{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:18:47Z","timestamp":1791195527160,"version":"4.1.0"},"reference-count":123,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Current Opinion in Pharmacology"],"published-print":{"date-parts":[[2026,8]]},"DOI":"10.1016\/j.coph.2026.102643","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T06:42:50Z","timestamp":1780641770000},"page":"102643","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":1,"special_numbering":"C","title":["Methotrexate: Integrating molecular pharmacology, systems toxicology, and precision rescue strategies"],"prefix":"10.1016","volume":"89","author":[{"given":"Rasha Mokhtar","family":"Abdelkareem","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walaa","family":"Obydah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3093-8572","authenticated-orcid":false,"given":"Ahmed M.","family":"Abd-Eldayem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.coph.2026.102643_bib1","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/0190-9622(91)70199-C","article-title":"The pharmacology of methotrexate","volume":"25","author":"Olsen","year":"1991","journal-title":"J Am Acad Dermatol"},{"key":"10.1016\/j.coph.2026.102643_bib2","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41584-020-0373-9","article-title":"Methotrexate and its mechanisms of action in inflammatory arthritis","volume":"16","author":"Cronstein","year":"2020","journal-title":"Nat Rev Rheumatol"},{"key":"10.1016\/j.coph.2026.102643_bib3","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1093\/rheumatology\/kem279","article-title":"Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis","volume":"47","author":"Wessels","year":"2008","journal-title":"Rheumatology"},{"key":"10.1016\/j.coph.2026.102643_bib4","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/nrrheum.2010.5","article-title":"Methotrexate\u2014How does it really work?","volume":"6","author":"Chan","year":"2010","journal-title":"Nat Rev Rheumatol"},{"key":"10.1016\/j.coph.2026.102643_bib5","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00228-023-03579-0","article-title":"Factors influencing methotrexate pharmacokinetics highlight the need for individualized dose adjustment: a systematic review","volume":"80","author":"Yang","year":"2024","journal-title":"Eur J Clin Pharmacol"},{"key":"10.1016\/j.coph.2026.102643_bib6","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1007\/s11926-023-01116-7","article-title":"Oral versus subcutaneous methotrexate in immune-mediated inflammatory disorders: an update of the current literature","volume":"25","author":"Vermeer","year":"2023","journal-title":"Curr Rheumatol Rep"},{"key":"10.1016\/j.coph.2026.102643_bib7","article-title":"Cellular pharmacokinetic of methotrexate and its modulation by folylpolyglutamate synthetase and \u03b3-glutamyl hydrolase in tumor cells","volume":"19","author":"Tang","year":"2024","journal-title":"PLoS One"},{"key":"10.1016\/j.coph.2026.102643_bib8","doi-asserted-by":"crossref","first-page":"5023","DOI":"10.3390\/ijms20205023","article-title":"Methotrexate an old drug with new tricks","volume":"20","author":"Bedoui","year":"2019","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.coph.2026.102643_bib9","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1080\/17425255.2025.2546127","article-title":"Evaluation of the drug-drug interaction between low-dose methotrexate and short-term use of non-steroidal anti-inflammatory drugs","volume":"21","author":"den Uil","year":"2025","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"10.1016\/j.coph.2026.102643_bib10","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1021\/acsomega.7b01437","article-title":"Simultaneous binding of Folic acid and methotrexate to human serum albumin: insights into the structural changes of protein and the location and competitive displacement of drugs","volume":"3","author":"Panja","year":"2018","journal-title":"ACS Omega"},{"key":"10.1016\/j.coph.2026.102643_bib11","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1111\/ijd.17758","article-title":"Comprehensive literature review evaluating the use, safety, and efficacy of subcutaneous methotrexate in the treatment of adult patients with moderate-to-severe plaque-type psoriasis","volume":"64","author":"Viguier","year":"2025","journal-title":"Int J Dermatol"},{"key":"10.1016\/j.coph.2026.102643_bib12","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1136\/annrheumdis-2022-eular.785","article-title":"POS0411 comparison of MTX-polyglutamate accumulation profiles in peripheral blood mononuclear cells and erythrocytes during 6 months MTX-therapy in the methotrexate monitoring (MeMo) trial","volume":"81","author":"Hebing","year":"2022","journal-title":"Ann Rheum Dis"},{"key":"10.1016\/j.coph.2026.102643_bib13","doi-asserted-by":"crossref","first-page":"66","DOI":"10.12793\/tcp.2025.33.e7","article-title":"Quantitation of methotrexate polyglutamates in red blood cells and application in patients with Crohn\u2019s disease","volume":"33","author":"Kim","year":"2025","journal-title":"Transl