Mapk14, also known as p38α, is a key member of the p38 mitogen-activated protein kinase (MAPK) signaling pathway, which includes p38β (MAPK11), p38γ (MAPK12) and p38δ (MAPK13). This pathway is associated with various biological processes, and Mapk14 plays a pivotal role in initiating different disease states such as inflammatory disorders, neurodegenerative diseases, cardiovascular cases, and cancer [2]. Genetic models, especially knockout mouse models, have been crucial in studying its function.

In prolactinoma research, knockout of Mapk14 in estradiol-induced mice and DRD2-/-MAPK14+ /-mice significantly inhibited tumor overgrowth and decreased prolactin (PRL) expression. In GH3 cells, Mapk14 knockout using siRNA also inhibited PRL production, suggesting that Mapk14 promotes prolactinoma formation [1]. In polycythemia vera (PV), Mapk14 over-expression was identified as a transcriptomic feature related to adverse clinical outcomes. It was the top hub gene in the PV-related protein-protein interaction network, and its expression was higher in PV patients, especially those with JAK2 homozygous mutation [3]. In metastatic gastric cancer, inhibition of Mapk14 (p38α) impaired cell proliferation, induced apoptosis, and inhibited cell migration. High levels of Mapk14 were found in advanced-stage gastric cancer samples, suggesting it could be a biomarker and pharmacological target [4]. In endometrial cancer, Mapk14 was identified as a specific requirement for high-grade endometrial carcinoma (HGEC) in 3D spheroid culture, promoting tumorigenicity in vivo [5].

In conclusion, Mapk14 is a significant player in the p38 MAPK signaling pathway, with its dysregulation involved in multiple disease conditions. The use of gene knockout mouse models has provided valuable insights into its role in prolactinoma, polycythemia vera, metastatic gastric cancer, and endometrial cancer, highlighting its potential as a therapeutic target in these diseases.