroptosis and lipid peroxidation signaling pathways (Review)". International Journal of Molecular Medicine 56.4 (2025): 156.
Chicago
Liao, Z., Huang, M., Zhang, Y., Huang, S., Lei, W., Shui, X."Potential role of AhR in ischemia‑reperfusion injury and cancers: Focus on ferroptosis and lipid peroxidation signaling pathways (Review)". International Journal of Molecular Medicine 56, no. 4 (2025): 156. https://doi.org/10.3892/ijmm.2025.5597
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