Clin Pharmacol"},{"key":"10.1016\/j.coph.2026.102643_bib14","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1093\/ibd\/izaf035","article-title":"Erythrocyte methotrexate\u2013polyglutamate concentrations in pediatric inflammatory bowel disease","volume":"31","author":"Vermeer","year":"2025","journal-title":"Inflamm Bowel Dis"},{"key":"10.1016\/j.coph.2026.102643_bib15","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2025.1578033","article-title":"Population pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphoma","volume":"16","author":"Wei","year":"2025","journal-title":"Front Pharmacol"},{"key":"10.1016\/j.coph.2026.102643_bib16","doi-asserted-by":"crossref","DOI":"10.1016\/j.dmpk.2022.100471","article-title":"CNS penetration of methotrexate and its metabolite 7-hydroxymethotrexate in mice bearing orthotopic group 3 medulloblastoma tumors and model-based simulations for children","volume":"48","author":"Perkins","year":"2023","journal-title":"Drug Metabol Pharmacokinet"},{"key":"10.1016\/j.coph.2026.102643_bib17","article-title":"Low-dose methotrexate adverse reaction risk in renal impairment: pharmacovigilance and physiological pharmacokinetic model assessment","volume":"16","author":"Zhang","year":"2025","journal-title":"Front Pharmacol"},{"key":"10.1016\/j.coph.2026.102643_bib18","doi-asserted-by":"crossref","first-page":"585","DOI":"10.3390\/pharmaceutics17050585","article-title":"Impact of pharmacogenetics on high-dose methotrexate toxicity in pediatric oncology","volume":"17","author":"Marangoni-Iglecias","year":"2025","journal-title":"Pharmaceutics"},{"key":"10.1016\/j.coph.2026.102643_bib19","doi-asserted-by":"crossref","DOI":"10.21037\/jlpm-25-7","article-title":"Personalized methotrexate treatment in immune-mediated inflammatory diseases: a narrative review","volume":"10","author":"Sundaresan","year":"2025","journal-title":"J Lab Precis Med"},{"key":"10.1016\/j.coph.2026.102643_bib20","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1634\/theoncologist.2015-0164","article-title":"Preventing and managing toxicities of high-dose methotrexate","volume":"21","author":"Howard","year":"2016","journal-title":"Oncologist"},{"key":"10.1016\/j.coph.2026.102643_bib21","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1634\/theoncologist.2017-0243","article-title":"Consensus guideline for use of glucarpidase in patients with high-dose methotrexate induced acute kidney injury and delayed methotrexate clearance","volume":"23","author":"Ramsey","year":"2018","journal-title":"Oncologist"},{"key":"10.1016\/j.coph.2026.102643_bib22","doi-asserted-by":"crossref","DOI":"10.1016\/j.tox.2021.152840","article-title":"Hepatotoxic potentials of methotrexate: understanding the possible toxicological molecular mechanisms","volume":"458","author":"Ezhilarasan","year":"2021","journal-title":"Toxicology"},{"key":"10.1016\/j.coph.2026.102643_bib23","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1080\/17425255.2023.2272593","article-title":"The use of glucarpidase as a rescue therapy for high dose methotrexate toxicity - a review of pharmacological and clinical data","volume":"19","author":"Kielbowski","year":"2023","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"10.1016\/j.coph.2026.102643_bib24","doi-asserted-by":"crossref","DOI":"10.3390\/diagnostics12071560","article-title":"Pharmacogenomics of methotrexate pathway in rheumatoid arthritis patients: approach toward personalized medicine","volume":"12","author":"Abdallah","year":"2022","journal-title":"Diagnostics"},{"key":"10.1016\/j.coph.2026.102643_bib25","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1517\/14656566.2.3.409","article-title":"The pharmacology of methotrexate","volume":"2","author":"Barnhart","year":"2001","journal-title":"Expert Opin Pharmacother"},{"key":"10.1016\/j.coph.2026.102643_bib26","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1097\/MPH.0000000000000206","article-title":"Mercaptopurine\/methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction","volume":"36","author":"Schmiegelow","year":"2014","journal-title":"J Pediatr Hematol Oncol"},{"key":"10.1016\/j.coph.2026.102643_bib27","doi-asserted-by":"crossref","DOI":"10.1016\/j.biopha.2022.113074","article-title":"Application and pharmacological mechanism of methotrexate in rheumatoid arthritis","volume":"150","author":"Zhao","year":"2022","journal-title":"Biomed Pharmacother"},{"key":"10.1016\/j.coph.2026.102643_bib28","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1080\/17512433.2024.2416674","article-title":"Methotrexate polyglutamates","volume":"17","author":"Yang","year":"2024","journal-title":"Expert Rev Clin Pharmacol"},{"key":"10.1016\/j.coph.2026.102643_sref29","doi-asserted-by":"crossref","first-page":"267","DOI":"10.3390\/ph19020267","article-title":"Drivers of methotrexate polyglutamate concentration in erythrocytes: insights from immune-mediated inflammatory diseases and pediatric acute lymphoblastic leukemia","volume":"19","author":"Sundaresan","year":"2026","journal-title":"Pharmaceuticals"},{"key":"10.1016\/j.coph.2026.102643_bib30","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.bbagen.2016.12.014","article-title":"Much