Search Results (825)

Background/Objectives: Immature watermelon (WM) rind contains higher levels of citrulline and potassium than mature fruit and may exert diuretic and metabolic benefits. This study aimed to evaluate the anti-obesity and diuretic effects of WM and salt-treated watermelon rind extract (WMS) in high-fat diet (HFD)-induced obese mice, focusing on changes in lipid metabolism, sodium handling, and tissue-level alterations. Methods: Citrulline concentrations in WM and WMS were quantified using high-performance liquid chromatography with ultraviolet detection (HPLC-UV). Four-week-old male C57BL/6 mice were fed an HFD for 6 weeks and subsequently administered WM (380 mg/kg) or WMS (380 mg/kg) orally for an additional 6 weeks. Body weight, food intake, organ and fat-pad weights, serum biochemical markers, and sodium (Na⁺) levels were measured. Histopathological analyses of liver and epididymal adipose tissue were performed to assess non-alcoholic steatohepatitis (NASH) scores and adipocyte morphology. Results: WM and WMS contained citrulline at levels substantially higher than those reported for mature watermelons. Both treatments significantly reduced body weight, liver weight, and epididymal fat mass compared with the HFD control. Serum total cholesterol and triglyceride levels were lowered in the WM- and WMS-treated groups. Serum Na⁺ concentrations increased by 43.2 ± 7.6% in WM-treated mice and 21.5 ± 6.6% in WMS-treated mice, suggesting enhanced sodium handling. Histological assessment revealed reduced NASH scores and smaller adipocyte sizes in both groups. These improvements are consistent with the known diuretic and metabolic actions of citrulline and potassium. Conclusions: WM and WMS exhibit significant anti-obesity and diuretic effects in HFD-induced obese mice. Their combined actions on sodium excretion, lipid metabolism, and adipose tissue remodeling suggest that immature watermelon rind extracts may serve as promising natural agents for preventing obesity and related metabolic dysfunction. Full article

Background: Non-alcoholic steatohepatitis (NASH) lacks approved pharmacotherapies despite affecting approximately 25% of the global population. Agrimonia pilosa, a traditional herb with anti-inflammatory and antioxidant properties, remains unexplored for NASH treatment. Objective: This study investigated the hepatoprotective effects and mechanisms of Agrimonia pilosa extract (APE) in NASH models. Methods: HepG2 cells were treated with free fatty acids (0.125 mM) and APE (+12.5–50 μg/mL). C57BL/6J mice received a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 12 weeks with APE (25–100 mg/kg/day), silymarin (100 mg/kg/day), or luteolin (20 mg/kg/day). Lipid accumulation, liver enzymes, histopathology, and molecular markers were assessed. Results: APE dose-dependently reduced lipid accumulation in FFA-treated cells, suppressed lipogenic factors (SREBF1, CEBPA, and PPARG), and upregulated fatty acid oxidation enzymes (CPT1A and PPARA) via AMPK/SIRT1 activation. In NASH mice, APE (100 mg/kg) significantly decreased serum ALT (160.0 ± 49.1 vs. 311.2 ± 66.7 U/L) and AST (96.0 ± 18.7 vs. 219.0 ± 55.7 U/L, p < 0.001), reduced hepatic macrophage infiltration by 68%, and substantially attenuated inflammatory markers (Ccl2, Tnf, and IL6), oxidative stress indicators (NRF2, HMOX1, and CYBB), and fibrogenic markers (ACTA2, COL1A1, and TGFB1) by 83–85% (p < 0.001). Collagen deposition decreased from 5.63 ± 0.39% to 1.54 ± 0.03% (p < 0.001). Conclusions: APE exerts potent hepatoprotective effects through multi-targeted modulation of lipid metabolism, inflammation, oxidative stress, and fibrosis via AMPK/SIRT1 pathway activation, supporting its potential as a natural therapeutic intervention for NASH. Full article

