BACKGROUND: Hepatic fibrosis is a pathophysiological process of extracellular matrix abnormal deposition induced by multiple pathogenic factors. Currently, there is still a lack of effective and non-toxic drugs for treating fibrosis in clinic. Flavonoids are polyphenolic compounds synthesized in plants and modern pharmacological studies confirmed flavonoids exhibit potent hepatoprotective effect.
OBJECTIVE: Summarize literature to elaborate the mechanism of HF and evaluate the potential of flavonoids in HF, aiming to provide a new perspective for future research.
METHODS: The literatures about hepatic fibrosis and flavonoids are collected via a series of scientific search engines including Google Scholar, Elsevier, PubMed, CNKI, WanFang, SciFinder and Web of Science database. The key words are \"flavonoids\", \"hepatic fibrosis\", \"pharmacokinetic\", \"toxicity\", \"pathogenesis\" \"traditional Chinese medicine\" and \"mechanism\" as well as combination application.
RESULTS: Phytochemical and pharmacological studies revealed that about 86 natural flavonoids extracted from Chinese herbal medicines possess significantly anti-fibrosis effect and the mechanisms maybe through anti-inflammatory, antioxidant, inhibiting hepatic stellate cells activation and clearing activated hepatic stellate cells.
CONCLUSIONS: This review summarizes the flavonoids which are effective in HF and the mechanisms in vivo and in vitro. However, fewer studies are focused on the pharmacokinetics of flavonoids in HF model and most studies are limited to preclinical studies, therefore there is no reliable data from clinical trials for the development of new drugs. Further in-depth research related it can be conducted to improve the bioavailability of flavonoids and serve the development of new drugs.

UNASSIGNED: Schistosomiasis is a zoonotic parasitic disorder induced by the infestation of schistosomes, a genus of trematodes. MicroRNAs (miRNAs) in egg-derived exosomes are crucial for modulating the host\'s immune responses and orchestrating the pathophysiological mechanisms. Although the exosomes secreted by S. japonicum contain abundant miRNAs, the specific roles of these miRNAs in the pathogenesis of schistosomiasis-induced hepatic fibrosis are yet to be comprehensively elucidated. The egg exosomes of S. japonicum secrete miRNA-30, a novel miRNA.
UNASSIGNED: In vitro, the effect of miRNA-30 was evaluated by transfecting HSCs with miRNA mimics. The target gene biosignature for miRNA-30 was predicted using the miRDB software. The effect of miRNA-30 in hepatic fibrosis was evaluated by either elevating its expression in healthy mice or by inhibiting its activity in infected mice by administration of recombinant adeno-associated virus serotype eight vectors expressing miRNA-30 or miRNA sponges.
UNASSIGNED: This novel miRNA can activate hepatic stellate cells (HSCs), the prinary effector cells of hepatic fibrosis, in vitro, i.e., it significantly increases the fibrogenic factors Col1(α1), Col3(α1), and α-SMA at both mRNA and protein levels. In addition, miRNA-30 may activate HSCs by targeting the host RORA gene. In addition, in vivo experiments were conducted by administering a recombinant adeno-associated viral vector to modulate the expression levels of miRNA-30. The overexpression of miRNA-30 in healthy mice significantly elevated the expression of Col1(α1), Col3(α1), and α-SMA at both the transcriptomic and proteomic scales. This overexpression was coupled with a pronounced augmentation in the hepatic hydroxyproline content. Conversely, the in vivo silencing of miRNA-30 in infected mice induced a considerable reduction in the size of hepatic granulomas and areas of collagen deposition. Hence, in vivo, modulation of miRNA-30 expression may play a pivotal role in ameliorating the severity of hepatic fibrosis in mice afflicted with S. japonica.
UNASSIGNED: The study results suggest that miRNA-30 may augment schistosomiasis-induced hepatic fibrosis through a probable interaction with the host RORA. Our study may improve the current theoretical framework regarding cross-species regulation by miRNAs of hepatic fibrosis in schistosomiasis.