more than you expected: the non-DHFR-mediated effects of methotrexate","volume":"1861","author":"Sramek","year":"2017","journal-title":"Biochim Biophys Acta Gen Subj"},{"key":"10.1016\/j.coph.2026.102643_bib31","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.jbspin.2018.07.004","article-title":"Methotrexate mechanism in treatment of rheumatoid arthritis","volume":"86","author":"Friedman","year":"2019","journal-title":"Jt Bone Spine"},{"key":"10.1016\/j.coph.2026.102643_bib32","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1002\/JLB.5RU0519-145R","article-title":"JAK inhibition by methotrexate (and csDMARDs) may explain clinical efficacy as monotherapy and combination therapy","volume":"106","author":"Gremese","year":"2019","journal-title":"J Leukoc Biol"},{"key":"10.1016\/j.coph.2026.102643_bib33","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0130078","article-title":"Methotrexate is a JAK\/STAT pathway inhibitor","volume":"10","author":"Thomas","year":"2015","journal-title":"PLoS One"},{"key":"10.1016\/j.coph.2026.102643_sref34","doi-asserted-by":"crossref","DOI":"10.1016\/j.pharmr.2026.100132","article-title":"Emerging mechanistic trends and clinical efficacy for methotrexate: applications to inflammatory bowel disease","volume":"78","author":"You","year":"2026","journal-title":"Pharmacol Rev"},{"key":"10.1016\/j.coph.2026.102643_bib35","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1007\/s12013-023-01168-7","article-title":"Infliximab ameliorates methotrexate-induced nephrotoxicity in experimental rat model: impact on oxidative stress, mitochondrial biogenesis, apoptotic and autophagic machineries","volume":"81","author":"Wasfey","year":"2023","journal-title":"Cell Biochem Biophys"},{"key":"10.1016\/j.coph.2026.102643_bib36","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nrrheum.2016.175","article-title":"Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers","volume":"12","author":"Brown","year":"2016","journal-title":"Nat Rev Rheumatol"},{"key":"10.1016\/j.coph.2026.102643_bib37","doi-asserted-by":"crossref","first-page":"4699","DOI":"10.1007\/s11033-020-05481-9","article-title":"Molecular mechanism of action and pharmacokinetic properties of methotrexate","author":"Maksimovic","year":"2020","journal-title":"Mol Biol Rep"},{"key":"10.1016\/j.coph.2026.102643_bib38","doi-asserted-by":"crossref","first-page":"32","DOI":"10.3390\/proteomes13030032","article-title":"Proteomic profiling reveals novel molecular insights into dysregulated proteins in established cases of rheumatoid arthritis","volume":"13","author":"Masood","year":"2025","journal-title":"Proteomes"},{"key":"10.1016\/j.coph.2026.102643_sref39","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1007\/s00018-026-06162-9","article-title":"Monocytes from inflammatory arthritis patients accumulate methotrexate and their transcriptome predicts methotrexate clinical response","author":"R\u00edos","year":"2026","journal-title":"Cell Mol Life Sci"},{"key":"10.1016\/j.coph.2026.102643_bib40","doi-asserted-by":"crossref","DOI":"10.12659\/MSM.943360","article-title":"Metabolomic alterations in methotrexate treatment of moderate-to-severe psoriasis","volume":"30","author":"Zhou","year":"2024","journal-title":"Med Sci Monit"},{"key":"10.1016\/j.coph.2026.102643_bib41","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1186\/s12967-023-04426-7","article-title":"A compendium of mitochondrial molecular characteristics provides novel perspectives on the treatment of rheumatoid arthritis patients","volume":"21","author":"Wang","year":"2023","journal-title":"J Transl Med"},{"key":"10.1016\/j.coph.2026.102643_sref42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2147\/DDDT.S581822","article-title":"From methotrexate resistance to biologic and targeted pharmacotherapy: a decade of phase 4 clinical trials evidence in rheumatoid arthritis","volume":"20","author":"Alsharif","year":"2026","journal-title":"Drug Des Dev Ther"},{"key":"10.1016\/j.coph.2026.102643_bib43","doi-asserted-by":"crossref","DOI":"10.1016\/j.drup.2025.101225","article-title":"Methotrexate resistance and its regulatory mechanisms in pediatric tumors and beyond","volume":"81","author":"Nie","year":"2025","journal-title":"Drug Resist Updates"},{"key":"10.1016\/j.coph.2026.102643_bib44","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.3390\/ph18091365","article-title":"Association of ABCG2 polymorphisms with methotrexate efficacy and toxicity in saudi rheumatoid arthritis patients","volume":"18","author":"Sharawi","year":"2025","journal-title":"Pharmaceuticals"},{"key":"10.1016\/j.coph.2026.102643_bib45","doi-asserted-by":"crossref","first-page":"6600","DOI":"10.1172\/JCI140797","article-title":"Pharmacogenomics of intracellular methotrexate polyglutamates in patients' leukemia cells in vivo","volume":"130","author":"Lopez-Lopez","year":"2020","journal-title":"J Clin