Chronic liver diseases pose a significant global health concern, ranking as the 11th leading cause of death worldwide. It often progresses to organ fibrosis and severe complications such as portal hypertension and cirrhosis. Liver transplantation is the most effective treatment for such diseases, however, the persistent shortage of donors highlights the need for alternatives. Radiofrequency ablation (RFA) is a promising alternative since it is a minimally invasive procedure. RFA uses heat to destroy abnormal tissues. Its benefits include reduced recovery time compared to surgery, precise targeting of affected areas, and long-lasting symptom relief in many cases. However, RFA has challenges, such as potential risks of nerve damage, infection, or incomplete ablation, requiring repeat treatments. Although significant progress in RFA techniques, effective monitoring remains challenging due to the limited ability to accurately characterize the dynamic thermal diffusion and complex tissue responses.

To address this challenge, hyperspectral imaging (HSI) shows promise in monitoring tissue necrosis post-ablation. Our study evaluated HSI's efficacy in monitoring RFA on ex vivo human fibrotic liver tissue samples.

Statistical analysis revealed correlations between spectral patterns and tissue conditions, which helped identify the optimal spectral bands of 543 nm and 579 nm for accurately distinguishing different tissue states. Analyzing the hemoglobin absorption profile indicated significant reductions in absorption of the green light band, showing approximately 40 % reduction in fibrotic tissue and around 20 % reduction in ablated tissue when compared to normal liver tissue. Additionally, a threshold was established for predicting the ablated area of liver samples, ensuring a condition of 90 % specificity.

Consequently, HSI proved to be a valuable tool for monitoring ablation and a step for improving treatment outcomes for liver fibrosis.

Alcoholic liver disease (ALD), caused by excessive alcohol abuse, encompasses a battery of liver conditions including fatty liver to more severe conditions such as alcoholic hepatitis and cirrhosis. Silymarin derived from the dried fruits of Silybum marianum can shield the liver cells from alcohol damage and prevent toxins from penetrating and damaging the liver. Overcoming the challenges of silymarin's poor solubility, low bioavailability, and limited absorption is crucial to fully realize its health benefits. Herein, spirulina platensis (SP) was used as a natural carrier for silymarin delivery to alleviate ALD in mice. The functional ingredient silymarin was loaded into SP via a single step to construct the hybrid of silymarin@SP. The inherent chlorophyll gives silymarin@SP incredible fluorescence imaging ability for noninvasive monitoring. The orally deliverable silymarin@SP markedly increased silymarin's blood concentration from 2.04 to 4.12 μg/mL and enhanced its hepatic retention. The helical structure of SP carriers allowed silymarin@SP to improve the biological effectiveness of silymarin, significantly enhancing its effectiveness in alleviating ALD. Treatment with silymarin@SP significantly decreased proinflammatory cytokine levels. The potential benefits of orally deliverable silymarin@SP suggest that the SP carrier is effective in enhancing the biological efficacy of encapsulated silymarin in treating alcohol-induced liver damage. The integration of SP with silymarin may also provide combinatorial effects in protecting against and repairing the ALD.

Limited data exist regarding the estimate of the prevalence of advanced liver fibrosis and cirrhosis in the general population. Therefore, we conducted a systematic review and meta-analysis to evaluate the global prevalence and risk factors of advanced fibrosis and cirrhosis.

We searched Embase, PubMed, Scopus, and Web of Science from inception to April 30 2024, with no language restriction. We included cross-sectional studies reporting the prevalence of advanced liver fibrosis and/or cirrhosis in a sample of at least 100 individuals aged ≥18 years from the general population. Subjects with cirrhosis were included in the advanced fibrosis group. The pooled prevalence proportions utilizing a random-effects model and 95% confidence intervals (CIs) were estimated using global data.

A total of 46 studies fulfilled the eligibility criteria, comprising approximately 8 million participants from 21 countries. The pooled prevalence rates of advanced liver fibrosis and cirrhosis in the general population were 3.3% (95% CI, 2.4%-4.2%) and 1.3% (95% CI, 0.9%-1.7%) worldwide, respectively. A trend was observed for an increase in the prevalence of advanced fibrosis (P = .004) and cirrhosis (P = .034) after 2016. There were significant geographic variations in the advanced fibrosis and cirrhosis prevalence at continental and national levels (P < .0001). Potential risk factors for cirrhosis were viral hepatitis, diabetes, excessive alcohol intake, obesity, and male sex.

