The synthesis and bioactivities of ROCK2 inhibitors with 1,2-dithiolan-3-yl motif.

Rho-associated coiled-coil containing kinase (ROCK) plays an important role in inflammation. Herein, a series of compounds were designed and synthesized as ROCK inhibitors based on the structure-based drug design (SBDD) strategy and were evaluated for cytotoxicity, antioxidant activity and anti-inflammatory activity. Among them, compound DC24 was identified as the optimal hit in enzymatic screening with an IC50 value of 0.124 µM against ROCK2 and 50-fold selectivity over ROCK1. DC24 has a novel lipid amide scaffold with a bis(4-fluorophenyl)methyl substituent, and DC24 is the first ROCK2 inhibitor interacting with the hinge region of ROCK2 via the 1,2-dithiolan-3-yl motif, which has been confirmed by the binding model of DC24 with ROCK2. In a complete Freund's adjuvant (CFA) induced acute inflammation model, DC24 at a dose of 5 mg kg-1 exhibited an anti-inflammatory effect better than that of belumosudil. Furthermore, DC24 exhibits good safety in vivo.

The preliminary study of delta checks for immunoglobulins and complements in the clinical laboratory.

BACKGROUND: To determine delta check limits for immunoglobulins and complements in outpatients and inpatients based on patient data and biological variation due to the lack of relevant studies. METHODS: Patient data for IgA, IgG, IgM, IgE, C3, and C4 from 1 January 2022 to 31 December 2023 was collected from laboratory information system (LIS) in our clinical laboratory of Wuhan Union Hospital, which includes both outpatients and inpatients. The delta difference (DD), delta percent change (DPC), and reference change value (RCV) were calculated based on patient data and biological variation. RESULTS: For DDs, there are significant differences between outpatients and inpatients in C4, IgE, IgG, and IgM. For DPCs, the corresponding analytes which are significantly different are C3, C4, IgE, IgG, and IgM. Two sources of CVI to calculate the RCV of IgA, IgG, IgM, C3, and C4 were applied in this study, which revealed that two kinds of RCVs based on different biological variation databases are similar to each other, but both were smaller than delta check limits based on patient data, except for C4. CONCLUSIONS: The delta check is a useful tool to monitor potential errors which may occur in total testing process. We hope our findings could be helpful for future studies focused on delta checks in immunological analytes.

Roles of TRIM21/Ro52 in connective tissue disease-associated interstitial lung diseases.

Multiple factors contribute to the development of connective tissue diseases (CTD), often alongside a range of interstitial lung diseases (ILD), including Sjögren's syndrome-associated ILD, systemic sclerosis-associated ILD, systemic lupus erythematosus-associated ILD, idiopathic inflammatory myositis-associated ILD. TRIM21(or Ro52), an E3 ubiquitin ligase, plays a vital role in managing innate and adaptive immunity, and maintaining cellular homeostasis, and is a focal target for autoantibodies in various rheumatic autoimmune diseases. However, the effectiveness of anti-TRIM21 antibodies in diagnosing CTD remains a matter of debate because of their non-specific nature. Recent studies indicate that TRIM21 and its autoantibody are involved in the pathogenesis of CTD-ILD and play an important role in diagnosis and prognosis. In this review, we focus on the contribution of TRIM21 in the pathogenesis of CTD-ILD, as well as the potential diagnostic value of its autoantibodies in different types of CTD-ILD for disease progression and potential as a novel therapeutic target.

Mdka produced by the activated HSCs drives bipotential progenitor cell redifferentiation during zebrafish biliary-mediated liver regeneration.

