DUSP18 (dual specificity phosphatase 18) is a protein tyrosine/serine/threonine phosphatase localized to chromosome 22.1 that dephosphorylates both phosphotyrosyl and phosphoserine/threonyl residues 1. The enzyme shows dual-substrate specificity with preference for phosphotyrosine over phosphothreonine forms [UniProt]. Primary substrates include MAPK pathway components and SAPK/JNK kinases 2. In bone tissue, DUSP18 functions downstream of the KISS1/GPR54 signaling pathway, where it dephosphorylates SRC at Tyr416 to suppress osteoclast differentiation and bone resorption 3. DUSP18 also inhibits MAPK14 phosphorylation in hypoxic hepatocellular carcinoma, promoting cell migration and invasion through p53 pathway suppression 4. Additionally, DUSP18 modulates ataxin-1 SUMOylation and aggregation through its phosphatase activity, inhibiting JNK-mediated pathways relevant to neurodegeneration 5. In colorectal cancer, DUSP18 stabilizes USF1 transcription factor to upregulate cholesterol biosynthesis, creating an immunosuppressive tumor microenvironment by depleting CD8+ T cell prenylated KRAS 6. DUSP18 expression is upregulated during TGFβ1-induced epithelial-mesenchymal transition 7, linking it to cancer progression and metastasis.