The prevalence of advanced fibrosis and cirrhosis is considerable and increasing worldwide with significant geographic variation. Further research is needed to better understand the risk factors and how to mitigate them worldwide to address the growing global burden of cirrhosis.

Direct-acting antivirals (DAAs) have dramatically changed the landscape of chronic hepatitis C virus (HCV) treatment and significantly reduced the risk of HCV-related hepatocellular carcinoma (HCC) after achieving sustained virologic response. However, the risk of HCC persists, particularly in patients with pre-treatment cirrhosis or fibrosis stage 3 (F3), even after DAA-induced viral eradication. While professional guidelines agree on the need for surveillance in cirrhotic patients, there is no consensus regarding surveillance for the pre-treatment F3 population following HCV eradication. The risk of HCC in the F3 population falls below the threshold for cost-effective surveillance. However, co-existing risk factors-such as diabetes, hepatic steatosis, alcohol use, advanced age, and elevated alpha-fetoprotein levels-may warrant reconsideration of HCC surveillance in this group. This underscores the need for an individualized, risk-based approach to HCC surveillance. This review provided a simplified algorithm to assist clinicians in managing patients with HCV after DAA-induced sustained virologic response.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and it poses a significant threat to public health. There is insufficient documented evidence about the problems and needs of patients and physicians in managing NAFLD. This study aimed to explore the challenges and needs in managing NAFLD from the perspective of gastroenterology and hepatology (GH) specialists.

This qualitative study was conducted from January to September 2023. Fifteen Iranian GH specialists selected by purposive sampling. Data were collected through semi-structured interviews. The interviews were analyzed inductively using the Elo and Kyngas content analysis approach. The criteria proposed by Guba and Lincoln were used to ensure the study's validity.

The identified challenges were divided into thirteen main categories (34 subcategories and 117 primary codes), and the identified needs were divided into eight main categories (21 subcategories and 97 primary codes). The main categories of the challenges were chronic nature and time-consuming differential diagnosis, complex treatment process, defects in the patient management process, shortcomings of the healthcare system, the effect of unhealthy eating and cultural and social factors on the diet, incorrect attitude of patients, lack of knowledge and awareness of patients, lack of comprehensive treatment plans based on patients' conditions, defect in knowledge and awareness of physicians, inadequate cooperation of patients, defects in the process of recording and monitoring information and providing feedback, insufficient policies and plans in the prevention of NAFLD, and economic problems. The main categories of needs included developing a comprehensive treatment plan, updating physicians' knowledge and creating standard treatment protocols, changing attitudes and empowering patients, informing and educating patients, establishing multi-specialty clinics for NAFLD treatment, establishing peer support groups and facilitating communication, utilizing digital technology to track patient information and monitor their progress, and supportive, educational, prevention, and management policies in the treatment of NAFLD.

This study showed that managing NAFLD involves physical, psychological, nutritional, sports, economic, and social aspects and requires multidisciplinary clinical approaches, digital technologies, and supportive and educational policies. These findings have important implications that can help patients, physicians, and policymakers design better lifestyle prescriptions to manage NAFLD.

Hepatic fibrosis, characterized by the excessive deposition of the extracellular matrix, represents a common consequence of various chronic liver disorders. However, no specific drugs are available for antifibrotic therapy to date. SMAD2 is phosphorylated by transforming growth factor-β and subsequently binds to SMAD4 to generate a heteromeric complex, which then translocates into the nucleus and aggravates liver fibrosis. Herein, based on molecular docking simulation and structure-activity relationship study, we report the discovery of a novel cyclic peptide CMF9 that targets SMAD2 and potently interferes with the SMAD2-SMAD4 interaction. The subsequent in vivo and in vitro pharmacological studies demonstrated that CMF9 dramatically suppressed hepatic stellate cells activation and collagen synthesis, alleviating CCl4-induced hepatic inflammation and fibrosis. Overall, we first demonstrated that the novel cyclic peptide CMF9 could efficiently block the SMAD2-SMAD4 interaction via selectively inhibiting SMAD2 phosphorylation, providing a promising therapeutic strategy for targeting SMAD2 and an alternative candidate for the treatment of liver fibrosis.

