Ddah1, or dimethylarginine dimethylaminohydrolase 1, is a crucial enzyme that degrades asymmetric NG,NG-dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS). By regulating ADMA levels, Ddah1 indirectly impacts NO production, which is involved in multiple biological processes, including neurotransmission, immune response, and metabolism [1,2,3,4,5,6,7,8,9]. Genetic models like knockout (KO) and conditional knockout (CKO) mice have been instrumental in understanding Ddah1's functions.

In KO mouse models, Ddah1 deficiency led to various adverse outcomes. In acute ischemic stroke, Ddah1-KO mice showed suppressed neurogenesis and neural repair, with reduced proliferation and neural differentiation of neural stem cells in the subgranular zone [1]. In osteoarthritis, global or chondrocyte-conditional knockout of Ddah1 accelerated disease development in mice, as ADMA, which accumulates in the absence of Ddah1, induced chondrocyte degeneration and senescence [2]. Hepatocyte-specific Ddah1-knockout mice developed more severe liver steatosis and insulin resistance compared to controls, indicating a role for Ddah1 in liver lipid metabolism [3]. Muscle-specific Ddah1-knockout mice had more severe muscle injury and delayed regeneration after cardiotoxin injection [4]. Also, Ddah1-/-mice had more severe acetaminophen-induced liver injury, associated with increased fibrosis, oxidative stress, and inflammation [6].

In conclusion, Ddah1 plays essential roles in multiple biological processes and disease conditions. The use of Ddah1 KO/CKO mouse models has significantly enhanced our understanding of its functions in areas such as stroke, osteoarthritis, liver diseases, and muscle injury. These models help reveal that Ddah1 is crucial for maintaining normal physiological functions and its deficiency can lead to the exacerbation of various diseases.