BACKGROUND AND AIMS: After extensive hepatocyte loss or impaired hepatocyte proliferation, liver regeneration occurs through trans-differentiation of biliary epithelial cells (BECs), which involves dedifferentiation of biliary epithelial cells into bipotential progenitor cells (BP-PCs) and subsequent redifferentiation of BP-PCs into nascent hepatocytes and biliary epithelial cells. Despite several studies on the redifferentiation process of BP-PCs into nascent hepatocytes, the contributions of nonparenchymal cells in this process remain poorly understood. APPROACH AND RESULTS: Using the zebrafish severe liver injury model, we observed specific expression of midkine a (Mdka) in the activated HSCs through single-cell analyses and fluorescence in situ hybridization. Genetic mutation, pharmacological inhibition, whole-mount in situ hybridizations, and antibody staining demonstrated an essential role of mdka in the redifferentiation of BP-PCs during liver regeneration. Notably, we identified Nucleolin (Ncl), the potential receptor for Mdka, specifically expressed in BP-PCs, and its mutant recapitulated the mdka mutant phenotypes with impaired BP-PC redifferentiation. Mechanistically, the Mdka-Ncl axis drove Erk1 activation in BP-PCs during liver regeneration. Furthermore, overexpression of activated Erk1 partially rescued the defective liver regeneration in the mdka mutant. CONCLUSIONS: The activated HSCs produce Mdka to drive the redifferentiation process of BP-PCs through activating Erk1 during the biliary-mediated liver regeneration, implying previously unappreciated contributions of nonparenchymal cells to this regeneration process.

Cholecystopleural fistula: A case report and literature review.

INTRODUCTION: Gallstone with acute cholecystitis is one of the most common diseases in the clinic. If the disease is serious, gallbladder gangrene, perforation, and sepsis may be caused. Gallbladder diseases rarely cause thoracic-related complications, especially pleural fistula, which is very rare in clinical practice. PATIENT CONCERNS: A 52-year-old male patient was admitted to the emergency department for 1 month with recurrent right middle and upper abdominal pain. DIAGNOSIS: Computed tomography diagnosis: cholecystitis and peri-inflammation, small abscess around the base of the gallbladder, local peritonitis, and bilateral pleural effusion. INTERVENTIONS: After admission, conservative treatment was given. On the 4th day of admission, the symptoms worsened, and an emergency catheter drainage was performed on the right thoracic cavity to extract 900 mL of dark yellow effusion. After the operation, a large amount of bili-like fluid was continuously drained from the thoracic drainage tube. After the iatrogenic biliary fistula caused by thoracic puncture was excluded, cholecystopleural fistula was considered to be cholecystopleural fistula. On the 6th day of admission, endoscopic retrograde cholangiopancreatography (ERCP) + cholecystography + Oddi sphincterotomy + laminating biliary stent was performed in the emergency department, and cholecystopleural fistula was confirmed during the operation. OUTCOMES: The patient recovered well after surgery, computed tomography examination on the 20th day after surgery indicated that pleural effusion was significantly reduced, and the patient was cured and discharged. The patient returned to the hospital 8 months after the ERCP operation to pull out the bile duct-covered stent. The patient did not complain of any discomfort after the postoperative follow-up for 3 years, and no recurrence of stones, empyema, and other conditions was found. CONCLUSION: Cholecystopleural fistula is one of the serious complications of acute cholecystitis, which is easy to misdiagnose clinically. If the gallbladder inflammation is severe, accompanied by pleural effusion, the pleural effusion is bili-like liquid, or the content of bilirubin is abnormally elevated, the existence of the disease should be considered. Once the diagnosis is clear, active surgical intervention is needed to reduce the occurrence of complications. Endoscopic therapy (ERCP) can be used as both a diagnostic method and an important minimally invasive treatment.

mTORC1 mediates the expansion of hematopoietic stem and progenitor cells through ribosome biogenesis protein Urb2 in zebrafish.