Background: Gut dysbiosis is implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH) caused by diets rich in advanced glycation end products (AGEs). European bilberry extract (EBE) exerts a regulatory effect on gut microbiota. Nevertheless, it is still unknown whether EBE influences NASH via gut microbiota and their metabolites. This study aimed to investigate the effects and underlying mechanisms of EBE on NASH caused by a long-term AGEs diet. Methods: Rats fed with a high-AGE diet were orally administered with EBE for 80 weeks, and NASH was measured. 16S rRNA analysis and targeted metabolomics were used to detect gut microbiota and SCFA, respectively. The hepatic expression of SCFA receptors and that of the HMGB1/RAGE/NF-κB signaling pathway were detected to investigate the possible molecular mechanism. Results: EBE reduced the accumulation of AGEs in the circulation and liver of high-AGE diet-fed rats. EBE also ameliorated impaired glucose tolerance and insulin sensitivity, liver inflammation, steatosis, fibrosis, and dysfunction in high-AGE-fed rats. EBE reshaped high-AGE diet-induced gut dysbiosis by increasing short-chain fatty acid (SCFA)-producing bacteria and SCFA levels and reducing deleterious bacteria. Mechanistically, EBE promoted the activation of GPR43 and inhibited the activation of downstream HDAC3 and HMGB1/RAGE/NF-κB signaling pathway in the liver of high-AGE diet-fed rats. Additionally, EBE decreased the levels of TNF-α, IL-1β, and IL-6 and increased the level of IL-10 in the liver of high-AGE diet-fed rats. Conclusions: EBE promoted the production of SCFA, which might engage with the GPR43 receptor and inhibited the activation of HDAC3 and HMGB1/RAGE/NF-κB signaling pathway, ultimately alleviating NASH caused by a high-AGE diet. Full article

Background/Objectives: Non-alcoholic steatohepatitis (NASH) is a progressive liver condition closely associated with gut microbial dysbiosis and hepatic metabolic abnormalities. Poria cocos polysaccharide (PCP), a bioactive component derived from the medicinal fungus Poria cocos, possesses hepatoprotective properties, yet the therapeutic mechanisms of PCP in NASH, particularly those involving microbial and metabolic regulation, remain incompletely elucidated. This study aimed to investigate the effects of PCP on improving NASH and explore its mechanisms related to prebiotic activity. Methods: Mice were induced to develop NASH using a Western diet, followed by PCP intervention for 12 weeks. Hepatic function, including liver enzymes and lipids, glucose metabolism, and liver histopathological changes, was assessed. Fatigue and neurobehavioral alterations were evaluated via rotarod, open field, and tail suspension tests. Hepatic pro-inflammatory cytokines were measured using RT-qPCR. Gut microbiota were analyzed through 16S RNA gene sequencing, and metabolites of liver tissue were analyzed through untargeted metabolomics. Results: PCP decreased blood glucose and hepatic lipid levels in NASH mice, alleviating liver inflammation, ballooning degeneration, and fibrosis. It also improved fatigue-like performance on rotarod test and reduced the hepatic expression of IL-6, IL-1β, TNF-α, and IL-18. Microbiota analysis revealed that PCP restored gut microbial diversity, promoted the growth of beneficial taxa such as Alistipes and Butyricoccaceae_UCG-009, and inhibited harmful bacteria, including Romboutsia ilealis. Liver metabolomics showed that PCP normalized key metabolites like taurocholate and regulated taurine and hypotaurine metabolism, which were correlated with reduced inflammation, fatigue-like performance, and fibrosis. Conclusions: PCP, as a promising edible agent, alleviates hepatic damage, metabolic disorders, and fatigue-like performance on rotarod test in NASH mice, probably by reshaping gut microbiota and modulating hepatic taurine and hypotaurine metabolism. Full article

Nowadays, nonalcoholic fatty liver disease (NAFLD) represents the most common cause of chronic liver disorder worldwide. From the clinical point of view, it evolves from steatosis to nonalcoholic steatohepatitis, which can lead to cirrhosis and finally to hepatocellular carcinoma. The mechanisms involved in its progression to more pathological stages and NAFLD pathogenesis are not completely understood. The research concerning NAFLD has become urgent and important because the age of NAFLD diagnosis is progressively decreasing, and its relationship with cancer risk is already well known. Because NAFLD ultimately leads to disability and imposes a major socioeconomic burden, timely diagnosis and effective treatment of NAFLD is particularly important. In the development of NAFLD, noncoding RNAs (ncRNAs) represented by microRNAs, long noncoding RNAs, circular RNAs, and piRNAs are epigenetic factors that play important regulatory roles. In the current review, we present updated information regarding the role of miRNAs, lncRNAs, circRNAs, and piRNAs, aiming to develop a good understanding of their regulatory functions in hepatic metabolism and concerning their potential use as biomarkers for early NAFLD/NASH diagnosis and as therapeutic targets. Full article

