Selective CYP8B1 inhibitors reshape bile acids in fatty liver mice
- Researchers targeted CYP8B1, a liver-specific enzyme making 12-hydroxylated bile acids, because selectivity over other CYPs has been hard to achieve.
- A sensitive enzyme-coupled fluorescence screen, combined with crystal-structure-guided design and SAR, yielded selective small-molecule inhibitors.
- In a MASLD mouse model the lead compound shifted bile acid composition, improved the gut microbiota and corrected metabolic disease, supporting a first-in-class approach.
💡 Points
Bile acid shifts can travel with a metabolic benefit without causing it, so I'd look for a knockout comparison before trusting the mechanism. Mouse bile acid pools also differ from ours, which means this model may flatter the human case. The selectivity panel and liver exposure behind the efficacy are the other things to ask for.
Development of CYP8B1-specific inhibitors for metabolic diseases ↗