Targeting the Ceramidase ACER3 Attenuates Cholestasis in Mice by Mitigating Bile Acid Overload via Unsaturated Ceramide-mediated LXRβ Signaling Transduction

In this work, we show that ACER3 expression is upregulated in cholestatic livers and positively correlates with the severity of CLI in patients. Targeting ACER3 increases CER(d18:1/18:1) in the cholestatic liver, which binds to LXRβ and activates its signaling transduction to enhance BA sulfation and restore lipogenesis. These mechanisms mitigate BA overload in hepatocytes and attenuate CLI. Our findings highlight the therapeutic potential of targeting ACER3 and CER(d18:1/18:1) to attenuate CLI.