Irgm1, the mouse orthologue of human IRGM (Immunity-related GTPase family M protein), is a GTPase that plays crucial roles in processes like autophagy, mitophagy, and immune-related responses. It is associated with pathways such as the cGAS-STING-dependent type I interferon pathway, MAPK signaling, and the PI3K/AKT/mTOR pathway. Its functions are vital for maintaining normal cellular homeostasis, host defense, and are linked to various diseases [1-10].

In gene-knockout (KO) mouse models, Irgm1 deficiency leads to multiple phenotypes. Mice lacking Irgm1 exhibit a type I interferonopathy with autoimmune features, impaired mitophagy, and tissue-selective autoimmune pathologies, suggesting a connection between mitochondrial quality control and autoimmunity [1]. Irgm1+/- mice show increased atherosclerotic plaque stability due to inhibited macrophage apoptosis via reduced ROS generation and MAPK signaling [2]. In ulcerative colitis, berberine's anti-inflammatory effect is related to its targeting of Irgm1, reducing its overexpression and blocking the PI3K/AKT/mTOR pathway [3]. T cell-specific KO of Irgm1 causes changes in T cell numbers, function, metabolism, and increased apoptosis [4]. In acute liver failure, Irgm1 knockdown decreases autophagy and upregulates NLRP3 inflammasome activation [5]. Irgm1 knockdown in early-atherosclerotic mice reduces plaque burden by promoting lymphangiogenesis through LEC autophagy [6]. Also, Irgm1-deficient mice have a longer occlusion time and lower growth rate in thrombosis models, with inhibited neutrophil-platelet interactions [7]. Irgm1 knockout in mice indirectly inhibits skeletal muscle regeneration after injury due to a high interferon-gamma microenvironment [8].

In conclusion, Irgm1 is essential for processes like autophagy, mitophagy, and immune responses. KO and CKO mouse models have revealed its significance in autoimmune diseases, atherosclerosis, ulcerative colitis, liver failure, thrombosis, and muscle regeneration. Understanding Irgm1's functions through these models provides insights into disease mechanisms and potential therapeutic targets.