Glypican-3 (GPC3), which is a membrane-associated antigen that is overexpressed in hepatocellular carcinoma (HCC). hGC33, a humanized anti-GPC3 antibody, has been validated as a potential antibody drug with good antitumor activity by preclinical studies and the Phase II clinical trial. However, free drug usually lack good tumor penetration. Outer membrane vesicles (OMVs) that are secreted by Escherichia coli function as natural vectors for molecule delivery and mediators of biological signals across tissues. Our study aimed to engineer E. coli for use as a platform to precisely deliver the hGC33 single-chain variable fragment (hGC33-scFv) for the targeted treatment of HCC.

In this study, we utilized E. coli BL21(DE3) to express Hbp-hGC33-scFv fusion protein and generated E. coli hGC33-OMVs. After isolation and characterization, we assessed their chemotaxis toward HepG2  cells by Transwell, coimmunoprecipitation (co-IP) to confirm hGC33-GPC3 binding, and immunofluorescence (IF) to evaluate the localization of hGC33 on OMV membranes. The in vivo efficacy was assessed in BALB/c nude mice harboring HepG2  cell-derived xenografts, and tumor targeting was analyzed with Cy7-labeled OMVs and live imaging. Proliferation assays, cell cycle analysis, and Wnt pathway expression analysis were performed to elucidate the underlying mechanisms.

hGC33-OMVs exhibited spherical bilayered nanostructures and displayed hGC33-scFv on their surface. hGC33-OMVs preferentially accumulated in tumors, significantly reducing tumor volume compared with controls and downregulating the proliferation markers Ki67 and PCNA. Transwell assays revealed increased tropism of hGC33-OMVs toward HepG2 cells, while Co-IP confirmed the direct interaction between hGC33 and GPC3. Meanwhile, hGC33-OMVs suppressed HepG2 cell proliferation, induced G1-phase arrest, and reduced Wnt3a, β-catenin, Cyclin D1, and C-myc expression.

Engineered E. coli hGC33-OMVs effectively target HCC via the hGC33-GPC3 interaction, inhibit tumor growth by suppressing Wnt signaling, and demonstrate potential for use as a versatile platform for antibody delivery.

We explored the effects of miR-133a-5p and ATP7B on cuproptosis in hepatocellular carcinoma.

Initially, we assessed the impact of miR-133a-5p on hepatocellular carcinoma (HCC) using CCK-8 assays, cell scratch assays, and flow cytometry. Subsequently, we utilized elesclomol in combination with copper ions to induce cuproptosis in the HCC cell lines PLC/PRF/5 and Huh-7. We evaluated the influence of miR-133a-5p on cuproptosis using CCK-8 assays, cell scratch assays, flow cytometry, and Western blotting. To elucidate the underlying mechanisms, we employed bioinformatics to identify potential downstream target genes of miR-133a-5p and conducted dual-luciferase reporter assays to confirm the binding sites. Finally, we validated the regulatory effect of miR-133a-5p on ATP7B by modulating miR-133a-5p expression through cell transfection experiments.

The results from the CCK-8 assay, cell scratch assay, and flow cytometry demonstrated that miR-133a-5p significantly inhibits the proliferation and migration of HCC cells while promoting their apoptosis. Furthermore, Elesclomol in combination with copper ions induces cuproptosis in HCC cells. Compared to the cuproptosis observed in HCC as a control, miR-133a-5p further suppresses the proliferation and migration of HCC cells, enhances their death, and increases the expression of cuproptosis-related proteins more prominently. Bioinformatics analysis suggested that ATP7B might be a downstream target gene of miR-133a-5p. This was confirmed by dual luciferase assays, which identified a binding site between miR-133a-5p and ATP7B. Additionally, the expression levels of ATP7B were found to decrease or increase in response to the regulation by miR-133a-5p.

MiR-133a-5p facilitates cuproptosis in hepatocellular carcinoma through targeting of ATP7B.

The prognostic value of the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study aimed to evaluate the associations between the NHHR and all-cause and cause-specific mortality in patients with MASLD.

Data for this study were obtained from the National Health and Nutrition Examination Survey (NHANES III and the National Death Index (NDI). The NHHR was calculated according to the formula. The results of mortality associated with the NDI were recorded as of December 31, 2019. We used a multivariate Cox proportional hazard model and restricted cubic spline (RCS) regression to assess the associations between the NHHR and all-cause and cause-specific mortality. In addition, subgroup analyses were performed to explore the relationships between the NHHR and all-cause and cause-specific mortality.

