# Ferroptosis as a Novel Therapeutic Strategy to Overcome Multidrug Resistance in Colorectal Cancer **Authors:** Dina Mahemuti, Lanfei Ma, Waqas Siddiqe, Ziyue Tang, Yuxin Kong, Wenfang Li, Zhiwei Zhang, Zhengding Su, Ayitila Maimaitijiang PMC · DOI: 10.3390/ph19020252 · 2026-02-01 ## TL;DR This review explores how triggering ferroptosis, a unique form of cell death, could help overcome drug resistance in colorectal cancer. ## Contribution The paper introduces ferroptosis as a novel strategy to bypass multidrug resistance in colon cancer. ## Key findings - MDR cancer cells suppress ferroptosis through antioxidant upregulation and iron sequestration. - Ferroptosis inducers like erastin and RSL3 can overcome apoptotic resistance and avoid efflux pathways. - Stimulating iron accumulation may reverse multidrug resistance in colon cancer. ## Abstract Colon cancer (CC) remains a leading cause of cancer-related mortality worldwide, with multidrug resistance (MDR) presenting a formidable barrier to successful chemotherapy. Ferroptosis—an iron-dependent, lipid peroxidation-driven form of cell death—offers a novel therapeutic avenue to bypass MDR by exploiting metabolic vulnerabilities distinct from traditional apoptosis pathways. Emerging evidence reveals a dynamic interplay between MDR and ferroptosis: MDR cancer cells suppress ferroptosis through NRF2/GPX4-mediated antioxidant upregulation, iron sequestration by ferritin, and lipid metabolism reprogramming, including SREBP1-driven monounsaturated fatty acid accumulation, while ABC transporters actively efflux ferroptosis inducers. On the other hand, ferroptosis inducers such as erastin and RSL3 have the potential to overcome apoptotic resistance and avoid efflux pathways, which recover therapeutic efficacy. This review first describes the primary mechanisms of chemotherapy resistance in colon cancer and then explains the molecular processes that prevent ferroptosis in resistant cells. We also review recent data on the complex interactions between resistance to chemotherapy and ferroptosis, and outline approaches that may stimulate iron accumulation to reverse MDR. By emphasizing novel methods to induce ferroptosis, this review highlights that this approach is a promising strategy to overcome chemotherapy resistance in colon cancer and will facilitate the development of more precise and efficient treatment. ## Linked entities - **Genes:** GABPA (GA binding protein transcription factor subunit alpha) [NCBI Gene 2551], GPX4 (glutathione peroxidase 4) [NCBI Gene 2879], SREBF1 (sterol regulatory element binding transcription factor 1) [NCBI Gene 6720] - **Chemicals:** erastin (PubChem CID 11214940), RSL3 (PubChem CID 1750826) - **Diseases:** colon cancer (MONDO:0002032), colorectal cancer (MONDO:0005575) ## Full-text entities - **Genes:** ABCC2 (ATP binding cassette subfamily C member 2) [NCBI Gene 1244] {aka ABC30, CMOAT, DJS, MRP2, cMRP}, PEBP1 (phosphatidylethanolamine binding protein 1) [NCBI Gene 5037] {aka HCNP, HCNPpp, HEL-210, HEL-S-34, HEL-S-96, PBP}, SLCO1A2 (solute carrier organic anion transporter family member 1A2) [NCBI Gene 6579] {aka OATP, OATP-A, OATP1A2, SLC21A3}, LCN2 (lipocalin 2) [NCBI Gene 3934] {aka 24p3, MSFI, NGAL, p25}, FDFT1 (farnesyl-diphosphate farnesyltransferase 1) [NCBI Gene 2222] {aka DGPT, ERG9, SQS, SQSD, SS}, GSR (glutathione-disulfide reductase) [NCBI Gene 2936] {aka CNSHA10, GR, GSRD, HEL-75, HEL-S-122m}, ABCB8 (ATP binding cassette subfamily B member 8) [NCBI Gene 11194] {aka EST328128, M-ABC1, MABC1, MITOSUR}, SLC11A2 (solute carrier family 11 member 2) [NCBI Gene 4891] {aka AHMIO1, DCT1, DMT1, NRAMP2}, FTH1 (ferritin heavy chain 1) [NCBI Gene 2495] {aka FHC, FTH, FTHL6, HFE5, NBIA9, PIG15}, TYMS (thymidylate synthetase) [NCBI Gene 7298] {aka DKCD, HST422, TMS, TS}, NCOA4 (nuclear receptor coactivator 