Mammalian target of rapamycin (mTOR) serves as the key sensor to control protein synthesis, cell growth, and survival. Despite mTOR is reported to regulate hematopoietic stem and progenitor cell (HSPC) engraftment and multiple-lineage hematopoiesis in mice, the roles of unique mTOR complexes (mTORCs) in early HSPC development and HSPC pool formation have not been adequately elucidated. Here, we uncover that mTORC1 is essential for early HSPC expansion in zebrafish. mTORC1 signaling was highly activated in definitive HSPCs during the emerging and expanding stages. Pharmacological or genetic inactivation of mTORC1 would cause defective HSPC expansion and migration due to disrupted cell proliferation. Interestingly, mTORC2 is dispensable for early HSPC development. Ribosome biogenesis protein Urb2 was downregulated upon mTORC1 inhibition, and urb2 overexpression partially rescued the hematopoietic defects in mTORC1-deficient embryos. These data demonstrate that mTORC1 signaling regulates early HSPC expansion through Urb2, and this work will deepen our understanding of mTOR in different physiological processes.

The oncogenic kinase TOPK upregulates in psoriatic keratinocytes and contributes to psoriasis progression by regulating neutrophils infiltration.

BACKGROUND: T-LAK cell-oriented protein kinase (TOPK) strongly promotes the malignant proliferation of cancer cells and is recognized as a promising biomarker of tumor progression. Psoriasis is a common inflammatory skin disease featured by excessive proliferation of keratinocytes. Although we have previously reported that topically inhibiting TOPK suppressed psoriatic manifestations in psoriasis-like model mice, the exact role of TOPK in psoriatic inflammation and the underlying mechanism remains elusive. METHODS: GEO datasets were analyzed to investigate the association of TOPK with psoriasis. Skin immunohistochemical (IHC) staining was performed to clarify the major cells expressing TOPK. TOPK conditional knockout (cko) mice were used to investigate the role of TOPK-specific deletion in IMQ-induced psoriasis-like dermatitis in mice. Flow cytometry was used to analyze the alteration of psoriasis-related immune cells in the lesional skin. Next, the M5-induced psoriasis cell model was used to identify the potential mechanism by RNA-seq, RT-RCR, and western blotting. Finally, the neutrophil-neutralizing antibody was used to confirm the relationship between TOPK and neutrophils in psoriasis-like dermatitis in mice. RESULTS: We found that TOPK levels were strongly associated with the progression of psoriasis. TOPK was predominantly increased in the epidermal keratinocytes of psoriatic lesions, and conditional knockout of TOPK in keratinocytes suppressed neutrophils infiltration and attenuated psoriatic inflammation. Neutrophils deletion by neutralizing antibody greatly diminished the suppressive effect of TOPK cko in psoriasis-like dermatitis in mice. In addition, topical application of TOPK inhibitor OTS514 effectively attenuated already-established psoriasis-like dermatitis in mice. Mechanismly, RNA-seq revealed that TOPK regulated the expression of some genes in the IL-17 signaling pathway, such as neutrophils chemokines CXCL1, CXCL2, and CXCL8. TOPK modulated the expression of neutrophils chemokines via activating transcription factors STAT3 and NF-κB p65 in keratinocytes, thereby promoting neutrophils infiltration and psoriasis progression. CONCLUSIONS: This study identified a crucial role of TOPK in psoriasis by regulating neutrophils infiltration, providing new insights into the pathogenesis of psoriasis.

Design and Synthesis of sEH/HDAC6 Dual-Targeting Inhibitors for the Treatment of Inflammatory Pain.

Soluble epoxide hydrolase (sEH) and HDAC6 mediate the NF-κB pathway in inflammatory responses, and their inhibitors exhibit powerful anti-inflammatory and analgesic activities in treating both inflammation and pain. Therefore, a series of dual-targeting inhibitors containing urea or squaramide and hydroxamic acid moieties were designed and synthesized, and their role as a new sEH/HDAC6 dual-targeting inhibitor in inflammatory pain was evaluated in a formalin-induced mice model and a xylene-induced mouse ear swelling model. Among them, compounds 28g and 28j showed the best inhibitory and selectivity of sEH and HDAC6. Compound 28g had satisfactory pharmacokinetic characteristics in rats. Following administration at 30 mg/kg, compound 28g exhibited more effective analgesic activity than either an sEH inhibitor (GL-B437) or an HDAC6 inhibitor (Rocilinostat) alone and coadministration of both inhibitors. Thus, these novel sEH/HDAC6 dual-targeting inhibitors exhibited powerful analgesic activity in nociceptive behavior and are worthy of further development.

