Irs2, short for insulin receptor substrate protein-2, is a key mediator of insulin signaling. It is also involved in regulating other signaling pathways, such as the PI3K/AKT pathway, and is essential for maintaining various biological functions [1,3,7,10]. It plays a significant role in processes like glucose homeostasis, cell growth, and differentiation, making it crucial for normal physiological function. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in understanding its functions.

In murine models, cardiomyocyte-restricted deletion of Irs2 (cIRS2-KO) makes the hearts more susceptible to stress-induced cardiac dysfunction and arrhythmias. The underlying mechanism involves overactivation of the AKT1/NOS3/CaMKII/RyR2 signaling pathway, leading to calcium mishandling [1]. Male mice lacking Irs2 (Irs2-/-/6J) show hippocampus-associated behavioral alterations, along with aberrant changes in energy and nutrient sensors and reduced core body temperature [2]. In pancreatic beta-cells, IRS2 is important for regulating the functional beta-cell mass, as overexpression in isolated islets can induce beta-cell proliferation and protect against apoptosis [3]. In female mouse reproductive organs, IRS2 expression changes during the estrous cycle, being greatest during estrus [4]. Irs2-deficient mice also display retinal neurodegenerative changes, with increased aromatase immunopositivity potentially as a repair mechanism [5]. In bovine and goat mammary epithelial cells, miR-200a and miR-181b respectively target IRS2, affecting milk fat metabolism [6,7]. In oesophageal cancer, YAP-TEAD up-regulates IRS2 expression to promote cancer progression [8]. In small cell lung cancer, IRS2 amplification may serve as a predictive biomarker for response to ceritinib [9]. In mouse granulosa cells, IRS2 knockdown inhibits cell proliferation, decreases hormone secretion, and affects folliculogenesis via the PI3K/AKT signaling pathway [10].

In conclusion, Irs2 is essential for maintaining normal physiological functions in multiple organ systems. Studies using KO and CKO mouse models have revealed its crucial roles in cardiac function, cognitive behavior, glucose homeostasis, reproduction, and cancer development. These findings provide valuable insights into the biological functions of Irs2 and potential therapeutic targets for related diseases.