Investig"},{"key":"10.1016\/j.coph.2026.102643_bib46","doi-asserted-by":"crossref","DOI":"10.1038\/srep35615","article-title":"Folylpolyglutamate synthase is a major determinant of intracellular methotrexate polyglutamates in patients with rheumatoid arthritis","volume":"6","author":"Yamamoto","year":"2016","journal-title":"Sci Rep"},{"key":"10.1016\/j.coph.2026.102643_bib47","article-title":"Combating methotrexate resistance in cancer treatment: a review on navigating pathways and enhancing its efficacy with fat-soluble vitamins","volume":"2025","author":"Kakkadath","year":"2025","journal-title":"Sci Tech Rep"},{"key":"10.1016\/j.coph.2026.102643_bib48","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1038\/s41416-024-02664-0","article-title":"Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance","volume":"130","author":"Meng","year":"2024","journal-title":"Br J Cancer"},{"key":"10.1016\/j.coph.2026.102643_bib49","article-title":"Overview of methotrexate toxicity: a comprehensive literature review","volume":"14","author":"Hamed","year":"2022","journal-title":"Cureus"},{"key":"10.1016\/j.coph.2026.102643_bib50","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.biopha.2018.08.050","article-title":"Mitochondrial dysfunction and oxidative stress are involved in the mechanism of methotrexate-induced renal injury and electrolytes imbalance","volume":"107","author":"Heidari","year":"2018","journal-title":"Biomed Pharmacother"},{"key":"10.1016\/j.coph.2026.102643_sref51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3892\/ijmm.2026.5741","article-title":"MTHFR-folate axis as a modulator of the epigenetic landscape in autoimmune diseases","volume":"57","author":"Navarro-Rodr\u00edguez","year":"2026","journal-title":"Int J Mol Med"},{"key":"10.1016\/j.coph.2026.102643_bib52","doi-asserted-by":"crossref","DOI":"10.1007\/s00210-026-05196-x","article-title":"L-carnitine protects against methotrexate-induced hepatotoxicity via regulation of apoptosis and metabolic pathways","author":"Pekgoz","year":"2026","journal-title":"Naunyn-Schmiedebergs Arch Pharmacol"},{"key":"10.1016\/j.coph.2026.102643_bib53","doi-asserted-by":"crossref","first-page":"10901","DOI":"10.1007\/s00210-025-03908-3","article-title":"Modulation of AMPK by esomeprazole and canagliflozin mitigates methotrexate-induced hepatotoxicity: involvement of MAPK\/JNK\/ERK, JAK1\/STAT3, and PI3K\/Akt signaling pathways","volume":"398","author":"El-Dessouki","year":"2025","journal-title":"Naunyn-Schmiedebergs Arch Pharmacol"},{"key":"10.1016\/j.coph.2026.102643_bib54","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1124\/dmd.114.058529","article-title":"Proton pump inhibitors inhibit methotrexate transport by renal basolateral organic anion transporter hOAT3","volume":"42","author":"Chioukh","year":"2014","journal-title":"Drug Metab Dispos"},{"key":"10.1016\/j.coph.2026.102643_bib55","first-page":"1355","article-title":"Recent advances on the regulations of organic anion transporters","volume":"16","author":"Yu","year":"2024","journal-title":"Pharm Times"},{"key":"10.1016\/j.coph.2026.102643_bib56","first-page":"135","article-title":"Losartan prevents methotrexate-induced liver and lung injury in rats via targeting PPAR-\u03b3\/TGF-\u03b21\/SMAD3 and Nrf2\/redox signaling","volume":"29","author":"Abbas","year":"2023","journal-title":"Zagazig Univ Med J"},{"key":"10.1016\/j.coph.2026.102643_bib57","first-page":"S546","article-title":"809Methotrexate toxicity: the systemic impact on the human body","volume":"369","author":"Mussarat","year":"2025","journal-title":"Am J Med Sci"},{"key":"10.1016\/j.coph.2026.102643_bib58","doi-asserted-by":"crossref","DOI":"10.1155\/omcl\/9407932","article-title":"Pharmacological mechanisms of phytochemicals and pharmaceutical agents in protecting against methotrexate-induced liver injury","volume":"2026","author":"Zia","year":"2026","journal-title":"Oxid Med Cell Longev"},{"key":"10.1016\/j.coph.2026.102643_bib59","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.aohep.2019.01.011","article-title":"Hepatic toxicity by methotrexate with weekly single doses associated with folic acid in rheumatoid and psoriatic arthritis. What is its real frequency?","volume":"18","author":"Garc\u00eda","year":"2019","journal-title":"Ann Hepatol"},{"key":"10.1016\/j.coph.2026.102643_bib60","doi-asserted-by":"crossref","DOI":"10.1016\/j.intimp.2024.112147","article-title":"Boswellic acid and apigenin alleviate methotrexate-provoked renal and hippocampal alterations in rats: targeting autophagy, NOD-2\/NF-\u03baB\/NLRP3, and connexin-43","volume":"134","author":"Abd El-Aal","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"10.1016\/j.coph.2026.102643_bib61","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.3390\/ijms24032856","article-title":"Kidney drug transporters in pharmacotherapy","volume":"24","author":"\u0141apczuk-Roma\u0144ska","year":"2023","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.coph.2026.102643_bib62","doi-asserted-by":"crossref","first-page":"316","DOI":"10.31138\/mjr.080225.arc","article-title":"Methotrexate-associated hypersensitivity pneumonitis after 15 