Interestingly, as a first-generation cancer chemotherapy drug and known to be a dihydrofolate reductase (DHFR) inhibitor, methotrexate has more recently been identified as a specific JAK/STAT pathway inhibitor, resulting in a reduced level of pSTAT without changing total STAT levels, therefore causing a relative increase in uSTAT levels23. This evidence concerns the gene DHFR and cancer.