BACKGROUND: Hepatic fibrosis is a reversible pathological phenomenon caused by the abnormal proliferation of connective tissues in the liver for self-repair after persistent liver injury. Among these tissues, the activation status of hepatic stellate cells (HSCs) is crucial. Glycyrrhizic acid (GA) agents have been proven to have excellent anti-fibrosis effects, but their targets are unclear.
OBJECTIVE: To investigate the anti-hepatic fibrosis effect of GA and its target in activated HSCs.
METHODS: A mouse model of hepatic fibrosis was prepared with 20 % carbon tetrachloride (CCl4) and GA was administered continuously for 4 weeks. Subsequently, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), type Ⅲ procollagen peptide (P III P), laminin (LN), hyaluronic acid (HA), and type Ⅳ collagen (Col Ⅳ) were measured. Liver tissues were subjected to hematoxylin and eosin (HE), Masson, and Sirius red staining and proteome sequencing analysis. Based on LX-2 cells, activity-based protein profiling (ABPP) was used to investigate the potential targets of GA, which was further validated by the cellular thermal shift assay (CETSA), immunofluorescence co-localization, molecular docking, small interfering RNA (siRNA) and western blot (WB) assays.
RESULTS: In vivo, GA significantly reduced serum ALT, AST, HA, P III P, Col IV, and LN levels. HE, Masson, and Sirius red staining showed that GA significantly ameliorated hepatic inflammatory response and collagen deposition in CCl4-treated mice. Proteome sequencing results showed that GA mainly regulated glutathione S-transferase family members involved in glutathione metabolism. In vitro, GA significantly inhibited LX-2 cell proliferation and reduced reactive oxygen species accumulation. ABPP suggested that aldo-keto reductase family 7 member A2 (AKR7A2) was the major binding protein of GA in LX-2 cells. CETSA, fluorescence co-localization, molecular docking, and surface plasmon resonance further validated GA binding to AKR7A2. The WB results showed that GA up-regulated AKR7A2 expression both in vitro and in vivo and was corroborated by siRNA experiments.
CONCLUSIONS: GA targeted AKR7A2 in LX-2 cells to defend against sustained oxidative stress injury, thereby inhibiting the proliferation of activated HSCs and reversing hepatic fibrosis.

BACKGROUND: Ligustrum lucidum W.T. Aiton is a traditional Chinese medicine that has long been used with high hepatoprotective therapeutic and condition value. Specnuezhenide (SP), the standard prominent secoiridoid compound of Fructus Ligustri Lucidi may ameliorate hepatic inflammation in chronic liver diseases.
OBJECTIVE: Regulating inflammation through SIRT6-P2X7R axis has caused the emergence of novel molecular mechanism strategies for reversing hepatic fibrosis. This study focused on the mechanism of SP in modulating the liver inflammatory microenvironment in hepatic fibrosis.
METHODS: C57BL/6 mice with hepatic fibrosis were stimulated with thioacetamide (TAA) prior to administration of SP. Hepatic stellate cells (HSCs) or normal mouse primary hepatocytes were exposed to transforming growth factor-β (TGF-β) treatment. Meanwhile, normal mouse bone marrow-derived macrophages (BMDMs) were treated with lipopolysaccharide/adenosine triphosphate (LPS/ATP), aiming to obtain the conditioned medium. HSCs and hepatocytes were transfected with SIRT6 knockdown vector (siRNA-SIRT6) to estimate the impact of SP on the SIRT6-P2X7R/NLRP3 signaling pathway.
RESULTS: SP suppressed the HSCs extracellular matrix (ECM) deposition as well as pro-inflammatory cytokine levels induced by the medium of BMDMs or TGF-β. In addition, SP also significantly up-regulated SIRT6, inhibited P2X7R-NLRP3 inflammasome in HSCs and hepatocytes, and functioned as MDL-800 (a SIRT6 agonist). SP reduced the hepatocytes pyroptosis and further prevented the occurrence of inflammatory response in the liver. SP could inhibit the activation of BMDMs and impede IL-1β and IL-18 from entering extracellular regions. Moreover, deficiency of SIRT6 in HSCs or hepatocytes reduced SP\'s regulation of P2X7R suppression. For TAA-treated mice, SP mitigated histopathological changes, ECM accumulation, EMT process, and NETs formation in hepatic fibrosis.
CONCLUSIONS: Therefore, SP decreased inflammatory response via SIRT6-P2X7R/NLRP3 pathway and suppressed fibrillogenesis. These findings supported SP as the novel candidate to treat hepatic fibrosis.