years of use: a case report and literature review","volume":"36","author":"G\u00f6kten","year":"2025","journal-title":"Mediterr J Rheumatol"},{"key":"10.1016\/j.coph.2026.102643_bib63","doi-asserted-by":"crossref","DOI":"10.3390\/biomedicines11092567","article-title":"ABCC1, ABCG2 and FOXP3: predictive biomarkers of toxicity from methotrexate treatment in patients diagnosed with moderate-to-severe psoriasis","volume":"11","author":"Membrive-Jim\u00e9nez","year":"2023","journal-title":"Biomedicines"},{"key":"10.1016\/j.coph.2026.102643_sref64","doi-asserted-by":"crossref","DOI":"10.1002\/jbt.70829","article-title":"Ameliorative role of silymarin in methotrexate-induced pulmonary damage: a multi-pathway molecular approach","volume":"40","author":"Genc","year":"2026","journal-title":"J Biochem Mol Toxicol"},{"key":"10.1016\/j.coph.2026.102643_bib65","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2025.1671369","article-title":"Severe hematologic toxicity after low-dose methotrexate in ectopic pregnancy: role of MTHFR polymorphism and drug interaction - a case report and literature review","volume":"16","author":"Huang","year":"2025","journal-title":"Front Pharmacol"},{"key":"10.1016\/j.coph.2026.102643_bib66","doi-asserted-by":"crossref","first-page":"8165","DOI":"10.1007\/s00210-024-03164-x","article-title":"Molecular mechanisms underlying methotrexate-induced intestinal injury and protective strategies","volume":"397","author":"Ali","year":"2024","journal-title":"Naunyn-Schmiedebergs Arch Pharmacol"},{"key":"10.1016\/j.coph.2026.102643_bib67","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2021.759805","article-title":"Effect of polymorphisms of ABCB1 and MTHFR on methotrexate-related toxicities in adults with hematological malignancies","volume":"11","author":"Han","year":"2021","journal-title":"Front Oncol"},{"key":"10.1016\/j.coph.2026.102643_bib68","doi-asserted-by":"crossref","DOI":"10.1186\/s13075-015-0748-5","article-title":"Assessment of global DNA methylation in peripheral blood cell subpopulations of early rheumatoid arthritis before and after methotrexate","volume":"17","author":"de Andres","year":"2015","journal-title":"Arthritis Res Ther"},{"key":"10.1016\/j.coph.2026.102643_bib69","article-title":"Adverse drug reactions related to methotrexate: a real-world pharmacovigilance study using the FAERS database from 2004 to 2024","volume":"16","author":"Liu","year":"2025","journal-title":"Front Immunol"},{"key":"10.1016\/j.coph.2026.102643_sref70","doi-asserted-by":"crossref","DOI":"10.1002\/ccr3.71977","article-title":"Strategies for managing toxicities with high-dose methotrexate in haematological malignancies: lessons from clinical cases","volume":"14","author":"McLelland","year":"2026","journal-title":"Clin Case Rep"},{"key":"10.1016\/j.coph.2026.102643_bib71","doi-asserted-by":"crossref","first-page":"159","DOI":"10.3892\/mco.2022.2592","article-title":"Outcomes of high-dose methotrexate for CNS prophylaxis in diffuse large B-cell lymphoma with an intermediate or high CNS-international prognostic index: a single-center retrospective cohort study","volume":"17","author":"Al-Mansour","year":"2022","journal-title":"Mol Clin Oncol"},{"key":"10.1016\/j.coph.2026.102643_bib72","doi-asserted-by":"crossref","first-page":"3631","DOI":"10.2147\/DDDT.S515535","article-title":"Prediction of high-dose methotrexate blood concentration in osteosarcoma patients using machine learning","volume":"19","author":"Zhao","year":"2025","journal-title":"Drug Des Dev Ther"},{"key":"10.1016\/j.coph.2026.102643_bib73","doi-asserted-by":"crossref","first-page":"7400","DOI":"10.3390\/jcm14207400","article-title":"Pharmacokinetics and monitoring of methotrexate in adults with acute lymphoblastic leukaemia: a 10-Year Follow-Up at an Italian centre","volume":"14","author":"Calabr\u00f2","year":"2025","journal-title":"J Clin Med"},{"key":"10.1016\/j.coph.2026.102643_bib74","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s41927-024-00381-y","article-title":"Methotrexate treatment strategies for rheumatoid arthritis: a scoping review on doses and administration routes","volume":"8","author":"Rubio-Romero","year":"2024","journal-title":"BMC Rheumatol"},{"key":"10.1016\/j.coph.2026.102643_bib75","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1186\/s13063-025-09020-4","article-title":"Methotrexate oral or subcutaneous for rheumatoid arthritis (MOOSE): study protocol for a multi-centre randomised trial","volume":"26","author":"McClure","year":"2025","journal-title":"Trials"},{"key":"10.1016\/j.coph.2026.102643_bib76","first-page":"CD010498","article-title":"Methotrexate for psoriasis","volume":"2019","author":"da","year":"2019","journal-title":"Cochrane Database Syst Rev"},{"key":"10.1016\/j.coph.2026.102643_bib77","doi-asserted-by":"crossref","DOI":"10.1177\/17562848221085889","article-title":"Evidence-based efficacy of methotrexate in adult Crohn\u2019s disease in different intestinal and extraintestinal indications","volume":"15","author":"Cassinotti","year":"2022","journal-title":"Therapeut Adv