Dusp9, also known as MAP kinase phosphatases-4 (MKP-4), is a cytoplasmic phosphatase belonging to the threonine/tyrosine dual-specificity phosphatase family. It dephosphorylates ERK1/2, p38, JNK and ASK1, thus controlling various mitogen-activated protein kinase (MAPK) pathway cascades, which are essential for proper cell functioning. Dusp9 plays a major role in human pathologies, including cardiac dysfunction, liver metabolic syndromes, diabetes, obesity and cancer [1].

In hepatic ischemia/reperfusion (I/R) injury, Dusp9 depletion leads to more severe injury, while its enrichment attenuates hepatic inflammation both in vivo and in vitro. Mechanistically, Dusp9 inhibits the phosphorylation of ASK1 by directly binding to it, thereby decreasing TRAF6, K63 ubiquitin and the phosphorylation of p38/JNK1 [2].

In clear cell renal cell carcinoma (ccRCC), Dusp9 is significantly down-regulated. It suppresses the proliferation and migration of ccRCC cell lines in vitro and tumor growth in vivo by inhibiting the phosphorylation of mTOR and the expression of its pathway-associated proteins [3].

In triple negative breast cancer, Dusp9-mediated reduction of pERK1/2 supports cancer stem cell-like traits and promotes tumor growth [4].

In colorectal cancer, the high methylation status of CpG island in the promoter of Dusp9 may lead to its down-regulation, and Dusp9 inhibits the proliferation, migration, invasion, and epithelial-mesenchymal transition of CRC cells both in vitro and in vivo [5].

In metabolic-associated steatohepatitis (MASH), knockdown of Dusp9 exacerbates glycolipid metabolism disorders and counteracts the beneficial effects of caffeine [6].

In sepsis-induced cardiomyopathy, inhibition of miR-194-5p avoids Dusp9 down-regulation and limits the disease [7].

In labor, miR-132-3p targets Dusp9-dependent p38 and JNK signaling pathways to enhance inflammation in the amnion, potentially leading to preterm birth [8].

In gestational diabetes mellitus (GDM), DUSP9 contributes to the disease progression by inhibiting the IRS1/PI3K/AKT pathway, leading to insulin resistance and metabolic dysfunction, and its knockdown ameliorates key pathological features of GDM [9].

In conclusion, Dusp9 is a crucial regulator in multiple biological processes and diseases. Through gene knockout or conditional knockout mouse models and other functional studies, it has been revealed that Dusp9 plays important roles in processes such as inflammation, cell proliferation and migration, and metabolism-related diseases, providing potential therapeutic targets for these diseases.