Wenxia Zhao

Background: Non-alcoholic fatty liver disease (NAFLD) is a major global health issue strongly associated with obesity. Available treatments have significant limitations. The traditional Chinese medicine Huatan Qushi Huoxue (HTQSHX) granules represent a potential alternative therapeutic option. This study evaluates their effects and safety in patients with obesity-associated NAFLD. Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial recruited 248 patients with obesity-associated NAFLD from three clinical sites. Participants were randomized 1:1 to receive HTQSHX granules or placebo granules for 12 weeks. The primary outcome was the absolute change in hepatic fat fraction from baseline to week 12, as measured by MRI-proton density fat fraction (MRI-PDFF), which is recommended as a primary endpoint in early-phase NAFLD clinical trials for its precision and objectivity. Secondary outcomes included the proportion of patients achieving ≥30% relative reduction in MRI-PDFF-assessed hepatic fat fraction, serum liver enzyme indicators, glucose and lipid metabolism parameters, non-alcoholic steatohepatitis-related serum biomarkers, anthropometric measures, and serum metabolomics analysis. Results: Among 228 participants included in the modified intention-to-treat (mITT) analysis, the median hepatic fat fraction decreased from 16.15% at baseline to 12.12% in the HTQSHX group (median change: 3.27%), and from 15.64% to 14.95% in the placebo group (median change: 0.96%). The between-group difference in absolute change was statistically significant (−2.32%; 95% CI, −4.50 to −0.23; P = 0.029). The proportion of patients achieving a ≥30% relative reduction in hepatic fat fraction was significantly higher in the HTQSHX group than in the placebo group (41.23% vs. 20.18%; P < 0.001). The HTQSHX group also showed significantly greater improvements in serum alanine aminotransferase ( P = 0.048), aspartate aminotransferase ( P = 0.033), free fatty acids ( P = 0.026), cytokeratin-18 fragment M30 ( P < 0.001), soluble triggering receptor expressed on myeloid cells 2 ( P < 0.001) and anthropometric parameters (body mass index, waist-to-hip ratio, body fat percentage). Metabolomics analysis of 30 HTQSHX-treated participants revealed that the formula restored multiple phospholipid levels and reduced markers of oxidative stress and mitochondrial dysfunction, with enrichment in fatty acid and sphingolipid metabolism pathways. Conclusion: HTQSHX granules may represent a potentially beneficial therapeutic option for obesity-associated NAFLD, with observed effects including significant reduction in hepatic fat fraction and modulation of lipid metabolism and oxidative stress, alongside an acceptable safety profile. These findings warrant further investigation in longer-term studies. Clinical Trial Registration: https://www.chictr.org.cn/ , identifier ChiCTR2200060901.

Objective: This study aimed to evaluate the diagnostic accuracy of the controlled attenuation parameter (CAP) for grading hepatic steatosis in metabolic dysfunction-associated steatotic liver disease (MASLD), using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) as the non-invasive reference standard. Methods: This single-center retrospective study included 120 participants (17 healthy controls and 103 patients with MASLD) who underwent MRI-PDFF, transient elastography (TE), and laboratory testing within predefined time intervals. Participants were stratified by MRI-PDFF values into no (S0, n = 17), mild (S1, n = 20), moderate (S2, n = 59), or severe (S3, n = 24) steatosis. Group comparisons were performed using ANOVA or Kruskal-Wallis tests, correlations were assessed with Pearson or Spearman coefficients, and independent factors associated with CAP were identified by multivariate linear regression. The diagnostic performance of CAP was evaluated using receiver operating characteristic (ROC) curve analysis. Bootstrap resampling (2000 iterations) was used to estimate the 95% confidence intervals (CIs) for the optimal CAP cut-off values for each steatosis grade. Results: CAP values increased progressively with steatosis severity (S3 > S2 > S1 > S0; all p < 0.001). Hepatic steatosis grade was independently associated with CAP values after adjusting for confounders ( p < 0.001). CAP showed good diagnostic performance for identifying ≥S1 (area under the curve [AUC] = 0.924) and ≥S2 steatosis (AUC = 0.947), and acceptable performance for identifying S3 steatosis (AUC = 0.837). The optimal CAP cut-offs were 239 dB/m (95% CI: 235.5–240.0) for ≥S1, 278 dB/m (95% CI: 273.0–307.5) for ≥S2, and 314 dB/m (95% CI: 303.5–357.5) for S3, with corresponding sensitivities of 95.0, 94.9, and 91.7%, and specificities of 88.2, 83.8, and 62.5%. Conclusion: CAP showed good diagnostic performance for grading hepatic steatosis in MASLD and may serve as a practical non-invasive tool for steatosis assessment, particularly in resource-limited settings where MRI-PDFF is not readily available.