Gastroenterol"},{"key":"10.1016\/j.coph.2026.102643_bib78","article-title":"Methotrexate use in the management of ectopic pregnancies: a retrospective study","volume":"17","author":"Slattery","year":"2025","journal-title":"Cureus"},{"key":"10.1016\/j.coph.2026.102643_bib79","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s13063-024-07905-4","article-title":"The meteoritics trial: efficacy of methotrexate after remission-induction with tocilizumab and glucocorticoids in giant cell Arteritis\u2014study protocol for a randomized, double-blind, placebo-controlled, parallel-group phase II study","volume":"25","author":"Kreis","year":"2024","journal-title":"Trials"},{"key":"10.1016\/j.coph.2026.102643_bib80","doi-asserted-by":"crossref","DOI":"10.1177\/17534666221135314","article-title":"Protective effect of methotrexate on lung function and mortality in rheumatoid arthritis-related interstitial lung disease: a retrospective cohort study","volume":"16","author":"Kim","year":"2022","journal-title":"Ther Adv Respir Dis"},{"key":"10.1016\/j.coph.2026.102643_sref81","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/s11671-026-04520-x","article-title":"Advances in methotrexate nano-formulations to enhance therapeutic efficacy against drug-resistant breast cancer","volume":"21","author":"Tripathy","year":"2026","journal-title":"Discov Nano"},{"key":"10.1016\/j.coph.2026.102643_bib82","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1002\/acr.24596","article-title":"American College of Rheumatology Guideline for the treatment of rheumatoid arthritis","volume":"73","author":"Fraenkel","year":"2021","journal-title":"Arthritis Care Res"},{"key":"10.1016\/j.coph.2026.102643_bib83","doi-asserted-by":"crossref","DOI":"10.26508\/lsa.202302058","article-title":"A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance","volume":"6","author":"van der Krift","year":"2023","journal-title":"Life Sci Alliance"},{"key":"10.1016\/j.coph.2026.102643_sref84","first-page":"1","article-title":"Multi-omics profiling of chronic immune-mediated skin diseases: SKINERGY protocol and strategic evaluation","volume":"00","author":"Koster","year":"2026","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"10.1016\/j.coph.2026.102643_bib85","article-title":"Methotrexate in sarcoidosis: hematologic and hepatic toxicity encountered in a large cohort over a six year period","volume":"37","author":"Baughman","year":"2020","journal-title":"Sarcoidosis Vasc Diffuse Lung Dis"},{"key":"10.1016\/j.coph.2026.102643_bib86","doi-asserted-by":"crossref","first-page":"3630","DOI":"10.57187\/s.3630","article-title":"Therapeutic management of fibrosis in systemic sclerosis patients \u2013 an analysis from the Swiss EUSTAR cohort","volume":"154","author":"Windirsch","year":"2024","journal-title":"Swiss Med Wkly"},{"key":"10.1016\/j.coph.2026.102643_bib87","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1097\/EBP.0000000000001086","article-title":"Is methotrexate an effective treatment for patients with fibromyalgia?","volume":"24","author":"Sheider","year":"2021","journal-title":"Evid-Based Pract"},{"key":"10.1016\/j.coph.2026.102643_bib88","doi-asserted-by":"crossref","DOI":"10.5812\/aapm.89990","article-title":"Efficacy of methotrexate on pain severity reduction and improvement of quality of life in patients with moderate to severe knee osteoarthritis","volume":"9","author":"Enteshari-Moghaddam","year":"2019","journal-title":"Anesthesiol Pain Med"},{"key":"10.1016\/j.coph.2026.102643_bib89","first-page":"2","article-title":"Relief and resolution of fibromyalgia symptoms with low dose Methotrexate- the origin of pain is inflammation and the inflammatory response","volume":"4","author":"Omoigui","year":"2014","journal-title":"Rheumatol Curr Res"},{"key":"10.1016\/j.coph.2026.102643_bib90","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7554\/eLife.58064","article-title":"Methotrexate attenuates vascular inflammation through an adenosine- microRNA-dependent pathway","volume":"10","author":"Yang","year":"2021","journal-title":"eLife"},{"key":"10.1016\/j.coph.2026.102643_bib91","doi-asserted-by":"crossref","DOI":"10.1155\/2017\/9632846","article-title":"Protective effects of methotrexate against proatherosclerotic cytokines: a review of the evidence","volume":"2017","author":"Mangoni","year":"2017","journal-title":"Mediat Inflamm"},{"key":"10.1016\/j.coph.2026.102643_bib92","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.1080897","article-title":"Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model","volume":"13","author":"Chen","year":"2022","journal-title":"Front Immunol"},{"key":"10.1016\/j.coph.2026.102643_bib93","first-page":"67","article-title":"Does post-COVID reactive arthritis exist? Experience of a tertiary care centre with a review of the literature","volume":"19","author":"Pal","year":"2023","journal-title":"Reumatol Cl\u00ednica (English Ed"},{"key":"10.1016\/j.coph.2026.102643_bib94","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1111\/jcpt.13739","article-title":"Leucovorin (folinic acid) rescue for high-dose methotrexate: a