BACKGROUND: Hepatic fibrosis (HF) is an essential stage in the progression of different chronic liver conditions to cirrhosis and even hepatocellular carcinoma. The activation of hepatic stellate cells (HSCs) plays a crucial role in the progression of HF. IFN- γ/Smad7 pathway can inhibit HSCs activation, while TGF-β1/CUGBP1 pathway can inhibit IFN-γ/Smad7 pathway transduction and promote HSCs activation. Thus, inhibiting the TGF-β1/CUGBP1 pathway and activating the IFN-γ/Smad7 pathway reverses HSCs activation and inhibits HF. Jiawei Taohe Chengqi Decoction (JTCD) was derived from the Taohe Chengqi Tang in the ancient Chinese medical text titled \"Treatise on Febrile Diseases\". We found several anti-HF components in JTCD including ginsenoside Rb1 and others, but the specific mechanism of anti-HF in JTCD is not clear.
OBJECTIVE: To elucidate the specific mechanism by which JTCD reverses HF by inhibiting the activation of HSCs, and to establish a scientific foundation for treating HF with Traditional Chinese medicine (TCM).
METHODS: We constructed a CCl4-induced mice HF model in vivo and activated human hepatic stellate cell line (LX-2) with TGF-β1 in vitro, after which they were treated with JTCD and the corresponding inhibitors. We examined the expression of pivotal molecules in the two pathways mentioned above by immunofluorescence staining, Western blotting and RT-PCR.
RESULTS: JTCD attenuated liver injury and reduced serum ALT and AST levels in mice. In addition, JTCD attenuated CCl4-induced HF by decreasing the expression of α-SMA, COL1A1 and other markers of HSCs activation in mice liver tissue. Moreover, JTCD effectively suppressed the levels of TGF-β1, p-Smad3, p-p38MAPK, p-ATF2, and CUGBP1 in vivo and in vitro and upregulated the levels of IFN-γ, p-STAT1, and Smad7. Mechanically, after using the inhibitors of both pathways in vitro, we found that JTCD inhibited the activation of HSCs by restoring the balance of the TGF-β1/CUGBP1 and IFN-γ/Smad7 pathways.
CONCLUSIONS: We demonstrated that JTCD inhibited HSCs activation and reversed HF by inhibiting the TGF-β1/CUGBP1 signalling pathway and upregulating the IFN-γ/Smad7 signalling pathway. Moreover, we have identified specific links where JTCD interferes with both pathways to inhibit HSCs activation. JTCD is an effective candidate for the clinical treatment of HF.

By replacing and removing defective or infected cells, programmed cell death (PCD) contributes to homeostasis maintenance and body development, which is ubiquitously present in mammals and can occur at any time. Besides apoptosis, more novel modalities of PCD have been described recently, such as necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death. PCD not only regulates multiple physiological processes, but also participates in the pathogenesis of diverse disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is mainly classified into metabolic dysfunction-associated steatotic liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), and the latter putatively progresses to cirrhosis and hepatocellular carcinoma. Owing to increased incidence and obscure etiology of MASH, its management still remains a tremendous challenge. Recently, hepatocyte PCD has been attracted much attention as a potent driver of the pathological progression from MASL to MASH, and some pharmacological agents have been proved to exert their salutary effects on MASH partly via the regulation of the activity of hepatocyte PCD. The current review recapitulates the pathogenesis of different modalities of PCD, clarifies the mechanisms underlying how metabolic disorders in MASLD induce hepatocyte PCD and how hepatocyte PCD contributes to inflammatory and fibrotic progression of MASH, discusses several signaling pathways in hepatocytes governing the execution of PCD, and summarizes some potential pharmacological agents for MASH treatment which exert their therapeutic effects partly via the regulation of hepatocyte PCD. These findings indicate that hepatocyte PCD putatively represents a new therapeutic point of intervention for MASH.

BACKGROUND: Treatment options for hepatic fibrosis, a prevalent liver condition closely linked to cirrhosis, are currently limited. While Guizhi Fuling Wan (GFW), a pill derived from traditional Chinese herbs, has been reported to possess hepatoprotective properties, its therapeutic effect and mechanism in hepatic fibrosis remain elusive.
OBJECTIVE: This study aimed to evaluate the anti-fibrotic impact of GFW and its underlying mechanisms in both in vivo and in vitro settings.
METHODS: Tetrachloromethane (CCl4) was used to induce hepatic fibrosis in male rats. In vitro, activation of hepatic stellate cells (HSCs) was triggered by platelet-derived growth factor-BB (PDGF-BB). In vivo, liver function, pathological alterations, and HSC activation were evaluated. Additionally, the impact of GFW on the activated phenotypes of Lieming Xu-2 (LX-2) cells was examined in vitro. Network pharmacology was employed to identify the potential targets of GFW in hepatic fibrosis. Lastly, the impact of GFW on the PTEN/AKT/mTOR pathway and PTEN ubiquitination in HSCs was investigated.
RESULTS: GFW alleviated CCl4-induced liver damage and scarring in rats in a dose-dependent manner and suppressed HSC activation in vivo. Moreover, GFW inhibited the proliferation, migration, differentiation, and extracellular matrix (ECM) production of activated HSCs in vitro. GFW also promoted autophagy and apoptosis of HSCs. Meanwhile, network pharmacology and in vitro studies suggested that GFW inhibits the AKT/mTOR pathway by preventing PTEN degradation by suppressing ubiquitination.
CONCLUSIONS: GFW attenuates Ccl4-induced hepatic fibrosis in male rats by regulating the PTEN/AKT/mTOR signaling pathway, positioning it as a potential candidate for the treatment of hepatic fibrosis.

