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INTRODUCTION Methotrexate (MTX) is a synthetic antimetabolite with many therapeutic indications, mainly anti-inflammatory and immunosuppressant at relatively low doses and antineoplastic at high doses.[ , ] MTX competitively inhibits dihydrofolate reductase, so decreasing tetrahydrofolate level leads to blocks the synthesis of purines, pyrimidines, DNA, ribonucleic acid, thymidylate, and proteins.[ , , ] It is well known that MTX is a hepatotoxic drug, and this leads to limitation of its clinical use

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PSMA/GCPII is also expressed in many healthy tissues, but its function has only been established in the brain and small intestine

Mammalian target of rapamycin (mTOR) serves as a primary negative regulator of autophagy, directly influencing the ULK1-ATG13-FIP200 complex in response to nutrient availability (17)

Determined the mechanisms of ibrutinib resistance and identified novel therapies to overcome resistance