Given the side effect profile of MTX including higher rates of mouth sores or stomatitis, liver enzyme elevations, mild leukopenia, and non-basal-cell skin cancers (Ridker et al., 2019), future studies that therapeutically target signaling downstream to MTX (e.g. the adenosine-ADORA3-SMAD3/4-MIR181B signaling pathway) may leverage its anti-inflammatory effects potentially without its dose-limiting toxicity or side effects. This evidence concerns the gene SMAD3 and Oral ulcer.