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Ferroptosis in colorectal cancer: Molecular mechanisms and regulatory crosstalk with therapeutic prospects (Review)

  • Authors:
    • Mingxing Wu
    • Mingrong Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Pharmacy, The People's Hospital of Jinyun, Jinyun, Zhejiang 321400, P.R. China, School of Medicine, Jingchu University of Technology, Jingmen, Hubei 448000, P.R. China
    Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 138
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    Published online on: May 27, 2026
       https://doi.org/10.3892/or.2026.9143
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Abstract

Colorectal cancer (CRC) is a common malignancy of the colonic and rectal epithelia. Numerous patients with CRC derive only limited and unsustained benefit from conventional chemotherapy or immunotherapy, underscoring the need for novel treatments. Ferroptosis is an iron‑dependent, lipid peroxidation‑driven form of regulated cell death, controlled by iron and lipid metabolism, as well as antioxidant defense pathways, which represent attractive therapeutic targets. Ferroptosis‑related genes are closely linked to immune status, and metabolic reprogramming within the tumor microenvironment can modulate immune cell activation and antitumor immunity. Induction of ferroptosis suppresses CRC proliferation and overcomes resistance to cytotoxic drugs, whereas inhibition of ferroptosis may alleviate inflammatory bowel disease and limit CRC initiation in specific settings. This review summarizes the molecular basis and immunological relevance of ferroptosis in CRC, and discusses recent advances in combination strategies involving chemotherapy, immunotherapy, gut microbiota‑based therapy and nanotherapy, as well as current clinical progress, potential biomarkers and translational challenges.
View Figures

Figure 1

Molecular mechanisms of ferroptosis.
Several key pathways are involved in regulating ferroptosis,
interconnected through iron metabolism, lipid metabolism and
antioxidant systems. Iron metabolism plays a dual regulatory role
in ferroptosis, both promoting and inhibiting the process.
Circulating Fe3+ ions bind to TF and TFR1 and are
internalized. They then act through two mechanisms: i) Promoting
the formation of the LIP, which activates the Fenton reaction,
triggering ferroptosis; and ii) being stored in ferritin to limit
free iron accumulation and reduce its redox activity, thereby
inhibiting ferroptosis. In lipid metabolism, PUFAs are esterified
by ACSL4 and incorporated into the cell membrane via LPCAT3. LOX
catalyzes the oxidation of PUFA-PL into peroxide derivatives,
leading to membrane instability. SFAs and MUFAs protect against
ferroptosis by antagonizing LPO. In the antioxidant system, GPX4
effectively inhibits LPO by converting GSH to GSSG and reducing
toxic lipid hydroperoxides to non-toxic phosphatidyl alcohols.
Additionally, the FSP1/CoQH2, DHODH/CoQH2 and
GCH1/BH4 systems contribute to mitigating LPO in a
GPX4-independent manner. TF, transferrin; TFR1, TF receptor 1;
PUFAs, polyunsaturated fatty acids; ACSL4, acyl-CoA synthetase
long-chain family member 4; LPCAT3, lysophosphatidylcholine
acyltransferase 3; PUFA-PLs, PUFA-containing phospholipids; SFAs,
saturated fatty acids; MUFAs, monounsaturated fatty acids; LPO,
lipid peroxidation; GPX4, glutathione peroxidase 4; GSH,
glutathione; GSSG, GSH disulfide; FSP1-CoQ10,
ferroptosis suppressor protein 1-coenzyme Q10;
DHODH-CoQ10, dihydroorotate
dehydrogenase-CoQ10; GCH1-BH4, guanosine
triphosphate cyclohydrolase 1-tetrahydrobiopterin; SCD1,
stearoyl-CoA desaturase 1; MBOAT1/2, membrane-bound
O-acyltransferase domain-containing 1 and 2; POR, cytochrome P450
reductase; Glu, glutamate; Cys, cysteine; GSH, glutathione; GPX4,
glutathione peroxidase 4; GCL, glutamate-cysteine ligase; GSS,
glutathione synthetase; NAD(P)H, nicotinamide adenine dinucleotide
phosphate; ALOXs, Arachidonate lipoxygenases; AA, arachidonic acid;
AdA, adrenic acid; αESA, α-eleostearic acid; STARD7, StAR-related
lipid transfer domain containing 7; FtMt, ferritin mitochondrial;
SLC25A37, solute carrier family 25 member 37; CoQ10H2,
reduced coenzyme Q10; ABCB7, ATP binding cassette subfamily B
member 7; NFS1, cysteine desulfurase 1; STEAP3, six transmembrane
epithelial antigen of the prostate 3; DMT1, divalent metal
transporter 1; LIP, labile iron pool; FPN1, ferroportin 1; NCOA4,
nuclear receptor coactivator 4; VDAC, voltage-dependent anion
channel.