Galectins represent a family of widely expressed lectins that have the ability to bind β-galactoside in modulating “cell-to-cell” and “cell-to-matrix” interactions in all organisms. These proteins are expressed in many inflammatory cells, such as macrophages, and depending on the inflammatory environment, they promote pro-inflammatory or anti-inflammatory responses. Galectin-3 (Gal-3) is predominantly located in the cytoplasm, but, as noted, it has also been detected in the nucleus, on the cell surface and in the extracellular environment, which indicates the multifunctionality of this molecule. It has been shown in many studies that Gal-3 is involved in immune regulation, fibrosis, and tissue remodeling, making it an important player in disorders such as inflammatory bowel disease (IBD), non-alcoholic steatohepatitis (NASH), and liver fibrosis. In IBD, this protein is associated with activation of the NLRP3 inflammasome, contributing to chronic intestinal inflammation. Also, in primary biliary cholangitis and autoimmune hepatitis, Gal-3 potentiate development of fibrosis through fibroblast-to-myofibroblast transition and extracellular matrix deposition, while in liver fibrosis, it is upregulated in hepatic stellate cells and macrophages, promoting fibrosis and inflammation. Studies show that Gal-3 inhibition reduces fibrosis and inflammation, making it a promising therapeutic target. Full article

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) encompasses a spectrum of liver conditions and involves gut–liver axis crosstalk. We aimed to evaluate whether oral vancomycin modifies liver injury and the cecal microbiota in a methionine–choline-deficient (MCD) diet model of NASH. Male C57BL/6J mice (n = 28) were block-randomized to four groups (n = 7 each) for 10 weeks: standard diet (STD); MCD diet; STD + vancomycin (VANC); and MCD + VANC (2 mg/mouse ≈ 50 mg/kg, every 72 h). After 10 weeks, liver tissues were analyzed for histological changes, cytokine levels [interleukin-6 (IL-6), interleukin-8 (IL-8), transforming growth factor beta 1 (TGF-β1)], and immunohistochemical markers [ubiquitin and cytokeratin 18 (CK18)]. Cecal microbiota composition was evaluated with 16S ribosomal RNA (rRNA) sequencing. The MCD reproduced key NASH features (macrovesicular steatosis, lobular inflammation). Vancomycin shifted steatosis toward a microvesicular pattern and reduced hepatocyte injury: CK18 and ubiquitin immunoreactivity were decreased in MCD + VANC vs. MCD, and hepatic IL-8 and TGF-β1 levels were lower in MCD + VANC vs. STD. Taxonomically, STD mice had Lactobacillus-rich microbiota. The MCD diet alone reduced alpha diversity (α-diversity), modestly lowered Firmicutes and increased Desulfobacterota/Fusobacteriota. Vancomycin alone caused a much larger collapse in richness, depleting Gram-positive commensals and promoting blooms of Escherichia–Shigella, Klebsiella, Parabacteroides, and Akkermansia. In the MCD + VANC group, vancomycin profoundly remodeled the microbiota, eliminating key commensals (e.g., Lactobacillus) and enriching Desulfobacterota, Fusobacteriota, and Campylobacterota. Oral vancomycin in the MCD model of NASH improved liver injury markers and altered steatosis morphology, but concurrently reprogrammed the gut into a low-diversity, pathobiont-enriched ecosystem with near-loss of Lactobacillus. These findings highlight a therapeutic trade-off—hepatic benefit accompanied by microbiome cost—that should guide microbiota-targeted strategies for NAFLD/NASH. Full article