VASE: A High-Entropy Alloy Short-Range Order Structural Descriptor for Machine Learning.

The short-range order (SRO) structure in high-entropy alloys (HEAs) is closely associated with many properties, which can be studied through density functional theory (DFT) calculations. Atomic-scale modeling and calculations require substantial computational resources, and machine learning can provide rapid estimations of DFT results. To describe SRO information in HEAs, a new descriptor based on Voronoi Analysis and Shannon Entropy (VASE) is proposed. Based on Voronoi analysis, the Shannon entropy is introduced to directly characterize atomic spatial arrangement information except for composition and atomic interactions, which is necessary for describing the disorder atomic occupancy in HEAs. The new descriptor is used for predicting the formation energy of FeCoNiAlTiCu system based on machine learning model, which is more accurate than other descriptors (Coulomb matrices, partial radial distribution functions, and Voronoi analysis). Moreover, the model trained based on VASE descriptors exhibits the best predictive performance for unrelaxed structures (24.06 meV/atom). The introduction of Shannon entropy provides an effective representation of atomic arrangement information in HEAs, which is a powerful tool for investigating the SRO phenomena.

Synthesis and evaluation of L-quebrachitol derivatives against platelet aggregation.

Thrombosis plays an important role in the occurrence and development of cardiovascular and cerebrovascular diseases that contribute to high mortality and morbidity in patients. L-(-)-Quebrachitol (QCT), a natural product, was first isolated from quebracho bark. It can inhibit PAF receptor and decrease gastric damage induced by indomethacin, as a drug against platelet aggregation. Here, five QCT derivatives were synthesized and investigated for their inhibitory effects on platelet aggregation. Among them, compound 3a showed anticoagulant effects comparable to aspirin, while compound 4b showed dose-independent inhibitory activities in rats that were stronger than aspirin.

Higher serum Lp-PLA2 is associated with cognitive impairment in Parkinson's disease patients.

Objective: To explore the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cognitive impairment in Parkinson's disease (PD-CI). Methods: A case-control study involving 100 hospitalized PD patients and 60 healthy controls was carried out. Serum Lp-PLA2 level was detected by automatic biochemical analyzer. Based on whether Parkinson's patients have cognitive impairment, PD patients were subdivided to analyze the clinical value of Lp-PLA2. Relationship between Lp-PLA2 and PD-CI risk was analyzed by logistic regression. Diagnostic value of Lp-PLA2 in PD-CI patients was investigated using receiver's operator characteristic curves. Results: The levels of serum Lp-PLA2 activity in Parkinson's disease with normal cognition (PD-NC) and PD-CI patients were significantly higher than those in healthy controls (HCs), respectively. Furthermore, compared to the PD-NC group, the serum Lp-PLA2 activity level was significantly higher in PD-CI patients. Multivariable logistic regression analysis indicated that higher Lp-PLA2 level was an independent risk factor for PD patients with cognitive impairment. Moreover, the area under the efficacy curve of Lp-PLA2 for predicting PD-CI is 0.659. Conclusion: Our study shows that higher levels of Lp-PLA2 activity in PD patients are associated with the risk of developing cognitive impairment. Therefore, given the wide availability, safety, and convenience of monitoring serum Lp-PLA2 activity, it may serve as an early biomarker for cognitive impairment in PD patients.

The prognostic value of Forkhead box P3 regulatory T cells in biliary tract cancer: A systematic review and meta-analysis.