4) [NCBI Gene 8031] {aka ARA70, ELE1, PTC3, RFG}, Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, PTGS2 (prostaglandin-endoperoxide synthase 2) [NCBI Gene 5743] {aka COX-2, COX2, GRIPGHS, PGG/HS, PGHS-2, PHS-2}, TNFSF10 (TNF superfamily member 10) [NCBI Gene 8743] {aka APO2L, Apo-2L, CD253, TANCR, TL2, TNLG6A}, SLC7A11 (solute carrier family 7 member 11) [NCBI Gene 23657] {aka CCBR1, xCT}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, PROM1 (prominin 1) [NCBI Gene 8842] {aka AC133, CD133, CORD12, MCDR2, MSTP061, PROML1}, BAX (BCL2 associated X, apoptosis regulator) [NCBI Gene 581] {aka BCL2L4}, ATM (ATM serine/threonine kinase) [NCBI Gene 472] {aka AT1, ATA, ATC, ATD, ATDC, ATE}, SPATA2 (spermatogenesis associated 2) [NCBI Gene 9825] {aka PD1, PPP1R145, tamo}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, NR1I2 (nuclear receptor subfamily 1 group I member 2) [NCBI Gene 8856] {aka BXR, ONR1, PAR, PAR1, PAR2, PARq}, MIR497 (microRNA 497) [NCBI Gene 574456] {aka MIRN497, hsa-mir-497, mir-497}, CFLAR (CASP8 and FADD like apoptosis regulator) [NCBI Gene 8837] {aka CASH, CASP8AP1, CLARP, Casper, FLAME, FLAME-1}, MLH1 (mutL homolog 1) [NCBI Gene 4292] {aka COCA2, FCC2, HNPCC, HNPCC2, LYNCH2, MLH-1}, FTL (ferritin light chain) [NCBI Gene 2512] {aka FTL1, LFTD, NBIA3}, MSH2 (mutS homolog 2) [NCBI Gene 4436] {aka COCA1, FCC1, HNPCC, HNPCC1, LCFS2, LYNCH1}, GCH1 (GTP cyclohydrolase 1) [NCBI Gene 2643] {aka DYT14, DYT5, DYT5a, GCH, GTP-CH-1, GTPCH1}, PTEN (phosphatase and tensin homolog) [NCBI Gene 5728] {aka 10q23del, BZS, CWS1, DEC, GLM2, MHAM}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, HDAC1 (histone deacetylase 1) [NCBI Gene 3065] {aka GON-10, HD1, KDAC1, RPD3, RPD3L1}, MIR145 (microRNA 145) [NCBI Gene 406937] {aka MIRN145, miR-145, miRNA145}, PGP (phosphoglycolate phosphatase) [NCBI Gene 283871] {aka AUM, G3PP, PGPase}, MSH3 (mutS homolog 3) [NCBI Gene 4437] {aka DUP, FAP4, MRP1}, CYCS (cytochrome c, somatic) [NCBI Gene 54205] {aka CYC, HCS, THC4}, TNFRSF10B (TNF receptor superfamily member 10b) [NCBI Gene 8795] {aka CD262, DR5, KILLER, KILLER/DR5, TRAIL-R2, TRAILR2}, NR0B2 (nuclear receptor subfamily 0 group B member 2) [NCBI Gene 8431] {aka SHP, SHP1}, ABCC1 (ATP binding cassette subfamily C member 1 (ABCC1 blood group)) [NCBI Gene 4363] {aka ABC29, ABCC, DFNA77, GS-X, MRP, MRP1}, CYP2C8 (cytochrome P450 family 2 subfamily C member 8) [NCBI Gene 1558] {aka CPC8, CYP2C8DM, CYPIIC8, MP-12/MP-20}, SREBF1 (sterol regulatory element binding transcription factor 1) [NCBI Gene 6720] {aka HMD, IFAP2, SREBP1, bHLHd1}, KDM5B (lysine demethylase 5B) [NCBI Gene 10765] {aka CT31, JARID1B, MRT65, PLU-1, PLU1, PPP1R98}, GCLC (glutamate-cysteine ligase catalytic subunit) [NCBI Gene 2729] {aka CNSHA7, GCL, GCS, GLCL, GLCLC}, COL11A2 (collagen type XI alpha 2 chain) [NCBI Gene 1302] {aka DFNA13, DFNB53, FBCG2, HKE5, OSMEDA, OSMEDB}, Slc7a11 (solute carrier family 7 (cationic amino acid transporter, y+ system), member 11) [NCBI Gene 26570] {aka 9930009M05Rik, sut, xCT}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, Gmcl1 (germ cell-less, spermatogenesis associated 1) [NCBI Gene 23885] {aka 2810049L19Rik, Btbd13, DIP, Gcl, Gcl-1, glc-1}, SOD1 (superoxide dismutase 1) [NCBI Gene 6647] {aka ALS, ALS1, HEL-S-44, IPOA, SOD, STAHP}, Gpx4 (glutathione peroxidase 4) [NCBI Gene 625249] {aka GPx-4, GSHPx-4, PHGPx, mtPHGPx, snGPx}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, ACSL4 (acyl-CoA synthetase long chain family member 4) [NCBI Gene 2182] {aka ACS4, FACL4, LACS4, MRX63, MRX68, XLID63}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, Hif1a (hypoxia inducible factor 1, alpha subunit) [NCBI Gene 15251] {aka HIF-1-alpha, HIF1-alpha, HIF1alpha, MOP1, bHLHe78}, B3GAT2 (beta-1,3-glucuronyltransferase 2) [NCBI Gene 135152] {aka GLCATS}, APEX1 (apurinic/apyrimidinic