Mechanism-Guided Combination Pharmacology of Curcumin and Methotrexate: Translational Strategies in Cancer and Emerging Applications in Rheumatoid Arthritis

Abstract Methotrexate (MTX) remains a cornerstone therapy in oncology and, to a lesser extent, rheumatoid arthritis (RA), yet its clinical utility in both settings is constrained by dose-limiting toxicities, interpatient pharmacokinetic variability, and the development of therapeutic resistance. Curcumin (CU), a pleiotropic small molecule with well-characterized anti-inflammatory, redox-modulating, and chemosensitizing properties, has emerged as a potential adjunct capable of enhancing MTX efficacy while mitigating adverse effects. This review provides a mechanistically integrated evaluation of MTX–CU combination strategies, with primary emphasis on the extensive preclinical evidence generated in oncology. In parallel, we critically examine the more limited yet mechanistically consistent body of evidence in RA. Through this analysis, we examine how CU modulates key signaling networks implicated in MTX response and toxicity, including NF-κB, MAPK, STAT, Nrf2, and oxidative stress pathways, and how these interactions influence apoptosis, macrophage polarization, drug resistance, and organ-specific toxicities. Particular emphasis is placed on nanoenabled codelivery systems that synchronize intracellular drug exposure, enhance folate receptor-mediated targeting, and improve therapeutic index through controlled release and microenvironment-responsive mechanisms. Preclinical oncology studies provide the most developed evidence base for MTX–CU cotherapy, spanning multiple cancer models, mechanistic studies, and nanoenabled delivery systems. However, formal drug-interaction evidence remains limited and heterogeneous: only four of approximately 25 oncology studies performed combination index analysis, yielding condition-specific synergy, additivity, or mixed context-dependent responses. In contrast, RA evidence is restricted to four in vivo Freund’s complete adjuvant studies and should be considered preliminary proof-of-concept. No published human trials have directly evaluated MTX–CU coadministration in cancer or RA. Accordingly, this review highlights key gaps in quantitative interaction analysis and PK–PD integration and proposes a translational framework incorporating biomarkers and precision nanomedicine. Overall, MTX–CU cotherapy remains a mechanistically supported but heterogeneous preclinical strategy, with the strongest rationale in oncology and RA representing an emerging application.