# Multifaceted Role of Copper Homeostasis in Gut Health: From Molecular Mechanisms to Therapeutic Interventions **Authors:** Fucheng Lu, Xuchen Wang, Xiaoyan Xue, Liqiang Liu, Dongmei Li, Anfang Liu, Simeng Qin, Lingbin Liu PMC · DOI: 10.3390/cells15060545 · 2026-03-19 ## TL;DR This review explores how copper balance in the gut affects gut health, immunity, and diseases like cancer, and suggests new therapeutic strategies targeting copper. ## Contribution The paper systematically evaluates copper-targeted therapies and highlights unresolved challenges in copper homeostasis research. ## Key findings - Copper homeostasis modulates gut iron metabolism, barrier integrity, and immunity. - Copper dyshomeostasis contributes to diseases like Menkes, Wilson, and intestinal cancers. - Copper-targeting agents show therapeutic potential in oncology, but challenges remain. ## Abstract What are the main findings? This review delineates the molecular machinery of intestinal copper absorption and transport, focusing on key transporters and regulatory mechanisms.We elucidate how copper homeostasis acts as a central modulator of gut iron metabolism, barrier integrity, mucosal immunity, the microbiome, and the gut–brain/liver axes. This review delineates the molecular machinery of intestinal copper absorption and transport, focusing on key transporters and regulatory mechanisms. We elucidate how copper homeostasis acts as a central modulator of gut iron metabolism, barrier integrity, mucosal immunity, the microbiome, and the gut–brain/liver axes. What are the implications of the main findings? The pathophysiological roles of copper dyshomeostasis in Menkes disease, Wilson disease, and intestinal cancers are comprehensively discussed.We explore the therapeutic potential and mechanisms of copper-targeting agents in oncology, evaluating current strategies and future directions. The pathophysiological roles of copper dyshomeostasis in Menkes disease, Wilson disease, and intestinal cancers are comprehensively discussed. We explore the therapeutic potential and mechanisms of copper-targeting agents in oncology, evaluating current strategies and future directions. Intestinal copper homeostasis governs gut health through its dual roles as an enzymatic cofactor and signaling mediator. This review discusses the molecular basis of copper absorption/transport, genetic regulation, and its functional impacts. Copper-dependent enzymes maintain intestinal barrier function and metabolism, while copper availability shapes the composition of gut microbiota and mucosal immunity. The dysregulation of copper homeostasis, specifically pathological accumulation, contributes to the development of CRC by inducing dysbiosis of gut microbiota, chronic inflammation, and metastasis. This review systematically evaluates copper-targeted therapies and the associated unresolved challenges. Future efforts should prioritize defining cell-specific copper handling, metal interaction networks, and the copper–gut microbiota–immune axis in non-cancer pathologies. Moreover, future studies should also focus on developing stratified biomarker panels and spatially precise interventions to harness copper biology for diagnostic and therapeutic innovation. ## Linked entities - **Diseases:** Menkes disease (MONDO:0010651), Wilson