This study included 3155 patients with a definite diagnosis of MASLD. A total of 1,381 (43.8%) patients with MASLD died, and 1,774 (56.2%) survived. Multivariate Cox proportional hazards model analysis showed that NHHR was not significantly associated with all-cause mortality in MASLD patients. The RCS curve showed a significant nonlinear trend between the NHHR and all-cause mortality in patients with MASLD. Subgroup analysis revealed that the NHHR was better suited to predict cardiovascular mortality in patients without advanced fibrosis.

Our study revealed the clinical value of the NHHR in the prediction of mortality in the MASLD population. The NHHR can be used as a biomarker for follow-up in people without advanced fibrosis.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder with significant metabolic implications. Metabolic age, determined through bioimpedance analysis, has emerged as a potential indicator of overall metabolic health. The objective of this study is to evaluate the association between metabolic age and MASLD risk scores in a cohort of Spanish workers. Methods: A cross-sectional study was conducted on 8590 Spanish workers who underwent annual occupational health examinations between 2019 and 2020. Metabolic age was determined using bioelectrical impedance analysis, and the Avoidable Lost Life Years (ALLY) index was calculated as the difference between their metabolic and chronological age. MASLD risk was assessed using various validated scales, including the Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), Zhejiang University Index (ZJU), Fatty Liver Disease Index (FLD), and Lipid Accumulation Product (LAP). A multinomial logistic regression analysis was performed to examine the association between metabolic age and MASLD risk scores, adjusting for sociodemographic and lifestyle variables. Results: Higher metabolic age values were observed in individuals with greater MASLD risk across all evaluated scales. The mean metabolic age was consistently lower in women compared to men, and these differences were statistically significant (p < 0.01). Multinomial logistic regression analysis revealed that the strongest associations with increased metabolic age were found for MASLD risk scores, physical inactivity, and poor adherence to the Mediterranean diet. ROC curve analysis demonstrated a high predictive capacity for the FLD (AUC: 0.935 in women and 0.917 in men) and FLI (AUC: 0.900 in women and 0.833 in men), with high Youden index values. Conclusions: Metabolic age is significantly associated with MASLD risk, suggesting its potential as a non-invasive biomarker for identifying individuals with a higher risk for metabolic liver disease. Lifestyle factors, including physical activity and dietary patterns, play a crucial role in modulating metabolic age, highlighting the importance of targeted interventions for MASLD prevention. Further research is warranted to validate metabolic age as a prognostic tool in MASLD risk assessment.

Circular RNAs (circRNAs) are increasingly recognized as significant regulators in multiple cancers, such as hepatocellular carcinoma (HCC), frequently affecting microRNA (miRNA) expression. The diagnostic and prognostic roles of circRNAs, specifically circ_0009910 and circ_0027478, in conjunction with miR-1236-3p, in HCC, have not yet been fully investigated. In this pilot study, we assessed the expression levels of circ_0009910, circ_0027478, and miR-1236-3p in plasma samples from 100 patients diagnosed with HCC and 50 healthy controls through reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). The diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis, and correlations with clinicopathological features were examined. Circ_0009910 and circ_0027478 exhibited significant upregulation in patients with HCC (p < 0.05), whereas miR-1236-3p demonstrated downregulation (p < 0.05). Circ_0009910 demonstrated significant diagnostic accuracy (area under the curve [AUC] = 0.90), effectively differentiating HCC from controls and showing a correlation with tumor size, metastasis, and alpha-fetoprotein (AFP) levels (p < 0.05). Both circ_0009910 and circ_0027478 exhibited a positive correlation with clinicopathological features, whereas miR-1236-3p demonstrated an inverse correlation. Logistic regression validated the diagnostic and prognostic capabilities of these biomarkers. The results indicate that circ_0009910, circ_0027478, and miR-1236-3p, in conjunction with AFP three, present a promising diagnostic and prognostic profile for HCC. Additional validation in larger cohorts is required to establish their clinical utility.