Objective: This study aimed to evaluate the therapeutic effect of the traditional Chinese medicine compound Huatan Qushi Huoxue prescription (HQHF) on Metabolic Associated Fatty Liver Disease (MAFLD) and explore its underlying mechanisms through a multi-method approach. Methods: A high-fat diet-induced MAFLD mouse model was established to assess HQHF’s effects on liver pathology, biochemical markers, and oxidative stress. The bioactive components and potential targets of HQHF were identified through network pharmacology. MAFLD-related signaling pathways were explored by integrating data from the Gene Expression Omnibus (GEO) database, followed by molecular docking analyses. For experimental validation, key inflammatory cytokines and proteins (Interleukin-6 (IL-6), Interleukin-1α (IL-1α), Interleukin-1β (IL-1β), Matrix Metallopeptidase 9 (MMP9), Chemokine Ligand 2 (CCL2), and Intercellular Adhesion Molecule 1 (ICAM1)) were measured using Enzyme-Linked Immunosorbent Assay (ELISA), immunohistochemistry (IHC), and immunofluorescence. Results: Histopathological analysis showed that HQHF significantly alleviated liver steatosis and inflammatory cell infiltration. Biochemical analysis indicated that HQHF reduced serum and liver triglyceride levels, serum total cholesterol, liver enzymes (Aspartate Aminotransferase, AST, and Alanine Aminotransferase, ALT), and malondialdehyde (MDA), while increasing glutathione (GSH) levels. Network pharmacology identified 33 bioactive components and 89 key targets, which were enriched in pathways including Mitogen-Activated Protein Kinase (MAPK), Toll-like Receptor (TLR), Interleukin-17 (IL-17), and Advanced Glycation End product-Receptor for Advanced Glycation End product (AGE-RAGE). Six core genes (MMP9, IL1α, CCL2, IL1β, IL6, ICAM-1) were highlighted. Molecular docking confirmed strong binding of major HQHF compounds (e.g., quercetin, baicalin) to these targets, and experimental assays further validated their downregulation in HQHF-treated mice. Conclusion: HQHF exerts lipid-lowering and anti-inflammatory effects in MAFLD by regulating multiple targets and pathways related to lipid metabolism and inflammation.