BACKGROUND: This study aimed to explore the value of tumor-infiltrating Forkhead box P3(FoxP3+) regulatory T cells (Tregs) in evaluating the prognosis of biliary tract cancer. METHODS: Four electronic databases were searched using 2 computers: PubMed, Embase, Web of Science, and Cochrane Library. The vocabulary and syntax were adapted according to the database. Two researchers independently selected the studies, collected information, and assessed the risk of bias. The Meta-analysis was performed using STATA 17.0, and HR and its corresponding 95% CI were used to evaluate the correlation between FoxP3+ Tregs and the overall survival of patients with biliary tract cancer. In addition, the quality of the included studies was evaluated. RESULTS: Ten articles were included in this study. The results of the meta-analysis showed that patients with high FoxP3+ Tregs infiltration had worse overall survival (OS) (HR = 1.34,95% CI 1.16 to 1.71; P < .001). Subgroup analysis of gallbladder carcinoma and cholangiocarcinoma showed that the high infiltration of FoxP3+ Tregs was significantly correlated with the OS of the former (HR = 1.55,95% CI 1.11 to 2.00; P < .001), but not with the OS of the latter (HR = 1.00,95% CI 0.62 to 1.38; P > .05). CONCLUSIONS: Our meta-analysis reveals that high infiltration of FoxP3 + Tregs is significantly associated with reduced overall survival in gallbladder carcinoma, endorsing their use as a prognostic biomarker for this subtype. In contrast, no significant prognostic correlation was identified for FoxP3+ Tregs in cholangiocarcinoma, indicating the need for subtype-specific evaluation of their prognostic relevance in biliary tract cancers.

VEGF signaling governs the initiation of biliary-mediated liver regeneration through the PI3K-mTORC1 axis.

Biliary epithelial cells (BECs) are a potential source to repair the damaged liver when hepatocyte proliferation is compromised. Promotion of BEC-to-hepatocyte transdifferentiation could be beneficial to the clinical therapeutics of patients with end-stage liver diseases. However, mechanisms underlying the initiation of BEC transdifferentiation remain largely unknown. Here, we show that upon extreme hepatocyte injury, vegfaa and vegfr2/kdrl are notably induced in hepatic stellate cells and BECs, respectively. Pharmacological and genetic inactivation of vascular endothelial growth factor (VEGF) signaling would disrupt BEC dedifferentiation and proliferation, thus restraining hepatocyte regeneration. Mechanically, VEGF signaling regulates the activation of the PI3K-mammalian target of rapamycin complex 1 (mTORC1) axis, which is essential for BEC-to-hepatocyte transdifferentiation. In mice, VEGF signaling exerts conserved roles in oval cell activation and BEC-to-hepatocyte differentiation. Taken together, this study shows VEGF signaling as an initiator of biliary-mediated liver regeneration through activating the PI3K-mTORC1 axis. Modulation of VEGF signaling in BECs could be a therapeutic approach for patients with end-stage liver diseases.

Utilizing the Intrinsic Mode of Weakly Coupled Resonators for Temperature Compensation.

Accelerometers based on outputting amplitude ratios in weakly coupled resonators (WCRs) are attractive because their parametric sensitivity is higher by two or three orders of magnitudes than those based on outputting frequency. However, the impact of temperature on the coupler is a key factor in accelerometer applications. This paper proposed a novel mode-localized WCR accelerometer with a temperature compensation mechanism, with sensitive elements incorporating a double-ended tuning fork (DETF) resonator, clamped-clamped (CC) resonator, and a micro-lever coupler. The DETF out-of-phase mode is utilized, which is only sensitive to temperature, to measure the temperature change of WCRs and complete the temperature compensation using the compensation algorithm. This proposed method has no time delay in measuring the temperature of sensitive elements and no temperature difference caused by the uneven temperature field. The parametric sensitivity in amplitude ratio (AR) to acceleration drifting with temperature was theoretically analyzed, and the novel device was designed and fabricated by a silicon-on-glass process. Both simulation and experiment results demonstrated that the coupling stiffness drifted with temperature, which resulted in the drifts of its sensitivity to acceleration and zero-bias stability. Using the intrinsic mode of WCRs, in terms of the DETF out-of-phase mode, as an in situ thermometer and carrying out the temperature compensation algorithm, the drift of zero bias could be suppressed from 102 mg to 4.5 mg (g is the gravity acceleration), and the drift of the parameter sensitivity in AR was suppressed from 0.74 AR/g to 0.02 AR/g with the temperature range from 330 K to 370 K and acceleration range from 0 g to 0.2 g.

