Nuak1-flox Mouse

NUAK1, also known as NUAK family kinase 1, is an AMP-activated protein kinase (AMPK)-related kinase. It plays a crucial role in multiple biological processes. NUAK1 is involved in regulating various signaling pathways, such as TGF-β, mTORC2/Akt, and is associated with processes like cell proliferation, apoptosis, differentiation, and migration. Aberrant NUAK1 signaling is implicated in diseases including fibrosis, cancer, and metabolic-associated steatohepatitis [2,3,4,5].

In fibrosis, fibroblast-specific loss of NUAK1 expression in mouse models of kidney, lung, and liver fibrosis significantly attenuated fibrosis. This indicates that NUAK1 promotes organ fibrosis via YAP and TGF-β/SMAD signaling, and there is a positive feedback loop with YAP and TAZ in the fibrogenic process [1].

In gastric cancer, NUAK1 depletion or inhibition in patient-derived xenograft and transgenic mouse models dramatically ameliorated gastric tumorigenesis, as it activates STAT5/GLI1/SOX2 signaling to enhance cancer cell expansion and drive chemoresistance [3].

In metabolic-dysfunction-associated steatohepatitis (MASH), NUAK1 inhibition in MASH mouse models ameliorated steatohepatitis development by down-regulating hepatic steatosis and fibrosis, as NUAK1 activates Caspase 6-driven pyroptosis and inflammation [5].

In conclusion, NUAK1 is a key regulator in multiple biological processes and diseases. Gene-knockout or conditional-knockout mouse models have been instrumental in revealing its role in fibrosis, gastric cancer, and MASH. These findings suggest that NUAK1 could be a potential therapeutic target for treating these diseases.