biostudies-literatureMercado-Gomez MRamon y Cajal ProgramAECC Scientific FoundationLa CaixaMICINNMiguel ServetInstituto de Salud Carlos IIICIMA, PamplonaJose Juan García MarínSpanish Ministry of Science and InnovationEuropean Regional Development Fund/European Social FundAECCFundação para a Ciência e a Tecnologia, PortugalUniversidad de SalamancaPNRRSara BorrellHealth ResearchCUPDepartment of Health of the Basque CountryFEDERInstituto de Salud Carlos III, SpainMcGill UniversityCarlos III Health InstituteMINECOMinisterio de Ciencia e Innovación, Programa Retos-Colaboración RTC2019European UnionAyudas Fundación Científica AECC para proyectos coordinadosNational Cancer Institute of the National Institutes of Health341-352https://www.ebi.ac.uk/biostudies/studies/S-EPMC12911659biostudies-literatureUnknown75(2)<h4>Background and objective</h4>Cholangiocarcinoma (CCA) is a heterogeneous neoplasm of the biliary epithelium that easily infiltrates, metastasises and recurs. Magnesium disbalance is a hallmark of CCA, with the magnesium transporter cyclin M4 (CNNM4) being a key driver of various hepatic diseases. This study aims to unravel the role of CNNM4 in the initiation and progression of CCA.<h4>Design</h4>CNNM4 protein and gene expression were assessed in vitro, in vivo and in patients with CCA. Silencing of <i>CNNM4</i> was effectively achieved by using small interfering RNA (siRNA) or short hairpin RNA in CCA cell lines and GalNAc-conjugated siRNA in a transposon-based CCA mice model. The impact of CNNM4 on tumour cell proliferation, migration and invasion to the lungs was evaluated using the GutRole of CNNM4 in the progression of cholangiocarcinoma: implications for ferroptosis and therapeutic potential.PMC12911659N/APRE2021-0970732023-CIEN-000008-01LCF/PR/HR21/52410028PRDVZ233980ZAPAIGTP-AECC_2022-0422023333041PRE2018-0848402020-CIEN-000067-012022111070EXOHEP2-CM2023/2027PI21/00922FAR/3492/2021S2022/BMD-7409DTS20/00138CP22/000732021-CIEN-000029-04-01CI23-201556/12/TT/2022/00001PI18/01075R01CA127817PI23/01850PNC 0000001CEX2021-001136-SPI23/00681PID2021-126096NB-I00RYC2018-024475-1SEV‐2016‐0644CPII19/00008HORIZON-HLTH-2022-STAYHLTH-02RED2018-102379-TPID2020-117116RB-I0020222J7W2KCN00000041HR17-00601SA113P23101095679CD19/00254PID2020-117941RBI00/AEI/10.13039PI22/00526B53C22006120001Rodrigues PMRodriguez-Agudo RMartinez-Cruz LABuccella DGonzalez Recio IMendizabal ILamarca ACarpino GWu HMartinez-Chantar MLMacarulla TRejano-Gordillo CMCubero FJSingh RTian TVYanez-Bartolome MAzkargorta MGine AECarracedo AMerlos Rodrigo MAG Fernandez-Barrena MBarrenechea-Barrenechea JABanales JRomero MRCalvisi DFElortza FMercado-Gomez MSchaeper UGarcia-Longarte SLapitz AMichalkova HMacias RIRAfonso MBGaudio EPena-SanFelix PDelgado TCHeger ZZapata-Pavas LERodrigues CMPConter CSerrano-Macia MMartin CGil-Pitarch CMarin JJGOveri DMoreno VOlaizola PGoikoetxea-Usandizaga NAvila MAfalseRole of CNNM4 in the progression of cholangiocarcinoma: implications for ferroptosis and therapeutic potential.<h4>Background and objective</h4>Cholangiocarcinoma (CCA) is a heterogeneous neoplasm of the biliary epithelium that easily infiltrates, metastasises and recurs. Magnesium disbalance is a hallmark of CCA, with the magnesium transporter cyclin M4 (CNNM4) being a key driver of various hepatic diseases. This study aims to unravel the role of CNNM4 in the initiation and progression of CCA.<h4>Design</h4>CNNM4 protein and gene expression were assessed in vitro, in vivo and in patients with CCA. Silencing of <i>CNNM4</i> was effectively achieved by using small interfering RNA (siRNA) or short hairpin RNA in CCA cell lines and GalNAc-conjugated siRNA in a transposon-based CCA mice model. The impact of CNNM4 on tumour cell proliferation, migration and invasion to the lungs was evaluated using the 2026-01-01T00:00:00Z2026 Jan2026-07-16T00:33:05.676Z2026-07-09T13:10:01.392ZS-EPMC129116594076406310.1136/gutjnl-2024-333255