Effect of local coordination on catalytic activities and selectivities of Fe-based catalysts for N2 reduction.

Electrochemical reduction of nitrogen is considered a promising route for achieving green and sustainable ammonia synthesis under ambient conditions. A transition metal atom loaded on N-doped graphene is commonly used in the nitrogen reduction reaction (NRR), but the effect of the graphene's coordination environment on electron transfer has rarely been studied. Herein, the NRR performance of Fe1/2/3 clusters, anchored on single-vacancy and N-doped graphene, is investigated systematically via density functional theory (DFT). The calculation results show that the Fe2 cluster supported by two N atom-modified single-vacancy graphene displays the highest catalytic performance of NRR with the lowest energy barrier of 0.62 eV among the 12 candidates, and exhibits efficient selectivity. It has superior performance because of the highly asymmetrical distribution of electrons on graphene, the large positive charge of the Fe2, and the strong adsorption of *NNH. This study provides a new strategy to improve the NRR performance by regulating the Fe1/2/3 clusters coordination environment.

Dynamic analysis of serum MMP-7 and its relationship with disease progression in biliary atresia: a multicenter prospective study.

PURPOSE: We aimed to assess the dynamic changing trend of serum matrix metalloproteinase-7 (MMP-7) in biliary atresia (BA) patients from diagnosis to LTx to further elucidate its clinical value in diagnosis and prognoses and its relationship with disease progression. METHODS: In this multicentre prospective study, 440 cholestasis patients (direct bilirubin level of > 17 µmol/L) were enrolled. Serum MMP-7 levels were measured using an enzyme-linked immunosorbent assay at diagnosis, 1 week, 2 weeks, 1 month, 6 weeks, 2 months, 3 months, 6 months and then every 6 months post-KPE. The medical record at each follow-up visit for post-Kasai portoenterostomy patient was collected and analyzed. RESULTS: Using a cut-off value of > 26.73 ng/mL, serum MMP-7 had an AUC of 0.954 in BA neonates and 0.983 in BA infants. A genetic mutation (G137D) was associated with low MMP-7 levels in serum of BA patients. MMP-7 showed a mediation effect on the association between inflammation and liver fibrosis in BA patients. Four dynamic patterns of serum MMP-7 post-KPE were associated with prognosis. Serum MMP-7 was the only significant predictor at 6 weeks post-KPE and the most accurate predictor at 3 months post-KPE of survival with the native liver in 2 years. CONCLUSION: As one of the critical factors associated with BA occurrence and progression, serum MMP-7 can be used for early diagnosis of BA and post-KPE MMP-7 level is the earliest prognostic biomarker so far.

An Evaluation of MEMS-IMU Performance on the Absolute Trajectory Error of Visual-Inertial Navigation System.

Nowadays, accurate and robust localization is preliminary for achieving a high autonomy for robots and emerging applications. More and more, sensors are fused to guarantee these requirements. A lot of related work has been developed, such as visual-inertial odometry (VIO). In this research, benefiting from the complementary sensing capabilities of IMU and cameras, many problems have been solved. However, few of them pay attention to the impact of different performance IMU on the accuracy of sensor fusion. When faced with actual scenarios, especially in the case of massive hardware deployment, there is the question of how to choose an IMU appropriately? In this paper, we chose six representative IMUs with different performances from consumer-grade to tactical grade for exploring. According to the final performance of VIO based on different IMUs in different scenarios, we analyzed the absolute trajectory error of Visual-Inertial Systems (VINS_Fusion). The assistance of IMU can improve the accuracy of multi-sensor fusion, but the improvement of fusion accuracy with different grade MEMS-IMU is not very significant in the eight experimental scenarios; the consumer-grade IMU can also have an excellent result. In addition, the IMU with low noise is more versatile and stable in various scenarios. The results build the route for the development of Inertial Navigation System (INS) fusion with visual odometry and at the same time, provide a guideline for the selection of IMU.