Objectives: The FibroScan–aspartate transaminase (AST) score (FAST score) is a hybrid biomarker combining ultrasound and blood test data for identifying nonalcoholic steatohepatitis (NASH). This study aimed to assess the feasibility of using quantitative ultrasound (QUS) biomarkers related to hepatic steatosis for NASH detection and to compare their diagnostic performance with the FAST score. Methods: A total of 137 participants, comprising 71 individuals with NASH and 66 with non-NASH (including 49 normal controls), underwent FibroScan and ultrasound exams. QUS imaging features (Nakagami parameter m, homodyned-K parameter μ, entropy H, and attenuation coefficient α) were extracted from backscattered radiofrequency data. A weighted QUS parameter based on m, μ, H, and α was derived via linear discriminant analysis. NASH was diagnosed based on liver biopsy findings using the nonalcoholic fatty liver disease activity score (NAS). Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUROC) and compared with the FAST score using the DeLong test. Separation metrics, including the complement of overlap coefficient, Bhattacharyya distance, Kullback–Leibler divergence, and silhouette score, were used to assess inter-group separability. Results: All QUS parameters were significantly elevated in NASH patients (p < 0.05). AUROC values for individual QUS features ranged from 0.82 to 0.91, with the weighted QUS parameter achieving 0.91. The FAST score had the highest AUROC (0.96), though differences with the weighted QUS and homodyned-K parameters were not statistically significant (p > 0.05). Separation metrics ranked the FAST score highest, closely followed by the weighted QUS parameter. Conclusions: QUS biomarkers can be repurposed for NASH detection, with the weighted QUS parameter offering diagnostic accuracy comparable to the FAST score and serving as a promising, blood-free alternative. Full article

Insulin resistance is a key driver of metabolic disorders, including type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), progressing to non-alcoholic steatohepatitis (NASH). This study investigated the effects of geniposide (GP) on insulin sensitivity and hepatic fibrosis in a high-fat diet (HFD)-induced NASH model. C57BL/6 mice were fed an HFD for five weeks and subsequently divided into normal chow (NC), HFD, HFD with GP 50 mg/kg (GP50), and HFD with GP 100 mg/kg (GP100) groups. The treatments were administered orally for 12 weeks. GP treatment significantly reduced body weight as well as epididymal fat and liver weights, while no differences were observed in food intake. Improvements in glucose and lipid metabolism were observed in oral glucose tolerance tests, homeostatic model assessment of insulin resistance (HOMA-IR), and blood lipid profiles. Histological analyses revealed that GP suppressed adipocyte hypertrophy and hepatic lipid accumulation and hepatic fibrosis. To further elucidate molecular mechanisms of GP, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was conducted in the liver tissue. GP downregulated expression of inflammatory markers, including F4/80, tumor necrosis factor (TNF)-α, and interleukin (IL)-6. GP treatment modulated genes involved in insulin signaling including Janus kinase 2 (JAK2), insulin receptor (INSR), insulin receptor substrate 2 (IRS-2), and protein kinase B (AKT1) gene expression levels. This suggests GP suppresses inflammation and mitigates insulin resistance by activating the INSR–IRS2–Akt pathway. Additionally, GP enhanced adenosine monophosphate-activated protein kinase (AMPK) expression, suggesting its potential role in improving glucose and lipid metabolism. In conclusion, GP improves insulin resistance, inflammation, and hepatic fibrosis, highlighting its therapeutic potential for NASH and related metabolic disorders. Full article

Patients with concurrent non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) exhibit increased susceptibility to non-alcoholic steatohepatitis (NASH), advanced hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. This study investigated the contribution of ketogenesis to T2DM-mediated NAFLD exacerbation and elucidated the therapeutic mechanism of cynaroside in NASH-complicated T2DM. Male C57BL/6J mice were given CDAHFD combined with streptozotocin to establish stage-specific NAFLD with T2DM models. Hepatic HMGCS2 expression was modulated via tail vein injection of adenoviral vectors for HMGCS2 overexpression or knockdown. Cynaroside was administered orally from week 5 to week 8. The results showed that concurrent T2DM accelerated NAFLD progression, accompanied by a dysregulated ketogenesis that was correlated with disease severity. Hepatic HMGCS2 expression paralleled circulating ketone body concentrations, indicating that HMGCS2-mediated ketogenic dysregulation contributed to NAFLD pathogenesis in T2DM contexts. HMGCS2 overexpression in NASH-T2DM models significantly attenuated steatohepatitis progression through the enhancement of ketogenesis. Cynaroside administration ameliorated hepatic pathology in NASH-T2DM mice by (1) reducing hepatocellular injury and lobular inflammation; (2) decreasing intrahepatic lipid accumulation; and (3) suppressing hepatocyte senescence and the secretion of SASP factors. Mechanistically, cynaroside exerted therapeutic effects via HMGCS2-mediated ketogenesis. Our data demonstrated that ketogenic modulation is a viable therapeutic strategy to delay T2DM-NAFLD progression. Full article

