ArticleActa pharmaceutica Sinica. B2023
SIRT1 activation synergizes with FXR agonism in hepatoprotection
Article in Acta pharmaceutica Sinica. B, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- Intestinal FXR agonism synergizes with leptin to improve obesity by reducing appetite via secretin.EMBO reports · 2026Article
- The Bile Acid Signaling Axis: Deciphering the Roles of FXR and TGR5 in Hepatic Steatosis, Fibrosis, and Cancer.Pharmacology research & perspectives · 2026Review
- Epigenetic regulation and posttranslational modifications of FXR: underlying mechanisms and implications in digestive diseases.Acta pharmacologica Sinica · 2026Review
- Integrated transcriptomic analysis and machine learning identify immunogenic cell death genes as prognostic markers and therapeutic targets in non-small cell lung cancer.Translational cancer research · 2026Article
- FXR in bone metabolism: An emerging regulator.iScience · 2026Review
- Comprehensive analysis of the TGF-β signaling pathway: molecular mechanisms, disease drivers, and frontiers in clinical translation.Frontiers in immunology · 2026Review
- Association between the subcellular localization of host proteins and gut microbiome and metabolome in metabolic dysfunction-associated steatotic liver disease: a pilot study.Frontiers in molecular biosciences · 2026Article
- The Role of Hepatic SIRT1: From Metabolic Regulation to Immune Modulation and Multi-target Therapeutic Strategies.Journal of clinical and translational hepatology · 2025Review
- Natural small molecule hinokitone mitigates NASH fibrosis by targeting regulation of FXR-mediated hepatocyte apoptosis.Journal of advanced research · 2025Article
- Novel insights into bexarotene's role in preventing cholestasis: mechanisms and implications.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Ultrasound-driven ROS-scavenging nanobubbles for synergistic NASH treatment via FXR activation.Ultrasonics sonochemistry · 2025Article
- Crosstalk Between Bile Acids and Intestinal Epithelium: Multidimensional Roles of Farnesoid X Receptor and Takeda G Protein Receptor 5.International journal of molecular sciences · 2025Review
- Diabetes-associated sleep fragmentation impairs liver and heart functionActa pharmaceutica Sinica. B · 2025Article
- Article
- Hepatoprotective Effects of Cilnidipine in Cholestatic Liver Disease: Role of FXR and NRF2 Signalling.Journal of experimental pharmacology · 2025Article
- Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation.Hepatology international · 2024Article
- SIRT1 and thrombosis.Frontiers in molecular biosciences · 2023Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.