disease (MONDO:0010200), CRC (MONDO:0005575) ## Full-text entities - **Genes:** IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, SLC31A2 (solute carrier family 31 member 2) [NCBI Gene 1318] {aka COPT2, CTR2, hCTR2}, MTF1 (metal regulatory transcription factor 1) [NCBI Gene 4520] {aka MTF-1, ZRF}, STEAP4 (STEAP4 metalloreductase) [NCBI Gene 79689] {aka STAMP2, SchLAH, TIARP, TNFAIP9}, ALPK1 (alpha kinase 1) [NCBI Gene 80216] {aka 8430410J10Rik, LAK, ROSAH}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, SOD1 (superoxide dismutase 1) [NCBI Gene 6647] {aka ALS, ALS1, HEL-S-44, IPOA, SOD, STAHP}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, COX17 (cytochrome c oxidase copper chaperone COX17) [NCBI Gene 10063], Ccs (copper chaperone for superoxide dismutase) [NCBI Gene 84485], TFF1 (trefoil factor 1) [NCBI Gene 7031] {aka BCEI, D21S21, HP1.A, HPS2, pNR-2, pS2}, SCO1 (synthesis of cytochrome C oxidase 1) [NCBI Gene 6341] {aka MC4DN4, SCOD1}, Atox1 (antioxidant 1 copper chaperone) [NCBI Gene 84355] {aka Atx1}, COPZ1 (coat protein complex I subunit zeta 1) [NCBI Gene 22818] {aka CGI-120, COPZ, HSPC181, SCN12, zeta-COP, zeta1-COP}, MAP2K7 (mitogen-activated protein kinase kinase 7) [NCBI Gene 5609] {aka JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7}, COPA (coat protein complex I subunit alpha) [NCBI Gene 1314] {aka AIAISD, AIAISD1, AILJK, HEP-COP, alpha-COP}, RYR1 (ryanodine receptor 1) [NCBI Gene 6261] {aka CCO, CMYO1A, CMYO1B, CMYP1A, CMYP1B, KDS}, Mapk12 (mitogen-activated protein kinase 12) [NCBI Gene 60352] {aka Sapk3}, TFF3 (trefoil factor 3) [NCBI Gene 7033] {aka ITF, P1B, TFI}, Sco1 (synthesis of cytochrome C oxidase 1) [NCBI Gene 497930] {aka RGD1559538}, COX11 [NCBI Gene 690300], STEAP1 (STEAP family member 1) [NCBI Gene 26872] {aka PRSS24, STEAP}, ATP7A (ATPase copper transporting alpha) [NCBI Gene 538] {aka DSMAX, HMNX, MK, MNK, SMAX3}, REG3G (regenerating family member 3 gamma) [NCBI Gene 130120] {aka LPPM429, PAP IB, PAP-1B, PAP1B, PAPIB, REG III}, Slc40a1 (solute carrier family 40 member 1) [NCBI Gene 170840] {aka Fpn1, Slc11a3, Slc39a1}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, CP (ceruloplasmin) [NCBI Gene 1356] {aka AB073614, CP-2}, FOS (Fos proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 2353] {aka AP-1, C-FOS, p55}, CXCL12 (C-X-C motif chemokine ligand 12) [NCBI Gene 6387] {aka IRH, PBSF, SCYB12, SDF1, TLSF, TPAR1}, NOS2 (nitric oxide synthase 2) [NCBI Gene 4843] {aka HEP-NOS, INOS, NOS, NOS2A}, CLDN15 (claudin 15) [NCBI Gene 24146], Epas1 (endothelial PAS domain protein 1) [NCBI Gene 29452] {aka HIF-2 alpha, HIF2 alpha, HLF, Hif2a}, SREBF1 (sterol regulatory element binding transcription factor 1) [NCBI Gene 6720] {aka HMD, IFAP2, SREBP1, bHLHd1}, HEPH (hephaestin) [NCBI Gene 9843] {aka CPL}, CEBPE (CCAAT enhancer binding protein epsilon) [NCBI Gene 1053] {aka C/EBP-epsilon, CRP1, IMD108, SGD1, c/EBP epsilon}, SNAP29 (synaptosome associated protein 29) [NCBI Gene 9342] {aka CEDNIK, SNAP-29}, GPX1 (glutathione peroxidase 1) [NCBI Gene 2876] {aka GPXD, GSHPX1}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, CYBRD1 (cytochrome b reductase 1) [NCBI Gene 79901] {aka CYB561A2, DCYTB, FRRS3}, COX11 (cytochrome c oxidase copper chaperone COX11) [NCBI Gene 1353] {aka COX11P, MC4DN23}, COMMD1 (copper metabolism domain containing 1) [NCBI Gene 150684] {aka C2orf5, MURR1}, PTK2 (protein tyrosine kinase 2) [NCBI Gene 5747] {aka FADK, FADK 1, FAK, FAK1, FRNK, PPP1R71}, CDH1 (cadherin 1) [NCBI Gene 999] {aka Arc-1, BCDS1, CD324, CDHE, ECAD, LCAM}, SLC31A1 (solute carrier family 31 member 1) [NCBI Gene 1317] {aka COPT1, CTR1, NSCT}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, ATP7B (ATPase copper transporting beta) [NCBI Gene 540] {aka PWD, WC1, WD, WND}, ZEB1 (zinc finger E-box binding homeobox 1) [NCBI Gene 6935] {aka AREB6, BZP, DELTAEF1, FECD6, NIL2A, PPCD3}, CARD16 (caspase recruitment domain family member 16) [NCBI Gene 114769] {aka COP, COP1, LLID-114769, PSEUDO-ICE}, CCND1 (cyclin D1) [NCBI Gene 595] {aka BCL1, D11S287E, PRAD1, U21B31}, Kras (KRAS proto-oncogene, GTPase) [NCBI Gene 24525] {aka K-ras, Kras2, c-Ki-ras, p21}, SLC11A2 (solute carrier family 11 member 2) [NCBI Gene 4891] {aka AHMIO1, DCT1, DMT1, NRAMP2}, MLRL (Myeloid leukemia-related gene (myeloid tumor suppressor)) [NCBI Gene 8201] {aka MLRG, MTS}, HEPHL1 (hephaestin like 1) [NCBI Gene 341208] {aka HJDD, ZP}, CLDN1 (claudin 1) [NCBI Gene 9076] {aka CLD1, ILVASC, SEMP1}, CASP3 (caspase 3) [NCBI Gene 836] {aka CPP32, CPP32B, SCA-1}, MUC2 (mucin 2, oligomeric mucus/gel-forming) [NCBI Gene 4583] {aka MLP, MUC-2, SMUC}, Slc11a2 (solute carrier family 11 member 2) [NCBI Gene 25715] {aka Dmt1, Nramp2}, CXCR4 (C-X-C motif chemokine receptor 4) [NCBI Gene 7852] {aka CD184, D2S201E, FB22, HM89, HSY3RR, LCR1} - **Diseases:** Metabolic gut disorders (MESH:D008659), alcoholic liver disease (MESH:D008108), hepatic damage (MESH:D056486), autoimmune (MESH:D001327), connective tissue abnormalities (MESH:D003240), bladder diverticula (MESH:D004240), hemolysis (MESH:D006461), ulcerative colitis (MESH:D003093), tissue injury (MESH:D017695), cirrhosis (MESH:D005355), Tumoral (MESH:D009369), acute liver failure (MESH:D017114), Crohn's disease (MESH:D003424), hypoxia (MESH:D000860), neurological damage (MESH:D020196), chronic (MESH:D002908), glioblastoma (MESH:D005909), Wilson disease (MESH:D006527), Copper deficiency (MESH:C535468), liver injury (MESH:D017093), neurodevelopmental deficits (MESH:D009461), breast cancer (MESH:D001943), diarrhea (MESH:D003967), hypoxic (MESH:D002534), fever (MESH:D005334), immune dysregulation (OMIM:614878), autosomal recessive disorder (MESH:D030342), gut dysfunction (MESH:C535334), myelodysplastic syndrome (MESH:D009190), histamine intolerance (MESH:D003027), lactose intolerance (MESH:D007787), Inflammatory (MESH:D007249), Iron deficiency (MESH:D000090463), multidrug (MESH:D018088), arterial aneurysms (MESH:D002532), ovarian cancer (MESH:D010051), microvillus inclusion disease (MESH:C537470), Infectious enteritis (MESH:D053489), copper overload (MESH:C566858), skin laxity (MESH:D007593), injury to (MESH:D014947), diaphragmatic hernia (MESH:D006548), hemorrhage (MESH:D006470), gastroesophageal reflux (MESH:D005764), infection (MESH:D007239), intestinal cancer (MESH:D007414), splenic or iliac artery aneurysms (MESH:D017543), impaired intestinal smooth muscle function (MESH:D018235), intestinal malabsorption (MESH:D008286), IBD (MESH:D015212), lung cancer (MESH:D008175), intestinal epithelial dysfunction (MESH:C567703), renal damage (MESH:D007674), oncogenesis (MESH:D063646), non-alcoholic fatty liver disease (MESH:D065626), TNBC (MESH:D064726), Brain injury (MESH:D001930), metal (MESH:D013651), vitamin B12 deficiency (MESH:D014806), intestinal damage (MESH:D007410) - **Chemicals:** ROS (MESH:D017382), proton (MESH:D011522), NAD(H) (MESH:D009243), RNS (MESH:D026361), hydroxyl radical (MESH:D017665), lenvatinib (MESH:C531958), N,N,N',N'-Tetrakis-[2-Pyridylmethyl]-Ethylenediamine (MESH:C044387), copper citrate (MESH:C111995), Polyethylene glycol (MESH:D011092), OH (MESH:C031356), temozolomide (MESH:D000077204), luteolin (MESH:D047311), cysteine (MESH:D003545), L (MESH:D007930), GSH (MESH:D005978), CQ (MESH:D007464), diethyldithiocarbamate-methyl ester (MESH:C016571), glutamate (MESH:D018698), H2O2 (MESH:D006861), histamine (MESH:D006632), yersiniabactin (MESH:C104398), metal (MESH:D008670), LPS (MESH:D008070), ATP (MESH:D000255), ES (MESH:C512195), DSF (MESH:D004221), melanin (MESH:D008543), chloroquine (MESH:D002738), CuS (MESH:C017846), Butyrate (MESH:D002087), Copper (MESH:D003300), acetate (MESH:D000085), heme (MESH:D006418), glycine (MESH:D005998), SCFA (MESH:D005232), (E)-8-((4-methylbenzylidene) amino) napthalen-1-amine (-), sulfate (MESH:D013431), NO (MESH:D009569), pyrophosphate (MESH:C107241), manganese (MESH:D008345), TTM (MESH:C020809), CuSO4 (MESH:D019327), 64Cu (MESH:C000615411), CuET (MESH:C530436), superoxide (MESH:D013481), sulfhydryl (MESH:D013438), rapamycin (MESH:D020123), methionine (MESH:D008715), TCA (MESH:D014233), lactic acid (MESH:D019344), oxygen (MESH:D010100), alcohol (MESH:D000438), Fe-S (MESH:D007501), lipid (MESH:D008055), D-penicillamine (MESH:D010396), trientine (MESH:D014266), doxorubicin (MESH:D004317), Zn (MESH:D015032) - **Species:** Histoplasma capsulatum (species) [taxon 5037], Pseudomonas aeruginosa (species) [taxon 287], Lactococcus (lactic streptococci, genus) [taxon 1357], Lactobacillus johnsonii (species) [taxon 33959], Fibrobacter (genus) [taxon 832], Rattus norvegicus (brown rat, species) [taxon 10116], Escherichia coli (E. coli, species) [taxon 562], Sus scrofa (pig, species) [taxon 9823], Salmonella enterica (species) [taxon 28901], Salmonella enterica subsp. enterica serovar Typhimurium (no rank) [taxon 90371], Staphylococcus aureus (species) [taxon 1280], Mus musculus (house mouse, species) [taxon 10090], Neisseria gonorrhoeae (species) [taxon 485], Monopterus albus (rice-field eel, species) [taxon 43700], Bos taurus (bovine, species) [taxon 9913], Caenorhabditis elegans (species) [taxon 6239], Acidaminococcus (genus) [taxon 904], Methanosphaera (genus) [taxon 2316], Deinococcus radiodurans (species) [taxon 1299], Homo sapiens (human, species) [taxon 9606], C. elegans [taxon 328850], Listeria monocytogenes (species) [taxon 1639], Cryptococcus neoformans (Cryptococcus neoformans serotype A, species) [taxon 5207], Mycobacterium tuberculosis (species) [taxon 1773], Roseburia (genus) [taxon 841], Drosophila melanogaster (fruit fly, species) [taxon 7227] - **Mutations:** Serine/Threonine, BRAFV600E - **Cell lines:** Caco-2 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0025), MEFs — Mus musculus (Mouse), Finite cell line (CVCL_9115) ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13024964/full.md --- Source: https://tomesphere.com/paper/PMC13024964