Background/Objectives: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver conditions globally. This study aimed to assess the long non-coding RNAs (lncRNAs) growth arrest-specific 5 (GAS5), miR-29a-3p, and neurogenic locus notch homolog protein 2 (NOTCH2) as biomarkers in patients with NAFLD and find out if they are related to any clinical factors. Subjects and Methods: Thirty-eight age-matched healthy persons and thirty-eight NAFLD patients were enrolled. Patients were split into the following three groups: non-alcoholic steatohepatitis (NASH) (n = 12), patients with NAFLD-related cirrhosis (n = 8), and patients with NAFLD-related simple steatosis (n = 18). Real-time PCR was utilized to examine the expression. Results: The lncRNA GAS5 and NOTCH2 were higher in NAFLD cases in comparison to controls. On the other hand, microRNA-29a-3p was underexpressed in NAFLD cases in comparison to controls. Regarding NAFLD diagnosis, lncRNA GAS5 was the best single marker with a sensitivity of 100% and a specificity of 94.7% at the cutoff values of ≥1.16-fold change. Regarding different stages of the disease, the highest level of lncRNA GAS5 was in cirrhosis. lncRNA GAS5 expression, among other studied parameters, is still a significant predictor of NAFLD (adjusted odds ratio of 162, C.I. = 5.7–4629) (p = 0.003). LncRNA GAS5 has a positive correlation with NOTCH2 and a negative correlation with miR-29a-3p. LncRNA GAS5, NOTCH2, and RNA-29a-3p were significantly different in NAFLD cases compared to controls. Conclusions: lncRNA GAS5 appears to be the most effective single marker for detecting NAFLD. LncRNA GAS5 expression is a significant independent predictor of NAFLD. LncRNA GAS5 can differentiate different NAFLD stages. Full article

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, projected to affect 55% globally by 2040. Up to one-third of NAFLD patients develop non-alcoholic steatohepatitis (NASH), with 40% progressing to fibrosis. However, there are currently few reliable tools to predict disease progression. Impaired mitochondrial dynamics, characterized by dysregulated fission, fusion, and mitophagy, have emerged as key events in NAFLD pathophysiology, contributing to hepatocyte death and inflammation. This study explored the transition from steatosis to NASH through transcriptomic analyses, including data from patients with steatosis and those with NASH at different fibrosis stages. By identifying a transcriptomic signature associated with disease progression, the study revealed increased expression of genes involved in mitochondrial dynamics in NASH compared to steatosis and during NASH-related fibrosis. Histological analyses highlighted the central role of Dynamin-related protein 1 (Drp1), a dynamin GTPase essential for mitochondrial fission and mitophagy. In human liver biopsies, Drp1 expression progressively increased from NAFLD to NASH and NASH-related fibrosis and cirrhosis, predominantly in Kupffer cells. These finding suggest Drp1 is a potential driver of the transition to more severe liver damage, making it a promising biomarker for NASH development and progression and a potential therapeutic target in metabolic disorders. Full article

