methotrexate

Overview

Methotrexate (MTX) is a Folate antagonist and one of the most widely used agents in both oncology and immunology. It acts by competitively inhibiting dihydrofolate reductase (DHFR), the enzyme responsible for reducing dihydrofolate to tetrahydrofolate, thereby disrupting DNA synthesis, repair, and cellular replication. This dual utility — as a cytotoxic chemotherapeutic and as an immunosuppressive disease-modifying antirheumatic drug (DMARD) — makes it a cornerstone of treatment across an exceptionally broad range of conditions, including malignancies such as osteosarcoma, acute lymphoblastic leukemia (ALL), and diffuse large B-cell lymphoma (DLBCL), as well as inflammatory and autoimmune disorders including rheumatoid arthritis, psoriasis, bullous pemphigoid, scleritis, and retroperitoneal fibrosis.

At lower doses, MTX modulates immune function by suppressing lymphocyte proliferation and downregulating pro-inflammatory cytokines, making it a preferred anchor agent in rheumatological and dermatological practice. At high doses, it exerts direct antiproliferative cytotoxicity, and its pharmacokinetics in these settings require careful monitoring given the potential for significant organ toxicity, including hepatotoxicity, nephrotoxicity, and mucositis. Because of this breadth of application and its established efficacy benchmark, MTX remains a critical comparator in experimental therapeutics and a frequent component of combination regimens evaluated in current research.

Focus of Latest Publications

Recent publications have used methotrexate in several distinct contexts, reflecting its broad therapeutic relevance.

In osteosarcoma-related research, methotrexate was mentioned alongside doxorubicin and cisplatin as one of the primary first-line chemotherapeutic agents used for the disease. In a study of liposome-mediated delivery of a ruthenium-based metallodrug designed to overcome cisplatin resistance, methotrexate served as part of the standard treatment background against which new delivery approaches were framed.

In pediatric acute lymphoblastic leukemia, methotrexate-induced oral mucositis was specifically investigated in relation to quality of life. The study assessed factors associated with mucositis severity and its impact on children’s daily functioning in a setting where photobiomodulation was routinely used as part of institutional care. This highlights methotrexate’s well-recognized mucosal toxicity and the clinical need for supportive interventions such as photobiomodulation and mucositis monitoring tools.

Several studies explored methotrexate in advanced drug-delivery systems for cancer. One investigation developed biopolymeric alginate nanocapsules co-loaded with methotrexate and curcumin for breast cancer therapy, aiming to exploit synergistic effects through oral or intratumoral administration. Another study designed Folate-targeted, EDTA-embedded, methotrexate-loaded albumin nanoparticles for in vitro anticancer evaluation in breast cancer cells, reflecting ongoing efforts to improve tumor targeting and efficacy. These studies position methotrexate as both a cytotoxic agent and a payload for nanomedicine-based optimization.

In inflammatory disease research, methotrexate remained central. A study on rheumatoid arthritis described cannabidiol as synergizing with methotrexate to attenuate disease via STAT3/NF-κB signaling-mediated M1 macrophage polarization. The publication explicitly characterized methotrexate as the anchor drug for rheumatoid arthritis, while also noting limitations from hepatotoxicity, gastrointestinal intolerance, and incomplete efficacy in some patients. Another rheumatoid arthritis-related protocol examined combinations of tripterygium glycoside tablets with conventional synthetic DMARDs such as methotrexate, leflunomide, and hydroxychloroquine, underscoring methotrexate’s role in combination csDMARD strategies.

Methotrexate also appeared in studies of other immune-mediated disorders. In bullous pemphigoid, a nationwide Swedish cohort study reported improved survival among patients treated with methotrexate, prednisolone, and potent topical corticosteroids. In retroperitoneal fibrosis, methotrexate was included among less intensive oral immunosuppressive therapies alongside mycophenolate mofetil and azathioprine. In scleritis associated with multiple systemic inflammatory diseases, relapse after tapering and discontinuation of methotrexate and corticosteroids suggested that disease control had not been maintained with tofacitinib-based treatment. In juvenile idiopathic arthritis-associated uveitis and chronic anterior antinuclear antibody-positive uveitis, baricitinib was studied in patients who had an inadequate response to methotrexate or biologic DMARDs, again reflecting methotrexate’s role as a standard first-line comparator.

In transplantation and hematology, methotrexate remained part of prophylactic immunosuppression. A nationwide Japanese cohort study of cord blood transplantation in high-risk AML reported graft-versus-host disease prophylaxis regimens combining cyclosporine or tacrolimus with either mycophenolate mofetil or methotrexate. Another study of allogeneic hematopoietic stem cell transplantation used tacrolimus and methotrexate as standard immune suppression for GVHD prophylaxis, with tildrakizumab added experimentally. Methotrexate was also used in CNS prophylaxis for diffuse large B-cell lymphoma, where a phase 3 trial compared high-dose intravenous methotrexate with intrathecal methotrexate based on CNS International Prognostic Index risk. In a case report of uterine lymphoma, methotrexate appeared in an intensive regimen with rituximab, cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide, and cytarabine, illustrating its inclusion in aggressive multi-agent chemotherapy.

Methotrexate was also studied in dermatologic and musculoskeletal contexts. A psoriasis study used dissolving microneedles co-loading methotrexate and a photosensitizer to enable green-light activated chemo-photodynamic therapy. In rheumatoid arthritis, peptide-drug conjugates were compared with methotrexate, with efficacy reported as comparable to or exceeding methotrexate in the referenced study. Additional work examined methotrexate-induced kidney and hepatic toxicities in vivo, using network pharmacology and molecular docking to evaluate Citrus aurantifolia peel essential oil as a potential protective intervention.

Finally, methotrexate appeared in broader pharmacology and aging research. In a mouse lifespan study, methotrexate was among several compounds tested by the Interventions Testing Program in UM-HET3 mice, but it did not increase lifespan. Across these studies, methotrexate consistently served as a benchmark therapy, a combination partner, or a toxicity-associated exposure of clinical interest.