To identify the pathway through which SIRT6 exerts its therapeutic effects in reducing cholestasis, we used N-acetylcysteine (NAC), KEAP1-NRF2-IN-1 (KNI-1), acadesine (AICAR), or adeno-associated virus to knock down Cyp7a1 to treat hepatic Sirt6-deficient mice. Here, CYP7A1 is linked to cholestasis.