Background: Alcoholic liver disease (ALD) is a key cause of chronic liver disease worldwide, which progresses to liver cirrhosis and even hepatocellular carcinoma. After years of application and research, the traditional Chinese medicine (TCM) Exocarpium Citri Grandis (ECG) has shown the significant function of lowering lipid and outering the effect of drinking, but the specific mechanism of its action in ALD is not clear. Purpose: The aim of this study is to investigate the anti-alcohol and lipid-lowering effects of ECG and its underlying pharmacological mechanisms in vitro and in vivo. Methods: First, this study initiated with a preliminary identification of the active components in the aqueous extract of ECG. Then zebrafish, mice, AML-12 cells and RAW264.7 cells were used as the research object. Serum and hepatic iron concentration were assessed by biochemical assays and iron assay kits. Besides, cells were constructed with the receptor for advanced glycation endproducts (RAGE) overexpression virus for further research. Results: ECG extract was low-toxicity and effectively alleviated alcohol-induced hepatic steatosis in mice and zebrafish. Besides, ECG extract intervention inhibited hepatic iron overload in ALD through mediating the iron-related pathways. Specifically, ECG reversed the down-regulation of ferroportin1 and up-regulation of hepcidin and ferritin in mice liver induced by alcohol, which subsequently suppressed iron dependent-lipid peroxidation and inflammation. In addition, flavonoids were the main components of ECG and could be combined with RAGE. The study indicated that ECG had a superior therapeutic effect against alcohol-induced liver injury in vivo and in vitro. Conclusions: The protective effect of ECG might be closely related to the modulation of RAGE-mediated lipid accumulation and iron overload. The evidence provides the therapeutic promise of ECG in ALD.

Non‐alcoholic fatty liver disease (NAFLD) is a major public health threat with currently limited therapeutic options. Inhalation therapy shows promise for treating metabolic disorders due to rapid absorption and high patient adherence, though relevant medications remain scarce. Eugenol (EUG), the primary component of Syzygium aromaticum volatile oil, emerges as a promising NAFLD inhibitor from lipid‐lowering aromatic Chinese medicine screening. EUG elicited significant anti‐steatotic effects in both cultured hepatocytes and comprehensive high‐fat diet‐induced NAFLD animal models. Mechanistically, EUG targeted the activation of the hepatic ectopic olfactory receptor Olfr544 and up‐regulated its downstream cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element binding protein signaling pathway, which further promoted fat lipolysis and oxidation. This effect is prevented by Olfr544 knockdown models both in vitro and in vivo, with supporting bioinformatics analysis. Moreover, EUG reversed gut microbiota dysbiosis and enriched two probiotic strains L. ruteri XR23 and L. johnsonii XR25 , and oral gavage potently mitigated NAFLD in mice, with the key metabolites 3‐indolepropionic acid (IPA) and 5‐hydroxyindole‐3‐acetic acid (5‐HIAA) inhibiting lipid synthesis. Lower levels of 5‐HIAA and IPA are observed in patients with NAFLD. These results highlight the considerable potential of EUG as an agonist of Olfr544 for treating NAFLD by inhalation.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and is closely associated with metabolic abnormalities. The causes of NAFLD are exceedingly complicated, and it is known that a variety of signaling pathways, endoplasmic reticulum stress, and mitochondrial dysfunction play a role in the pathogenesis of NAFLD. Recent studies have shown that ubiquitination and deubiquitination are involved in the regulation of the NAFLD pathophysiology. Protein ubiquitination is a dynamic and diverse post-translational alteration that affects various cellular biological processes. Numerous disorders, including NAFLD, exhibit imbalances in ubiquitination and deubiquitination. To highlight the significance of this post-translational modification in the pathogenesis of NAFLD and to aid in the development of new therapeutic approaches for the disease, we will discuss the role of enzymes involved in the processes of ubiquitination and deubiquitination, specifically E3 ubiquitin ligases and deubiquitinating enzymes that are important in the regulation of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a progressive disease. Without effective interventions, NAFLD can gradually develop to non-alcoholic steatohepatitis, fatty liver fibrosis, liver cirrhosis and even hepatocellular carcinoma. It is still to investigate the precise molecular mechanism behind the pathophysiology of NAFLD. Triggering receptor expressed on myeloid cells 2 (TREM2) can sense tissue injury and mediate immune remodeling, thereby inducing phagocytosis, lipid metabolism, and metabolic transfer, promoting cell survival and combating inflammatory activation. NAFLD might develop as a result of TREM2's regulatory role. We here briefly summarize the biological characteristics of TREM2 and its functions in the disease progression of NAFLD. Moreover, we propose to broaden the therapeutic strategy for NAFLD by targeting TREM2.