Figure 2

Cancer-related signaling pathways
regulating ferroptosis. (A) GINS4 inhibits the stability of p53,
affecting its function. p53 promotes ferroptosis by downregulating
SLC7A11 and upregulating SAT1. Additionally, p53 inhibits
ferroptosis by promoting CDKN1A or suppressing DPP4. (B) NRF2
inhibits ferroptosis by regulating components related to the
antioxidant system and iron metabolism. During ferroptosis, NRF2
activity is regulated by target genes such as PRMT5, DPP9 and CTSS.
(C) Interaction between autophagy and ferroptosis. Ferritinophagy,
lipophagy, mitophagy, clock autophagy and CMA regulate ferroptosis
by modulating iron accumulation, ROS levels and LPO. SLC7A11,
solute carrier family 7 member 11; SAT1, spermidine/spermine
N1-acetyltransferase 1; CDKN1A, cyclin-dependent kinase inhibitor
1A; DPP4, dipeptidyl peptidase-4; PRMT5, protein arginine
methyltransferase 5; CTSS, cathepsin S; CMA, chaperone-mediated
autophagy; GINS4, GINS complex subunit 4; GSH, glutathione; ALOXs,
Arachidonate lipoxygenases; NOX1, NADPH oxidase 1; Keap1,
Kelch-1ike ECH- associated protein l; RNF217, ring finger protein
217; TMEM160, transmembrane protein 160; FTH1, ferritin heavy chain
1; FPN1, ferroportin 1; FTL, ferritin light chain; FECH,
ferrochelatase; GCLC, glutamate-cysteine ligase catalytic subunit;
GCLM, glutamate-cysteine ligase modifier subunit; HO-1, heme
oxygenase 1; ATM, ataxia-telangiectasia mutated; SKP2, S-phase
kinase-associated protein 2; DTX2, E3 ubiquitin ligase deltex 2;
PLTP, phospholipid transfer protein; RAB7A, Ras related protein Rab
7a; SQSTM1, sequestosome 1; BMAL1, brain and muscle ARNT-like 1;
DCAF7, DDB1- and CUL4-associated factor 7; CKB, Creatine kinase B;
HSC70, heat shock cognate protein 70; HSP90, heat shock protein 90;
LAMP2A, lysosomal membrane protein type 2A; ATF4, activation
transcription factor 4; ROS, reactive oxygen species; LDs, lipid
droplets.