Liver disease accounts for 4 % of global mortality. The advent of mobile technology has introduced a novel domain in liver disease management. Identifying effective mobile apps with pertinent information on liver diseases is essential. This study seeks to evaluate liver disease-related mobile applications using the Mobile Application Rating Scale (MARS) quality assessment tool.

This research employs a cross-sectional descriptive and analytical methodology focusing on liver disease-related mobile applications. We evaluated all Persian and English mobile applications available on the Google Play, Cafe Bazaar, and Myket Stores dedicated to liver diseases until 2023. After eliminating duplicates, evaluators extracted technical specifications and features of apps. The MARS was employed to assess the quality of the mobile applications. Both statistical and machine learning methods were employed for analysis.

A total of 2,044 mobile applications were identified, with 49 selected for final analysis. The apps focused on liver-related issues included general liver disease (n = 20, 40.82 %), hepatitis (n = 9, 18.37 %), and fatty liver disease (n = 8, 16.33 %). In terms of functionality, the majority of apps (n = 20, 40.82 %) served as calculators, with 15 specifically for calculation. Among these, three integrated educational elements, and two also supported diet and fitness alongside calculator functions. Additionally, 20 apps aimed to provide educational and informative content. The average quality score was 3.17 (SD = 0.20), with scores ranging from 2.33 to 4.45. Generally, the mean score of Engagement, Functionality, Aesthetics and Information were 4.20 (SD = 0.67), 4.00 (SD = 0.67), 4.00 (SD = 0.92), and 4.00 (SD = 0.67), respectively. The highest Subjective quality score was 4.75.

Liver disease-related mobile applications serve users in educational, diet and lifestyle, calculation, risk assessment, and management domains, focusing mainly on general liver diseases and hepatitis. However, the results revealed that the apps lack sufficient and reliable information.

Mexican-origin adults have one of the highest rates of metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe form metabolic dysfunction steatohepatitis (MASH) in the US. Given the costs and invasiveness of liver biopsy, this study assessed the application of Hepatoscope® 2DTE, the latest-generation transient elastography for liver stiffness in Mexican adult immigrants from Southern Arizona and compared it with FibroScan® VCTE™.

Participants (n = 199) from a cross-sectional community-based study completed anthropometric measures, demographic information, a blood draw, and liver stiffness measurements (LSM) with FibroScan VCTE and the ultraportable Hepatoscope 2DTE. LSM2DTE and LSMVCTE were compared using Spearman's correlation and Bland-Altman analysis. The number of at-risk for fibrosis participants as assessed using each system was compared according to FIB-4.

A total of 122 participants were considered for this sub-analysis which consisted of 71.3 % women. Mean age was 51.9 ± 12.1 years, BMI was 30.7 ± 5.7 kg/m², 43.4 % of participants had obesity, and 19.7 % were diabetic. Mean FIB-4 was 1.00 ± 0.53, and median LSM were 5.6 [4.7 - 6.7] and 5.3 [4.1 - 5.8] kPa for 2DTE and VCTE, respectively. 2DTE significantly correlated with VCTE (r = 0.53, p < 0.0001) and there was no systematic bias between the two LSM. There was no difference in the number of at-risk for fibrosis participants between the two LSM per FIB-4 categories.

Hepatoscope can be used for point-of-care liver stiffness assessment and risk stratification of adults at risk of liver fibrosis in community-based settings.

Silymarin is a natural flavonoid component isolated from the Silybum Marianum (Milk Thistle) plant with multiple pharmacological activities. We investigated its anti-fibrotic effect on the liver and demonstrated its role in activating hepatic progenitor stem cells during liver regeneration.

Hybrid polymeric protein nanoparticles were prepared by loading silymarin with an albumin-hyaluronic acid complex to achieve stem cell targeting and increase silymarin's bioavailability.

TEM, Zeta potential, DLS, UV-visible spectrophotometer, Fluorescence analysis, and FTIR verified the successful formation of nanoparticles and efficient encapsulation. In the present study, The liver fibrotic model was induced by the intraperitoneal injection of carbon tetrachloride, followed by the injection of silymarin NPs into mice twice a week for 4 weeks. We evaluated the expression of hepatic fibrosis markers such as (Collagen I, TGF-β1, SMAD3, and MMP-3) and hepatic progenitor stem cell activation markers such as (HNF1β, FOXl1, CD90, Vimentin, and CD105). The results showed that the targeted silymarin NPs caused significant suppression and downregulation of Collagen I, TGF-β, SMAD-3, and MMP-3 and upregulation of the hepatic progenitor stem cells markers HNF1β, FOXl1, CD90, Vimentin, and CD105. They also didn't induce expression of IL-6, IL-1β, and TNF-α, proving that they cause no signs of inflammation.