review","volume":"47","author":"Jiang","year":"2022","journal-title":"J Clin Pharm Therapeut"},{"key":"10.1016\/j.coph.2026.102643_bib95","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.3390\/pharmaceutics16091180","article-title":"Anticipating leucovorin rescue therapy in patients with Osteosarcoma through methotrexate population pharmacokinetic model","volume":"16","author":"Olivo","year":"2024","journal-title":"Pharmaceutics"},{"key":"10.1016\/j.coph.2026.102643_bib96","first-page":"127","article-title":"Reduced dose folinic acid rescue after rapid high-dose methotrexate clearance is not associated with increased toxicity in a pediatric cohort","volume":"30","author":"Niinim\u00e4ki","year":"2021","journal-title":"Support Care Cancer"},{"key":"10.1016\/j.coph.2026.102643_bib97","doi-asserted-by":"crossref","DOI":"10.1016\/j.biopha.2023.115292","article-title":"Glucarpidase (carboxypeptidase G2): biotechnological production, clinical application as a methotrexate antidote, and placement in targeted cancer therapy","volume":"166","author":"Moradbeygi","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"10.1016\/j.coph.2026.102643_bib98","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1182\/blood.2024026211","article-title":"Glucarpidase for treatment of high-dose methotrexate toxicity","volume":"145","author":"Gupta","year":"2025","journal-title":"Blood"},{"key":"10.1016\/j.coph.2026.102643_bib99","doi-asserted-by":"crossref","DOI":"10.1002\/adbi.202500326","article-title":"Biologics, biosimilars, and biobetters: therapeutic innovations reshaping modern medicine","volume":"9","author":"Kalaw San Pascual","year":"2025","journal-title":"Adv Biol"},{"key":"10.1016\/j.coph.2026.102643_bib100","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s40199-023-00499-3","article-title":"Oral regimen for high dose methotrexate urine alkalinization: a systematic review and meta-analysis","volume":"32","author":"Kaveh-Ahangaran","year":"2024","journal-title":"Daru J Pharm Sci"},{"key":"10.1016\/j.coph.2026.102643_bib101","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1093\/ckj\/sfu093","article-title":"Methotrexate toxicity treated with continuous venovenous hemofiltration, leucovorin and glucarpidase","volume":"7","author":"Connors","year":"2014","journal-title":"Clin Kidney J"},{"key":"10.1016\/j.coph.2026.102643_bib102","first-page":"87","article-title":"High-dose continuous venovenous hemofiltration combined with charcoal hemoperfusion for methotrexate removal","volume":"4","author":"Grafft","year":"2011","journal-title":"NDT Plus"},{"key":"10.1016\/j.coph.2026.102643_bib103","article-title":"L-Methionine attenuates methotrexate-induced cardiotoxicity by modulating oxidative stress, inflammation, and dyslipidemia in rats","volume":"16","author":"Abdel-Wahab","year":"2026","journal-title":"Toxicol Rep"},{"key":"10.1016\/j.coph.2026.102643_bib104","doi-asserted-by":"crossref","first-page":"430","DOI":"10.3390\/antiox8100430","article-title":"Formononetin upregulates Nrf2\/HO-1 signaling and prevents oxidative stress, inflammation, and kidney injury in methotrexate-induced rats","volume":"8","author":"Aladaileh","year":"2019","journal-title":"Antioxidants"},{"key":"10.1016\/j.coph.2026.102643_bib105","doi-asserted-by":"crossref","first-page":"13302","DOI":"10.3390\/ijms222413302","article-title":"Genophenotypic factors and pharmacogenomics in adverse drug reactions","volume":"22","author":"Cacabelos","year":"2021","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.coph.2026.102643_bib106","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41431-025-01950-6","article-title":"Pharmacogenomics in drug therapy: global regulatory guidelines for managing high-risk drug reactions","volume":"34","author":"Omran","year":"2025","journal-title":"Eur J Hum Genet"},{"key":"10.1016\/j.coph.2026.102643_bib107","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1111\/jdv.19730","article-title":"Sex differences in adverse events from systemic treatments for psoriasis: a decade of insights from the Swiss Psoriasis Registry (SDNTT)","volume":"38","author":"Verardi","year":"2024","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"10.1016\/j.coph.2026.102643_bib108","doi-asserted-by":"crossref","DOI":"10.1136\/rmdopen-2023-003827","article-title":"Severe methotrexate toxicity in elderly patients under diuretics","volume":"10","author":"Kumar","year":"2024","journal-title":"RMD Open"},{"key":"10.1016\/j.coph.2026.102643_bib109","doi-asserted-by":"crossref","DOI":"10.1016\/j.semarthrit.2022.152031","article-title":"Methotrexate use reduces mortality risk in rheumatoid arthritis: a systematic review and meta-analysis of cohort studies","volume":"55","author":"Xu","year":"2022","journal-title":"Semin Arthritis Rheum"},{"key":"10.1016\/j.coph.2026.102643_bib110","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2023.1030832","article-title":"Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: an assessment using the FDA adverse event reporting system","volume":"14","author":"Onda","year":"2023","journal-title":"Front