Cholesterol stress profoundly modulates cellular processes, but its underlying mechanisms remain incompletely understood. To investigate cholesterol-responsive networks, we performed integrated transcriptome (RNA-seq) and metabolome (LC-MS) analyses on HeLa cells treated with cholesterol for 6 and 24 h. Through transcriptomic analysis of cholesterol-stressed HeLa cells, we identified stage-specific responses characterized by early-phase stress responses and late-phase immune-metabolic coordination. This revealed 1340 upregulated and 976 downregulated genes after a 6 h cholesterol treatment, including induction and suppression of genes involved in cholesterol efflux and sterol biosynthesis, respectively, transitioning to Nuclear Factor kappa-B (NF-κB) activation and Peroxisome Proliferator-Activated Receptor (PPAR) pathway modulation by 24 h. Co-expression network analysis prioritized functional modules intersecting with differentially expressed genes. We also performed untargeted metabolomics using cells treated with cholesterol for 6 h, which demonstrated extensive remodeling of lipid species. Interestingly, integrated transcriptomic and metabolic analysis uncovered GFPT1-driven Uridine Diphosphate-N-Acetylglucosamine (UDP-GlcNAc) accumulation and increased taurine levels. Validation experiments confirmed GFPT1 upregulation and ANGPTL4 downregulation through RT-qPCR and increased O-GlcNAcylation via Western blot. Importantly, clinical datasets further supported the correlations between GFPT1/ANGPTL4 expression and cholesterol levels in Non-Alcoholic Steatohepatitis (NASH) liver cancer patients. This work establishes a chronological paradigm of cholesterol sensing and identifies GFPT1 and ANGPTL4 as key regulators bridging glycosylation and lipid pathways, providing mechanistic insights into cholesterol-associated metabolic disorders. Full article

Background: Liver fibrosis, a consequence of various chronic liver diseases, is characterized by excessive accumulation of extracellular matrix (ECM), leading to impaired liver function and potentially progressing to cirrhosis or hepatocellular carcinoma. The molecular mechanisms underlying liver fibrosis are complex and not fully understood. In vivo experiments are essential for studying the molecular mechanisms of the disease. However, the diverse principles behind mouse modeling techniques for liver fibrosis can complicate the elucidation of specific fibrotic mechanisms. Methods: Five distinct liver fibrosis models were utilized: CONTROL, NASH (non-alcoholic steatohepatitis), BDL (bile duct ligation), TAA (thioacetamide), and CCl₄ (carbon tetrachloride). Patents for these drugs were reviewed using Patentscope^® and Worldwide Espacenet^®. ScRNA-seq was performed to analyze and compare the cellular and molecular differences in these models. Results: The analysis revealed that, particularly in the drug-induced fibrosis models, hepatic stellate cells (HSCs), Kupffer cells, and T-cell subsets exhibit distinct regulatory patterns and dynamic remodeling processes across different liver fibrosis models. These findings highlight the heterogeneity of immune responses and extracellular matrix (ECM) remodeling in various models, providing important insights into the complex mechanisms underlying liver fibrosis. Conclusions: The study enhances our understanding of liver fibrosis development and provides valuable insights for selecting the most representative animal models in future research. This comprehensive analysis underscores the importance of model-specific immune responses and ECM remodeling in liver fibrosis. Full article

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic condition characterized by hepatic lipid deposits, insulin resistance, and inflammation which may progress to non-alcoholic steatohepatitis (NASH) and fibrosis. Protein kinases play an important role in NAFLD development by regulating metabolic and inflammatory pathways. Mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), AMP-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K)/AKT, and mechanistic target of rapamycin (mTOR) are all involved in NAFLD and NASH progression. Emerging evidence indicates that Farnesoid X Receptor (FXR) agonists have therapeutic potential by modulating bile acid metabolism, lipid balance, and inflammatory responses. This review examines the mechanistic interplay between FXR agonists and important protein kinases in NAFLD and NASH. FXR agonists activate AMPK, which promotes fatty acid oxidation and reduces hepatic steatosis. They also regulate MAPK signaling, which reduces c-Jun NH2-terminal kinase (JNK)- and p38 MAPK-mediated inflammation. Furthermore, FXR agonists activate the PI3K/AKT pathway, enhancing insulin sensitivity and modulating mTOR signaling to reduce hepatic fibrosis. Clinical studies in NAFLD/NASH indicate that FXR agonists confer metabolic and anti-inflammatory benefits, although optimizing efficacy and minimizing adverse effects remain challenging. Future studies should focus on combination therapies targeting FXR alongside specific kinases to improve therapeutic outcomes. This review highlights the potential of FXR agonists to modulate protein kinase signaling, opening new avenues for targeted NAFLD/NASH therapy. Full article