NR1I3 (constitutive androstane receptor, CAR) is a nuclear receptor that functions as a xenosensor, regulating the transcription of drug-metabolizing enzymes and transporters in response to xenobiotic exposure 1. The receptor activates transcription of major phase I and II drug-metabolizing enzymes and drug transporters, facilitating xenobiotic elimination from the body 2. NR1I3 can be activated through both direct ligand binding and indirect mechanisms, with recent studies identifying diindole compounds produced from commensal bacterial metabolites as endogenous agonists with nanomolar affinities 3. Transactivation assays using full-length NR1I3 with native promoters can detect both direct and indirect activators, including kinase inhibitors that activate the receptor through indirect mechanisms 4. Genetic polymorphisms in NR1I3 significantly affect drug pharmacokinetics, particularly for immunosuppressants like tacrolimus, and contribute to interindividual variability in drug-drug interactions 5. Beyond xenobiotic metabolism, NR1I3 influences lipid metabolism, with genetic variants affecting triglyceride levels in a gender-specific manner 6. Recent research suggests NR1I3 also functions as a tumor suppressor in colorectal cancer by enhancing PCK1-mediated gluconeogenesis, shifting cellular metabolism from glycolysis to gluconeogenesis and inhibiting cancer cell growth 7.