huMTARC1/huMTARC2 Mouse

MTARC1 and MTARC2 encode the mitochondrial amidoxime-reducing components 1 and 2 (mARC1/mARC2), two paralogous molybdenum-containing enzymes anchored to the outer mitochondrial membrane that form a three-component system with cytochrome b5 (CYB5B) and NADH-cytochrome b5 reductase 3 (CYB5R3) to catalyze the reduction of N-oxygenated compounds ^[1]. These genes are widely expressed, with particularly high levels in liver hepatocytes, as well as in other tissues like adipose and various fetal/adult organs; the encoded proteins function primarily in N-reduction of substrates including amidoximes (for prodrug activation), nitrite, Nω-hydroxy-L-arginine (NOHA), N-hydroxyurea, and hydrogen peroxide, contributing to detoxification, nitric oxide homeostasis, lipid metabolism regulation, and mitochondrial redox balance ^[2-3]. MTARC1 has gained significant attention due to a common protective missense variant (p.A165T) strongly associated with reduced liver fat, lower plasma lipids and liver enzymes (e.g., ALT), decreased risk of metabolic dysfunction-associated steatotic liver disease (MASLD/MASH), all-cause cirrhosis, and liver-related mortality; genetic and experimental knockdown of MTARC1 in hepatocytes reduces steatosis, fibrosis, and inflammation in mouse models, positioning mARC1 inhibition (e.g., via liver-specific siRNA) as a promising therapeutic strategy for MASH ^[4-5]. MTARC2 shares overlapping substrate specificities and roles but appears less central to the liver disease associations compared to MTARC1 ^[6].

The huMTARC1/huMTARC2 mouse is a dual-gene humanized model generated via gene editing. The sequences from upstream of exon 1 of the mouse Mtarc2 gene to downstream of exon 7 of the mouse Mtarc1 gene were replaced with the sequences from upstream of exon 1 of the human MTARC2 gene to downstream of exon 7 of the human MTARC1 gene. This model is applicable for evaluating drug efficacy in MASLD/MASH, elucidating mechanisms of hepatic lipid metabolism, conducting PK/PD and reductase activity studies, and facilitating the development of MTARC1/MTARC2-targeted therapeutics.