GNAI2, also known as G protein subunit alpha i2 and proto-oncogene gip2, is a crucial signaling modulator or transducer. It is involved in multiple transmembrane signaling systems, such as the melanogenesis signaling pathway, Hippo/YAP pathway, and is associated with the PI3K/AKT pathway [1,2,4]. GNAI2 is also involved in the regulation of adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production as a key component in heterotrimeric G protein signal transduction [5].

In rabbit melanocytes, overexpression of GNAI2 promotes proliferation, inhibits apoptosis, and increases melanin content, while knockdown has the opposite effects [1]. In ovarian cancer cells, silencing GNAI2/gip2 affects the expression of oncogenic/growth-promoting genes [3]. In patients with diabetes-accelerated atherosclerosis, S-nitrosylation of GNAI2 (SNO-GNAI2) at Cysteine 66 couples with CXCR5 to drive endothelial inflammation [2]. In gastric cancer, high GNAI2 expression is associated with poor prognosis and activates the PI3K/AKT pathway to promote cell growth and migration [4]. In NASH, GNAI2 is up-regulated in patient liver tissues, and hepatocyte-specific Gnai2-deficient mice show reduced steatohepatitis, suggesting GNAI2 exacerbates NASH progression [7]. In colitis-associated tumorigenesis, GNAI1 and GNAI3 reduce tumor development by down-regulating GNAI2 expression [6].

In conclusion, GNAI2 plays diverse and significant roles in various biological processes and disease conditions. Studies using gene knockout or knockdown models, such as in mice, have revealed its functions in cell proliferation, apoptosis, inflammation, and tumorigenesis. Understanding GNAI2 can provide potential therapeutic targets for diseases like melanoma, ovarian cancer, diabetes-associated atherosclerosis, gastric cancer, NASH, and colitis-associated cancer.