Pharmacol"},{"key":"10.1016\/j.coph.2026.102643_bib111","doi-asserted-by":"crossref","DOI":"10.1016\/j.ebiom.2024.105339","article-title":"Therapeutic single-cell landscape: methotrexate exacerbates interstitial lung disease by compromising the stemness of alveolar epithelial cells under systemic inflammation","volume":"108","author":"Chang","year":"2024","journal-title":"EBioMedicine"},{"key":"10.1016\/j.coph.2026.102643_sref112","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/s13256-025-05774-2","article-title":"Effective high-dose methotrexate toxicity reversal using fixed-dose glucarpidase in obese patients: a case series","volume":"20","author":"Grofvert","year":"2026","journal-title":"J Med Case Rep"},{"key":"10.1016\/j.coph.2026.102643_bib113","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.3390\/jcm12041599","article-title":"Predicting hepatotoxicity associated with low-dose methotrexate using machine learning","volume":"12","author":"Hu","year":"2023","journal-title":"J Clin Med"},{"key":"10.1016\/j.coph.2026.102643_bib114","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1001\/jama.2018.10136","article-title":"Real-world evidence and real-world data for evaluating drug safety and effectiveness","volume":"320","author":"Corrigan-Curay","year":"2018","journal-title":"JAMA"},{"key":"10.1016\/j.coph.2026.102643_bib115","doi-asserted-by":"crossref","first-page":"468","DOI":"10.3390\/genes11040468","article-title":"Pharmacogenomic markers of methotrexate response in the consolidation phase of pediatric acute lymphoblastic leukemia treatment","volume":"11","author":"Kotur","year":"2020","journal-title":"Genes"},{"key":"10.1016\/j.coph.2026.102643_bib116","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/cts.12694","article-title":"Metabolomic profiling to identify molecular biomarkers of cellular response to methotrexate in vitro","volume":"13","author":"Funk","year":"2020","journal-title":"Clin Transl Sci"},{"key":"10.1016\/j.coph.2026.102643_sref117","series-title":"Development of a web-based machine learning model for early prediction of delayed high-dose methotrexate clearance in pediatric osteosarcoma","author":"Duan","year":"2026"},{"key":"10.1016\/j.coph.2026.102643_bib118","article-title":"Punicalagin protects against the development of methotrexate-induced hepatotoxicity in mice via activating Nrf2 signaling and decreasing oxidative stress, inflammation, and cell death","volume":"23","author":"Al-khawalde AA marddyah","year":"2022","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.coph.2026.102643_bib119","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s12911-023-02248-7","article-title":"Predicting delayed methotrexate elimination in pediatric acute lymphoblastic leukemia patients: an innovative web-based machine learning tool developed through a multicenter, retrospective analysis","volume":"23","author":"Jian","year":"2023","journal-title":"BMC Med Inf Decis Making"},{"key":"10.1016\/j.coph.2026.102643_bib120","series-title":"Developing an innovative web-based machine learning tool for predicting delayed methotrexate elimination in pediatric patients with Osteosarcoma","author":"Chang","year":"2025"},{"key":"10.1016\/j.coph.2026.102643_bib121","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.3390\/ph17111550","article-title":"Artificial intelligence and machine learning models for predicting drug-induced kidney injury in small molecules","volume":"17","author":"Rao","year":"2024","journal-title":"Pharmaceuticals"},{"key":"10.1016\/j.coph.2026.102643_bib122","doi-asserted-by":"crossref","first-page":"121","DOI":"10.26502\/aimr.0203","article-title":"Factors underlying failure of methotrexate treatment in rheumatoid arthritis: implications in personalized care","volume":"8","author":"Srivastava","year":"2025","journal-title":"Arch Intern Med Res"},{"key":"10.1016\/j.coph.2026.102643_sref123","doi-asserted-by":"crossref","DOI":"10.1093\/medlaw\/fwaf005","article-title":"The fifty shades of black: about black box AI and explainability in healthcare","volume":"33","author":"Raposo","year":"2025","journal-title":"Med Law Rev"}],"container-title":["Current Opinion in Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1471489226000391?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1471489226000391?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T16:27:55Z","timestamp":1784910475000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1471489226000391"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":123,"alternative-id":["S1471489226000391"],"URL":"https:\/\/doi.org\/10.1016\/j.coph.2026.102643","relation":{},"ISSN":["1471-4892"],"issn-type":[{"value":"1471-4892","type":"print"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Methotrexate: Integrating molecular pharmacology, systems toxicology, and precision rescue strategies","name":"articletitle","label":"Article Title"},{"value":"Current Opinion in Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.coph.2026.102643","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"102643"}}