BACKGROUND: Obesity has become a major global public health challenge. Studies examining the associations between different obesity patterns and the risk of nonalcoholic fatty liver disease (NAFLD) are limited. This study aimed to investigate the relationships between different obesity patterns and the risk of NAFLD in a large male population in the US.
METHODS: Data from the 2017 to March 2020 National Health and Nutrition Examination Survey (NHANES) were utilized. Liver steatosis and fibrosis were assessed with FibroScan using the controlled attenuation parameter (CAP) and liver stiffness measurements (LSM). Steatosis was identified with a CAP value of 248 dB/m or higher. Abdominal obesity was defined by a waist circumference (WC) of 102 cm or more for males and 88 cm or more for females. Overweight was defined as a body mass index (BMI) of 24.0 kg/m2 and above. General obesity was identified with a BMI of 28.0 kg/m2 or higher. Obesity status was categorized into four types: overweight, general obesity, abdominal obesity, and combined obesity. Multivariate logistic regression, adjusting for potential confounders, was used to examine the link between obesity patterns and NAFLD risk. Subgroup analysis further explored these associations.
RESULTS: A total of 5,858 adults were included. After multivariable adjustment, compared to the normal weight group, the odds ratios (ORs) [95% confidence interval (CI)] for NAFLD in individuals with overweight, general obesity, abdominal obesity, and combined obesity were 6.90 [3.74-12.70], 2.84 [2.38-3.39], 3.02 [2.02-4.51], and 9.53 [7.79-11.64], respectively. Subgroup analysis showed the effect of different obesity patterns on NAFLD risk was stable among individuals with different clinical conditions. In the fully adjusted multivariate logistic regression model, WC was positively associated with NAFLD risk (OR: 1.48; 95% CI: 1.42-1.53; P < 0.001). WC also demonstrated strong discriminatory ability for NAFLD in Receiver Operating Characteristic (ROC) analysis, achieving an Area Under the Curve (AUC) of 0.802.
CONCLUSIONS: Different patterns of obesity are risk factors for NAFLD. An increase in WC significantly increased NAFLD risk. More attention should be paid to preventing different patterns of obesity among adults.

Hepatic fibrosis (HF) is a pathological process of structural and functional impairment of the liver and is a key component in the progression of chronic liver disease. There are no specific anti-hepatic fibrosis (anti-HF) drugs, and HF can only be improved or prevented by alleviating the cause. Autophagy of hepatic stellate cells (HSCs) is closely related to the development of HF. In recent years, traditional Chinese medicine (TCM) has achieved good therapeutic effects in the prevention and treatment of HF. Several active ingredients from TCM (AITCM) can regulate autophagy in HSCs to exert anti-HF effects through different pathways, but relevant reviews are lacking. This paper reviewed the research progress of AITCM regulating HSCs autophagy against HF, and also discussed the relationship between HSCs autophagy and HF, pointing out the problems and limitations of the current study, in order to provide references for the development of anti-HF drugs targeting HSCs autophagy in TCM. By reviewing the literature in PubMed, Web of Science, Embase, CNKI and other databases, we found that the relationship between autophagy of HSCs and HF is currently controversial. HSCs autophagy may promote HF by consuming lipid droplets (LDs) to provide energy for their activation. However, in contrast, inducing autophagy in HSCs can exert the anti-HF effect by stimulating their apoptosis or senescence, reducing type I collagen accumulation, inhibiting the extracellular vesicles release, degrading pro-fibrotic factors and other mechanisms. Some AITCM inhibit HSCs autophagy to resist HF, with the most promising direction being to target LDs. While, others induce HSCs autophagy to resist HF, with the most promising direction being to target HSCs apoptosis. Future research needs to focus on cell targeting research, autophagy targeting research and in vivo verification research, and to explore the reasons for the contradictory effects of HSCs autophagy on HF.

Eugenol possesses anti-inflammatory and antioxidant properties, and may serve as a potential therapeutic agent for hepatic fibrosis. However, the development of solid eugenol formulations is challenging due to its volatility. To address this issue, this study employed porous silica to adsorb solidified eugenol. The solidified powder was characterized using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). In addition, the differences in in vitro release and oral bioavailability between eugenol and solidified eugenol powder were investigated. The effectiveness of eugenol and eugenol powder in treating liver fibrosis was investigated using enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), and histopathological observations. Our results indicate that porous silica can effectively solidify eugenol into powder at a lower dosage. Furthermore, we observed that porous silica accelerates eugenol release in vitro and in vivo. The pharmacodynamic results indicated that eugenol has a positive therapeutic effect against hepatic fibrosis and that porous silica does not affect its efficacy. In conclusion, porous silica was able to solidify eugenol, which may facilitate the preparation and storage of solid formulations.