Arg2, or arginase 2, is a key hydrolase in the urea cycle, hydrolyzing L-arginine to urea and L-ornithine. It is involved in multiple biological pathways, influencing processes like fatty acid oxidation, cell cycle regulation, and mitochondrial function, and has significance in various disease conditions [4]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions.

In non-alcoholic steatohepatitis (NASH), macrophage-derived osteopontin (SPP1) protects against the disease by upregulating oncostatin-M (OSM), which increases Arg2 through STAT3 signaling. The Arg2-mediated increase in fatty acid oxidation reduces steatosis [1]. In adenomyosis, Arg2 knockdown promotes G0/G1 cell cycle arrest and mitochondrial dysfunction via regulation of NF-κB and Wnt/β-catenin signaling cascades [2]. In osteoarthritis, lactate-upregulated Arg2 expression induces cellular senescence in fibroblast-like synoviocytes via activating the mTOR/S6K1 signaling pathway [3]. In contrast-induced acute kidney injury (CI-AKI), Arg2 accumulates in the tubules, facilitating nitrosative stress. ARG2 knockout mice show ameliorated kidney dysfunction, tubular injury, decreased nitrosative stress and apoptosis [5]. In palmitic acid-induced hepatic insulin resistance, ETNPPL impairs autophagy through regulation of the ARG2-ROS signaling axis [6]. In advanced atherosclerosis, ARG2 impairs endothelial autophagy through regulation of MTOR and PRKAA/AMPK signaling [7]. In obese murine models, hepatocyte-specific Arg2 overexpression protects from weight gain, insulin resistance, and hepatic steatosis, while Arg2 suppresses the expression of RGS16 [8].

In conclusion, Arg2 plays essential roles in multiple biological processes, with its dysregulation contributing to various diseases including NASH, adenomyosis, osteoarthritis, CI-AKI, hepatic insulin resistance, atherosclerosis, and obesity-related complications. Studies using KO/CKO mouse models have been crucial in uncovering these disease-related functions of Arg2, providing insights into potential therapeutic targets.