Farnesoid X receptor (FXR) is widely accepted as a promising target for various liver diseases; however, panels of ligands in drug development show limited clinical benefits, without a clear mechanism. Here, we reveal that acetylation initiates and orchestrates FXR nucleocytoplasmic shuttling and then enhances degradation by the cytosolic E3 ligase CHIP under conditions of liver injury, which represents the major culprit that limits the clinical benefits of FXR agonists against liver diseases. Upon inflammatory and apoptotic stimulation, enhanced FXR acetylation at K217, closed to the nuclear location signal, blocks its recognition by importin KPNA3, thereby preventing its nuclear import. Concomitantly, reduced phosphorylation at T442 within the nuclear export signals promotes its recognition by exportin CRM1, and thereby facilitating FXR export to the cytosol. Acetylation governs nucleocytoplasmic shuttling of FXR, resulting in enhanced cytosolic retention of FXR that is amenable to degradation by CHIP. SIRT1 activators reduce FXR acetylation and prevent its cytosolic degradation. More importantly, SIRT1 activators synergize with FXR agonists in combating acute and chronic liver injuries. In conclusion, these findings innovate a promising strategy to develop therapeutics against liver diseases by combining SIRT1 activators and FXR agonists.

法尼醇 X 受体 (FXR) 被广泛认为是各种肝病的有希望的靶点；然而，药物开发中的配体组显示出有限的临床益处，且没有明确的机制。在这里，我们发现乙酰化启动并协调 FXR 核质穿梭，然后在肝损伤条件下增强胞质 E3 连接酶 CHIP 的降解，这是限制 FXR 激动剂对肝病临床益处的主要原因。在炎症和细胞凋亡刺激下，K217 处增强的 FXR 乙酰化，接近核定位信号，阻止其被 importin KPNA3 识别，从而阻止其核输入。同时，核输出信号中 T442 磷酸化的减少促进了输出 CRM1 对它的识别，从而促进 FXR 输出到胞质溶胶。乙酰化控制 FXR 的核质穿梭，导致 FXR 的细胞溶质保留增强，易于被 CHIP 降解。SIRT1 激活剂可减少 FXR 乙酰化并防止其胞质降解。更重要的是，SIRT1 激活剂与 FXR 激动剂协同对抗急性和慢性肝损伤。总之，这些发现创新了一种有前途的策略，通过结合 SIRT1 激活剂和 FXR 激动剂来开发针对肝病的疗法。SIRT1 激活剂与 FXR 激动剂协同对抗急性和慢性肝损伤。总之，这些发现创新了一种有前途的策略，通过结合 SIRT1 激活剂和 FXR 激动剂来开发针对肝病的疗法。SIRT1 激活剂与 FXR 激动剂协同对抗急性和慢性肝损伤。总之，这些发现创新了一种有前途的策略，通过结合 SIRT1 激活剂和 FXR 激动剂来开发针对肝病的疗法。