Figure 3

Ferroptosis-mediated crosstalk in the
TME. (A) Ferroptosis of tumor-associated immune cells can either
promote or suppress antitumor immunity. (B) Immune cells act on
tumor cells by regulating ferroptosis in the TME. TME, tumor
microenvironment; IFNγ, interferon γ; ACSL4, acyl-CoA synthetase
long-chain family member 4; AA, arachidonic acid; GSH, glutathione;
GPX4, glutathione peroxidase 4; PUFA-PLs, PUFA-containing
phospholipids; NK cell, natural killer cell; TAMs, tumor-associated
macrophages; DC, dendritic cell; Tregs, regulatory T cell; TGF-β,
transforming growth factor β; SMAD3, SMAD family member 3; HLF,
hepatic leukemia factor; GGT1, γ-glutamyltransferase 1; DEPDC5, DEP
domain-containing protein 5; PUFA, polyunsaturated fatty acid;
MTORC1, mechanistic target of rapamycin complex 1; FA, fatty acid;
IL-1β, interleukin 1β; APOC1, apolipoprotein C1; SLC3A2, solute
carrier family 3 member 2; ZFAND5, zinc finger AN1
domain-containing protein 5; PD-L1, programmed death ligand-1;
SLC7A11, solute carrier family 7 members 11; CAF, cancer-associated
fibroblast; Nrf2, nuclear factor E2-related factor 2; ATF3,
activation transcription factor 3; FSTL1, follistatin-like protein
1.

Figure 4

Integration of ferroptosis inducers
with chemotherapy, immunotherapy, gut microbiota-based therapy and
nanotherapy to suppress CRC progression, overcome therapeutic
resistance and limit immune evasion. BsADCs, bispecific ADCs; FMT,
fecal microbiota transplantation; CAR-T, chimeric antigen receptor
T-cell; PDT, photodynamic therapy; PTT, photothermal therapy; CRC,
colorectal cancer; TRIM36, tripartite motif containing 36; MTCH2,
mitochondrial carrier homolog 2; ZER6, zinc-finger estrogen
receptor interaction clone 6; UBR5, ubiquitin protein ligase E3
component N-recognition protein 5; lncRNAs, long non-coding RNAs;
WBP1, WW domain-binding protein 1; APOL3, apolipoprotein L3; PD-1,
programmed cell death protein 1; mAbs, monoclonal antibodies; IDA,
trans-3-indoleacrylic acid; L. plantarum MM89,
Lactobacillus plantarum MM89; F. nucleatum, Fusobacterium
nucleatum; Ce6, chlorin e6; Evo, evodiamine; CPT, camptothecin;
RSV, resveratrol.
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Copy and paste a formatted citation
Spandidos Publications style
Wu M and Zhang M: Ferroptosis in colorectal cancer: Molecular mechanisms and regulatory crosstalk with therapeutic prospects (Review). Oncol Rep 56: 138, 2026.
APA
Wu, M., & Zhang, M. (2026). Ferroptosis in colorectal cancer: Molecular mechanisms and regulatory crosstalk with therapeutic prospects (Review). Oncology Reports, 56, 138. https://doi.org/10.3892/or.2026.9143
MLA
Wu, M., Zhang, M."Ferroptosis in colorectal cancer: Molecular mechanisms and regulatory crosstalk with therapeutic prospects (Review)". Oncology Reports 56.1 (2026): 138.
Chicago
Wu, M., Zhang, M."Ferroptosis in colorectal cancer: Molecular mechanisms and regulatory crosstalk with therapeutic prospects (Review)". Oncology Reports 56, no. 1 (2026): 138. https://doi.org/10.3892/or.2026.9143
Copy and paste a formatted citation
x
Spandidos Publications style
Wu M and Zhang M: Ferroptosis in colorectal cancer: Molecular mechanisms and regulatory crosstalk with therapeutic prospects (Review). Oncol Rep 56: 138, 2026.
APA
Wu, M., & Zhang, M. (2026). Ferroptosis in colorectal cancer: Molecular mechanisms and regulatory crosstalk with therapeutic prospects (Review). Oncology Reports, 56, 138. https://doi.org/10.3892/or.2026.9143
MLA
Wu, M., Zhang, M."Ferroptosis in colorectal cancer: Molecular mechanisms and regulatory crosstalk with therapeutic prospects (Review)". Oncology Reports 56.1 (2026): 138.
Chicago
Wu, M., Zhang, M."Ferroptosis in colorectal cancer: Molecular mechanisms and regulatory crosstalk with therapeutic prospects (Review)". Oncology Reports 56, no. 1 (2026): 138. https://doi.org/10.3892/or.2026.9143
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