endodeoxyribonuclease 1) [NCBI Gene 328] {aka APE, APE1, APEN, APEX, APX, HAP1}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, ABCB6 (ATP binding cassette subfamily B member 6 (LAN blood group)) [NCBI Gene 10058] {aka ABC, LAN, MTABC3, PRP, umat}, FAS (Fas cell surface death receptor) [NCBI Gene 355] {aka ALPS1A, APO-1, APT1, CD95, FAS1, FASTM}, HDAC9 (histone deacetylase 9) [NCBI Gene 9734] {aka HD7, HD7b, HD9, HDAC, HDAC7B, HDAC9B}, TF (transferrin) [NCBI Gene 7018] {aka HEL-S-71p, PRO1557, PRO2086, TFQTL1}, BCL2 (BCL2 apoptosis regulator) [NCBI Gene 596] {aka Bcl-2, PPP1R50} - **Diseases:** MSI (MESH:D053842), Cancer (MESH:D009369), lung cancer (MESH:D008175), MDR (MESH:D018088), mitochondrial metabolic dysfunction (MESH:D028361), cervical cancer (MESH:D002583), iron overload (MESH:D019190), glioma (MESH:D005910), metabolic disturbances (MESH:D024821), injury to (MESH:D014947), neurodegenerative disorders (MESH:D019636), osteosarcoma (MESH:D012516), inflammation (MESH:D007249), hypoxia (MESH:D000860), NSCLC (MESH:D002289), cardiotoxicity (MESH:D066126), metabolic diseases (MESH:D008659), mesenchymal (MESH:C535700), HRD (MESH:C535296), hypoxic (MESH:D002534), Toxicity (MESH:D064420), Colon Cancer (MESH:D015179), deaths (MESH:D003643), immunodeficient (MESH:D007153), tumor metastasis (MESH:D009362), necrosis (MESH:D009336), HCC (MESH:D006528), ovarian and lung cancer (MESH:D010051), malignant tumor of the gastrointestinal system (MESH:D005770), breast cancer (MESH:D001943), neuronal death (MESH:D009410) - **Chemicals:** LOOH (MESH:D008054), CoQ10 (MESH:C024989), DFO (MESH:D003676), 2-DG (MESH:D003847), Tariquidar (MESH:C402343), Venetoclax (MESH:C579720), paclitaxel (MESH:D017239), PEG (MESH:D011092), sulfate (MESH:D013431), Osimertinib (MESH:C000596361), oxygen (MESH:D010100), thioether (MESH:D013440), AdA (MESH:C011395), Ps (MESH:D010758), PSC833 (MESH:C070272), Biricodar (MESH:C106077), platinum (MESH:D010984), hydroxyl radicals (MESH:D017665), Oxaliplatin (MESH:D000077150), LY335979 (MESH:C095179), Sorafenib (MESH:D000077157), glutamate (MESH:D018698), Artemisinin (MESH:C031327), Base (MESH:D009711), AA (MESH:D016718), Iron (MESH:D007501), glucosylceramide (MESH:D005963), LGK974 (MESH:C586458), phospholipids (MESH:D010743), water (MESH:D014867), 5-FU (MESH:D005472), MUFA (MESH:D005229), selenium (MESH:D012643), SFAs (MESH:D005227), GSSG (MESH:D019803), BH4 (MESH:C003402), heme (MESH:D006418), Elacridar (MESH:C083501), Pirfenidone (MESH:C093844), peroxides (MESH:D010545), thiol (MESH:D013438), Vorinostat (MESH:D000077337), Erastin (MESH:C477224), Cystine (MESH:D003553), cyclosporin A (MESH:D016572), glucuronic acid (MESH:D020723), DOX (MESH:D004317), atorvastatin (MESH:D000069059), PUFA (MESH:D005231), chloroacetamide (MESH:C013874), PE (MESH:C483858), Fe3+ (-), H2O2 (MESH:D006861), cisplatin (MESH:D002945), berberine (MESH:D001599), CB-839 (MESH:C000593334), ROS (MESH:D017382), glucose (MESH:D005947), 5-azacitidine (MESH:D001374), rosuvastatin (MESH:D000068718) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606] - **Mutations:** T790M, glutamate-cysteine - **Cell lines:** A549 — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_0023), HCT116 colon cancer — Homo sapiens (Human), Colon carcinoma, Cancer cell line (CVCL_7685), MCF-7/AdrVp — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_4Y46), MCF-7 — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_0031), UO-31 renal carcinoma — Homo sapiens (Human), Renal cell carcinoma, Cancer cell line (CVCL_1911), T47D-TR — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_1D36), A549 lung cancer — Homo sapiens (Human), Lung squamous cell carcinoma, Cancer cell line (CVCL_3008) ## Figures 5 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12944271/full.md --- Source: https://tomesphere.com/paper/PMC12944271