DUSP16 is a dual-specificity phosphatase that inactivates mitogen-activated protein kinases (MAPKs), particularly c-jun N-terminal kinase (JNK) and p38, through dephosphorylation of substrates including MAPK10 bound to ARRB2. The enzyme negatively regulates MAPK signaling cascades across multiple cellular compartments. In cancer, DUSP16 displays context-dependent roles. High DUSP16 expression promotes chemoresistance in nasopharyngeal carcinoma, colorectal cancer, gastric, and breast cancer by suppressing JNK and p38 activation, thereby reducing mitochondrial BAX accumulation and apoptosis 1. DUSP16 also protects cancer cells from senescence by antagonizing p53 and Rb tumor suppressors 2. Conversely, DUSP16 destabilization through ubiquitination or protein–protein interactions accelerates malignant progression; in bladder cancer, KLF16-mediated DUSP16 mRNA degradation leads to ERK1/2 activation and enhanced MYC-driven oncogenesis 3, while FBXL18-induced DUSP16 degradation activates JNK signaling in endometrial carcinoma 4. MKP7/DUSP16 dysfunction correlates with cancer progression and drug resistance across multiple cancer types 5. Beyond cancer, suppressing DUSP16 overexpression induced by ELK1 promotes neural progenitor cell differentiation and cognitive recovery in Alzheimer's disease models 6. Protein stability of DUSP16 is controlled through ubiquitin-mediated degradation 7. Clinically, bromodomain inhibitors such as OTX015 and ABBV-744, combined with chemotherapy agents like gemcitabine or DDP, represent emerging therapeutic strategies in DUSP16-regulated cancers 3.