A Novel Self-Temperature Compensation Method for Mode-Localized Accelerometers.

Mode-localized sensing paradigms applied to accelerometers have recently become popular research subjects. However, the output of mode-localized accelerometers is influenced by environment temperature due to the difference in the thermal properties of the coupling resonators and the temperature dependence of coupling stiffness. To improve the performance of mode-localized accelerometers against temperature, we proposed an in situ self-temperature compensation method by utilizing the resonant frequency besides of amplitude ratios, which can be implied online. Experimental results showed that there were nearly 79-times and 87-times improvement in zeros bias and scale factor, respectively.

An Improved Difference Temperature Compensation Method for MEMS Resonant Accelerometers.

Resonant accelerometers are promising because of their wide dynamic range and long-term stability. With quasi-digital frequency output, the outputs of resonant accelerometers are less vulnerable to the noise from circuits and ambience. Differential structure is usually adopted in a resonant accelerometer to achieve higher sensitivity to acceleration and to reduce common noise at the same time. Ideally, a resonant accelerometer is only sensitive to external acceleration. However, temperature has a great impact on resonant accelerometers, causing unexcepted frequency drift. In order to cancel out the frequency drift caused by temperature change, an improved temperature compensation method for differential vibrating accelerometers without additional temperature sensors is presented in this paper. Experiment results demonstrate that the temperature sensitivity of the prototype sensor is reduced from 43.16 ppm/°C to 0.83 ppm/°C within the temperature range of -10 °C to 70 °C using the proposed method.

Farnesoid X Receptor Is Required for the Redifferentiation of Bipotential Progenitor Cells During Biliary-Mediated Zebrafish Liver Regeneration.

BACKGROUND AND AIMS: Liver regeneration after extreme hepatocyte loss occurs through transdifferentiation of biliary epithelial cells (BECs), which includes dedifferentiation of BECs into bipotential progenitor cells (BPPCs) and subsequent redifferentiation into nascent hepatocytes and BECs. Although multiple molecules and signaling pathways have been implicated to play roles in the BEC-mediated liver regeneration, mechanisms underlying the dedifferentiation-redifferentiation transition and the early phase of BPPC redifferentiation that is pivotal for both hepatocyte and BEC directions remain largely unknown. APPROACH AND RESULTS: The zebrafish extreme liver damage model, genetic mutation, pharmacological inhibition, transgenic lines, whole-mount and fluorescent in situ hybridizations and antibody staining, single-cell RNA sequencing, quantitative real-time PCR, and heat shock-inducible overexpression were used to investigate roles and mechanisms of farnesoid X receptor (FXR; encoded by nuclear receptor subfamily 1, group H, member 4 [nr1h4]) in regulating BPPC redifferentiation. The nr1h4 expression was significantly up-regulated in response to extreme liver injury. Genetic mutation or pharmacological inhibition of FXR was ineffective to BEC-to-BPPC dedifferentiation but blocked the redifferentiation of BPPCs to both hepatocytes and BECs, leading to accumulation of undifferentiated or less-differentiated BPPCs. Mechanistically, induced overexpression of extracellular signal-related kinase (ERK) 1 (encoded by mitogen-activated protein kinase 3) rescued the defective BPPC-to-hepatocyte redifferentiation in the nr1h4 mutant, and ERK1 itself was necessary for the BPPC-to-hepatocyte redifferentiation. The Notch activities in the regenerating liver of nr1h4 mutant attenuated, and induced Notch activation rescued the defective BPPC-to-BEC redifferentiation in the nr1h4 mutant. CONCLUSIONS: FXR regulates BPPC-to-hepatocyte and BPPC-to-BEC redifferentiations through ERK1 and Notch, respectively. Given recent applications of FXR agonists in the clinical trials for liver diseases, this study proposes potential underpinning mechanisms by characterizing roles of FXR in the stimulation of dedifferentiation-redifferentiation transition and BPPC redifferentiation.