# Metformin in gastrointestinal cancers and inflammatory bowel disease: Unraveling its mechanisms and therapeutic applications **Authors:** Yanxi Li, Xingqi Guo, Xinxin Dong, Tong Xia, Siping Ma, Zhexian Liu PMC · DOI: 10.1016/j.isci.2026.114877 · iScience · 2026-02-02 ## TL;DR This paper reviews how metformin, a diabetes drug, may help treat gastrointestinal cancers and inflammatory bowel disease by targeting specific biological pathways. ## Contribution The paper provides a comprehensive review of metformin's mechanisms and therapeutic potential in gastrointestinal diseases. ## Key findings - Metformin shows therapeutic effects in gastrointestinal cancers through the AMPK/mTOR pathway. - Combination therapies with metformin enhance its effectiveness in treating gastrointestinal diseases. - Metformin benefits extend beyond diabetes to include cancer and inflammatory bowel disease. ## Abstract Gastrointestinal diseases have become a global health concern with high incidence and prevalence. Considering that a great many patients with gastrointestinal cancers still suffer from tumor recurrence or distant metastasis even after surgical intervention or neoadjuvant chemotherapy, it is urgently needed to identify new therapeutic drugs. Metformin, originally derived from natural herbs, has been found to be beneficial for many diseases, including not only type 2 diabetes mellitus, cardiovascular disease, liver and kidney disease, and age-related diseases but also different types of cancers. Herein, we comprehensively review the roles and the underlying mechanisms of metformin in gastrointestinal cancers including colorectal, esophageal, and gastric cancers and also inflammatory bowel disease. By integrating the latest research findings, we systematically elaborate on how metformin exerts therapeutic effects on gastrointestinal diseases through the AMPK/mTOR pathway and the effects of combination therapies. This review may offer novel insights for developing therapeutic strategies against gastrointestinal malignancies and related diseases. Therapeutics; Human metabolism; Cancer ## Linked entities - **Chemicals:** metformin (PubChem CID 4091) - **Diseases:** inflammatory bowel disease (MONDO:0005265), type 2 diabetes mellitus (MONDO:0005148), cardiovascular disease (MONDO:0004995), liver disease (MONDO:0005154), kidney disease (MONDO:0001343), colorectal cancer (MONDO:0005575), esophageal cancer (MONDO:0007576), gastric cancer (MONDO:0001056) ## Full-text entities - **Genes:** MCL1 (MCL1 apoptosis regulator, BCL2 family member) [NCBI Gene 4170] {aka BCL2L3, EAT, MCL1-ES, MCL1L, MCL1S, Mcl-1}, Adamts12 (ADAM metallopeptidase with thrombospondin type 1 motif 12) [NCBI Gene 239337] {aka ADAMTS-12}, CCND1 (cyclin D1) [NCBI Gene 595] {aka BCL1, D11S287E, PRAD1, U21B31}, Cxcl15 (C-X-C motif chemokine ligand 15) [NCBI Gene 20309] {aka Il8, Scyb15, lungkine, weche}, DNMT1 (DNA methyltransferase 1) [NCBI Gene 1786] {aka ADCADN, AIM, CXXC9, DNMT, HSN1E, MCMT}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 20848] {aka 1110034C02Rik, Aprf}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, HMOX1 (heme oxygenase 1) [NCBI Gene 3162] {aka HMOX1D, HO-1, HSP32, bK286B10}, PRKAA2 (protein kinase AMP-activated catalytic subunit alpha 2) [NCBI Gene 5563] {aka AMPK, AMPK2, AMPKa2, PRKAA}, Fasn (fatty acid synthase) [NCBI Gene 14104] {aka A630082H08Rik, FAS}, JAK2 (Janus kinase 2) [NCBI Gene 3717] {aka JTK10}, Ptgs2 (prostaglandin-endoperoxide synthase 2) [NCBI Gene 29527] {aka COX-2, Cox2, PGHS-2, PHS II, Pghs2}, Prkaa2 (protein kinase AMP-activated catalytic subunit alpha 2) [NCBI Gene 78975] {aka Ampk, Ampka2}, PLA2G4A (phospholipase A2 group IVA) [NCBI Gene 5321] {aka GURDP, PLA2G4, cPLA2, cPLA2-alpha}, Klf4 (Kruppel-like transcription factor 4 (gut)) [NCBI Gene 16600] {aka EZF, Gklf, Zie}, SNAI1 (snail family transcriptional repressor 1) [NCBI Gene 6615] {aka SLUGH2, SNA, SNAH, SNAIL, SNAIL1, dJ710H13.1}, HDAC9 (histone deacetylase 9) [NCBI Gene 9734] {aka HD7, HD7b, HD9, HDAC, HDAC7B, HDAC9B}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, Muc2 (mucin 2) [NCBI Gene 17831] {aka 2010015E03Rik, MCM, wnn}, KLF10 (KLF transcription factor 10) [NCBI Gene 7071] {aka EGR-alpha, EGRA, TIEG, TIEG1}, YWHAZ (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta) [NCBI Gene 7534] {aka 14-3-3-zeta, HEL-S-3, HEL-S-93, HEL4, KCIP-1, POPCHAS}, KRAS (KRAS proto-oncogene, GTPase) [NCBI Gene 3845] {aka 'C-K-RAS, C-K-RAS, CFC2, K-RAS2A, K-RAS2B, K-RAS4A}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, Bcl2 (B cell leukemia/lymphoma 2) [NCBI Gene 12043] {aka Bcl-2, C430015F12Rik, D630044D05Rik, D830018M01Rik}, Il10 (interleukin 10) [NCBI Gene 16153] {aka CSIF, If2a, Il-10}, SLC9D1 (solute carrier family 9 member D1) [NCBI Gene 55002] {aka C13orf11, TMCO3}, Cd274 (CD274 antigen) [NCBI Gene 60533] {aka A530045L16Rik, B7h1, Pdcd1l1, Pdcd1lg1, Pdl1}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, Jak2 (Janus kinase 2) [NCBI Gene 24514], Il6 (interleukin 6) [NCBI Gene 24498] {aka ILg6, Ifnb2}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, LITAF (lipopolysaccharide induced TNF factor) [NCBI Gene 9516] {aka PIG7, SIMPLE, TP53I7}, Pdcd1 (programmed cell death 1) [NCBI Gene 18566] {aka Ly101, PD-1, Pdc1}, Il18 (interleukin 18) [NCBI Gene 16173] {aka Igif, Il-18}, Trp53-ps (transformation related protein 53, pseudogene) [NCBI Gene 22060], Cldn2 (claudin 2) [NCBI Gene 12738], INHBA (inhibin subunit beta A) [NCBI Gene 3624] {aka EDF, FRP}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, PELP1 (proline, glutamate and leucine rich protein 1) [NCBI Gene 27043] {aka MNAR, P160}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, MIR375 (microRNA 375) [NCBI Gene 494324] {aka MIRN375, hsa-mir-375, miRNA375, mir-375}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, Mtor (mechanistic target of rapamycin kinase) [NCBI Gene 56718] {aka Frap1, RAFT1}, PRKAB1 (protein kinase AMP-activated non-catalytic subunit beta 1) [NCBI Gene 5564] {aka AMPK, HAMPKb}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 25125], INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, Rps6kb1 (ribosomal protein S6 kinase B1) [NCBI Gene 72508] {aka 2610318I15Rik, P70S6K1, S6K, S6K-beta-1, S6K1, p70 S6K-alpha}, Cdh1 (cadherin 1) [NCBI Gene 12550] {aka ARC-1, E-cad, Ecad, L-CAM, UVO, Um}, VIM (vimentin) [NCBI Gene 7431], Mtor (mechanistic target of rapamycin kinase) [NCBI Gene 56717] {aka 2610315D21Rik, FRAP, FRAP2, Frap1, RAFT1, RAPT1}, Vegfa (vascular endothelial growth factor A) [NCBI Gene 22339] {aka L-VEGF, Vegf, Vpf}, Icam1 (intercellular adhesion molecule 1) [NCBI Gene 15894] {aka CD54, Icam-1, Ly-47, MALA-2}, Nos2 (nitric oxide synthase 2) [NCBI Gene 24599] {aka Nos2a, iNos}, Pten (phosphatase and tensin homolog) [NCBI Gene 19211] {aka 2310035O07Rik, A130070J02Rik, B430203M17Rik, MMAC1, PTENbeta, TEP1}, Il13 (interleukin 13) [NCBI Gene 16163] {aka Il-13}, Ccnd1 (cyclin D1) [NCBI Gene 12443] {aka CycD1, Cyl-1, PRAD1, bcl-1, cD1} - **Diseases:** EC (MESH:D004938), oncology (MESH:D000072716), UC (MESH:D003093), ileitis (MESH:D007079), mitochondrial fragmentation (MESH:D012892), T2DM (MESH:D003924), breast cancer (MESH:D001943), IBD (MESH:D015212), heart failure (MESH:D006333), gastrointestinal cancers (MESH:D005770), cardiovascular disease (MESH:D002318), Crohn's disease (MESH:D003424), colitis (MESH:D003092), Gastrointestinal diseases (MESH:D005767), Insulin resistance (MESH:D007333), liver metastasis (MESH:D009362), immunodeficient (MESH:D007153), hypertension (MESH:D006973), CRC (MESH:D015179), metabolic abnormalities (MESH:D008659), SCID (MESH:D053632), colon tumors (MESH:D003110), Obesity (MESH:D009765), GC (MESH:D013274), colorectal carcinogenesis (MESH:D063646), Cancer (MESH:D009369), Diabetes (MESH:D003920), liver and kidney disease (MESH:D008107), gastrointestinal inflammation (MESH:D007249), degenerative skeletal disease (MESH:D019636) - **Chemicals:** tryptophan (MESH:D014364), glucose (MESH:D005947), ROS (MESH:D017382), SCFA (MESH:D005232), dextran sulfate sodium (MESH:D016264), pioglitazone (MESH:D000077205), butyrate (MESH:D002087), vitamin D3 (MESH:D002762), propionate (MESH:D011422), fatty acids (MESH:D005227), DSS (-), hydrogen peroxide (MESH:D006861), bile acids (MESH:D001647), 1,2-dimethylhydrazine (MESH:D019813), doxorubicin (MESH:D004317), rosiglitazone (MESH:D000077154), oxaliplatin (MESH:D000077150), 5-FU (MESH:D005472), 1,1-dimethylbiguanide hydrochloride (MESH:D008687), lactic acid (MESH:D019344), paclitaxel (MESH:D017239), fat (MESH:D005223), 5-ASA (MESH:D019804), temsirolimus (MESH:C401859) - **Species:** gut metagenome (species) [taxon 749906], Akkermansia (genus) [taxon 239934], Rattus norvegicus (brown rat, species) [taxon 10116], Galega (genus) [taxon 47100], Homo sapiens (human, species) [taxon 9606], Paenibacillus mucilaginosus (species) [taxon 61624], Erysipelatoclostridium [taxon 1505663], Prevotella (genus) [taxon 838], Mus musculus (house mouse, species) [taxon 10090], Lactobacillus (genus) [taxon 1578], Galega officinalis (goat's rue, species) [taxon 47101] - **Cell lines:** HT-29 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0320), DLD-1 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0248), TE-1 — Homo sapiens (Human), Esophageal squamous cell carcinoma, Cancer cell line (CVCL_1759), SNO — Homo sapiens (Human), Esophageal squamous cell carcinoma, Cancer cell line (CVCL_M848), Colo205 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0218), KYSE450 EC — Homo sapiens (Human), Esophageal squamous cell carcinoma, Cancer cell line (CVCL_1353), MC38 — Mus musculus (Mouse), Mouse colon adenocarcinoma, Cancer cell line (CVCL_B288), HCT15 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0292), BALB/c — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0184), Eca-109 — Homo sapiens (Human), Esophageal squamous cell carcinoma, Cancer cell line (CVCL_6898), SW480 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0546), KYSE70 — Homo sapiens (Human), Esophageal squamous cell carcinoma, Cancer cell line (CVCL_1356), MKN1 — Homo sapiens (Human), Gastric adenosquamous carcinoma, Cancer cell line (CVCL_1415), AGS — Homo sapiens (Human), Gastric adenocarcinoma, Cancer cell line (CVCL_0139), EC — Homo sapiens (Human), Induced pluripotent stem cell (CVCL_E025), HCT-116 — Homo sapiens (Human), Colon carcinoma, Cancer cell line (CVCL_0291), KYSE30 — Homo sapiens (Human), Esophageal squamous cell carcinoma, Cancer cell line (CVCL_1351), MKN74 — Homo sapiens (Human), Gastric tubular adenocarcinoma, Cancer cell line (CVCL_2791), MKN45 — Homo sapiens (Human), Gastric adenocarcinoma, Cancer cell line (CVCL_0434) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12927091/full.md ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12927091/full.md ## References 155 references — full list in the complete paper: https://tomesphere.com/paper/PMC12927091/full.md --- Source: https://tomesphere.com/paper/PMC12927091