Prkaa2, encoding AMP-activated protein kinase (AMPK) subunit α2, is crucial in multiple biological processes. AMPK is a key energy-sensing enzyme complex, regulating cellular energy homeostasis. It modulates various metabolic pathways like glycolysis, fatty acid oxidation, and autophagy, and is associated with important physiological functions such as energy metabolism regulation in cells and tissues [1-9].

In disease-related research, in the Asian population, variation in PRKAA2, especially at rs2746342, is associated with an increased risk of type 2 diabetes mellitus (T2DM). The G allele might be a major factor contributing to T2DM susceptibility [1]. In hypertensive disorder complicating pregnancy (HDCP), PRKAA2 expression is enhanced in placental tissues. Overexpression accelerates primary placental cell apoptosis, while knockdown attenuates it. SIRT5-mediated PRKAA2 succinylation modulates placental cell apoptosis, suggesting PRKAA2 as a potential therapeutic target for HDCP [2]. In hepatoblastoma (HB) and non-small cell lung cancer (NSCLC), PRKAA2 promotes tumor growth and inhibits ferroptosis. In HB, it regulates HIF-1α and TFR1, and in NSCLC, it activates the SLC7A11/GSH/GPX4 antioxidant pathway [3,4]. In lung adenocarcinoma, miR-186-5p can inhibit cell proliferation, migration, and invasion by promoting ferroptosis through targeting PRKAA2 [9]. In addition, in sheep and Xiangsu hybrid pigs, polymorphisms in PRKAA2 are associated with growth-related traits, and it could be used in marker-assisted selection [5,7]. In yak renal tubular epithelial cells under chronic hypoxia, PRKAA2-mediated mitophagy is crucial for reducing oxygen consumption [8]. In mice, adipocyte-specific knockdown of Prkaa2 impairs physical endurance, indicating its role in circadian metabolic coordination between fat and muscle [6].

In conclusion, Prkaa2 is a significant gene involved in energy metabolism-related biological processes and plays important roles in various diseases including T2DM, HDCP, and multiple cancers. Research on Prkaa2, especially through loss-of-function models like adipocyte-specific knockdown in mice, helps to understand its functions in different physiological and pathological conditions, providing potential targets for disease diagnosis, prognosis, and treatment.