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FXR/ASS1 axis attenuates the TAA-induced liver injury through arginine metabolism

Previous studies demonstrated that arginine biosynthesis was frequently impaired in acute liver injury. However, the underlying mechanisms remain elusive. In this study, we found that Argininosuccinate synthetase 1 (ASS1), a rate-limiting enzyme in arginine metabolism, was downregulated in the TAA-induced liver injury model. Single-cell RNA-seq data found that ASS1 was highly enriched in the hepatocytes. The reduction of ASS1 was attributed to the decreased expression of Farnesoid X receptor (FXR), which is a bile acid-activated nuclear hormone receptor with high expression in the liver. Subsequent studies demonstrated that activation of FXR by its agonist obeticholic acid (OCA) directly promoted ASS1 transcription and enhanced arginine synthesis, leading to the alleviation of TAA-mediated liver injury. Further experiments found that OCA, ASS1, and arginine supplement can rescue TAA-mediated hepatocytes apoptosis by decreasing the protein levels of Cyto C, PARP, and Caspase 3. Taken together, our study illustrated a protective role of the FXR/ASS1 axis in TAA-induced liver injury by targeting arginine metabolism, which might shed light on the development of novel therapeutic approaches for acute liver injury.

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S7754 Gilteritinib (ASP2215) Gilteritinib (ASP2215) is a small-molecule FLT3/AXL inhibitor with IC50 values of 0.29 nM and 0.73 nM for FLT3 and AXL, respectively. It inhibits FLT3 at an IC50 value that was approximately 800-fold more potent than the concentration required to inhibit c-KIT (230 nM).

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FLT3 Axl