The novel point is that these results demonstrated that the targeted Silymarin NPs not only could efficiently alleviate CCl4-induced liver fibrosis more than using only free silymarin; by inhibiting the TGF-β/Smad-3 signaling pathway, but also could activate hepatic progenitor stem cells causing liver regeneration.

Cynaropicrin, a sesquiterpene lactone found in artichoke leaves exerts diverse pharmacological effects. This study investigated whether cynaropicrin has a paraptosis-like cell death effect in human hepatocellular carcinoma Hep3B cells in addition to the apoptotic effects reported in several cancer cell lines. Cynaropicrin-induced cytotoxicity and cytoplasmic vacuolation, a key characteristic of paraptosis, were not ameliorated by inhibitors of necroptosis, autophagy, or pan caspase inhibitors in Hep3B cells. Our study showed that cynaropicrin-induced cytotoxicity was accompanied by mitochondrial dysfunction and endoplasmic reticulum stress along with increased cellular calcium ion levels. These effects were significantly mitigated by endoplasmic reticulum stress inhibitor or protein synthesis inhibitor. Moreover, cynaropicrin treatment in Hep3B cells increased reactive oxygen species generation and downregulated apoptosis-linked gene 2-interacting protein X (Alix), a protein that inhibits paraptosis. The addition of the reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) neutralized cynaropicrin-induced changes in Alix expression and endoplasmic reticulum stress marker proteins counteracting endoplasmic reticulum stress and mitochondrial impairment. This demonstrates a close relationship between endoplasmic reticulum stress and reactive oxygen species generation. Additionally, cynaropicrin activated p38 mitogen activated protein kinase and a selective p38 mitogen activated protein kinase blocker alleviated the biological phenomena induced by cynaropicrin. NAC pretreatment showed the best reversal of cynaropicrin induced vacuolation and cellular inactivity. Our findings suggest that cynaropicrin induced oxidative stress in Hep3B cells contributes to paraptotic events including endoplasmic reticulum stress and mitochondrial damage.

Background: Liver diseases are a global health issue with an annual mortality of 80,000 patients, mainly due to complications that arise during disease progression, as effective treatments are lacking. Objectives: This study evaluated the hepatoprotective effects of two derivatives of cinnamic acid, LQM717 and LQM755, in a murine model of acute liver damage induced by carbon tetrachloride (CCl4, 4 g/kg, single dose p.o.). Methods: Male Wistar rats were pretreated with five doses of LQM717 (20 mg/kg i.p.) or LQM755 (equimolar dose), starting 2 days before inducing hepatotoxic damage with CCl4. Results: The key parameters of hepatocellular function and damage showed significant increases in ALT, ALP, GGT, and total and direct bilirubin in rats intoxicated with CCl4, with decreased liver glycogen and serum albumin. Macroscopic and microscopic liver examinations revealed reduced inflammation, necrosis, and steatosis in animals pretreated with LQM717 or LQM755. Hepatomegaly was observed only in the LQM717 + CCl4 group. LQM755 statistically provided partial protection against increases in ALT and ALP and completely prevented elevations in GGT and total and direct bilirubin. LQM755 completely prevented albumin reduction, while LQM717 only partially prevented it. Both compounds partially prevented glycogen depletion. Bioinformatic analysis identified 32 potential liver protein targets for LQM717 and 36 for LQM755. Conclusions: These findings suggest that LQM717 and LQM755 have significant hepatoprotective effects against CCl4-induced acute liver injury, providing information for future studies in other acute and chronic models, as well as to elucidate their mechanisms of action.

Liver cirrhosis is posing a global public health concern despite improvements in early diagnosis and therapeutic innovations. The present work evaluates the acute toxicity and prophylactic effects of an O-methylated flavonoid (Ombuin) in thioacetamide (TAA)-induced liver injury in rats and its underlying mechanisms. Thirty Sprague-Dawley rats were aligned into five cages and treated for two months as follows: group A ingested orally 1% CMC + distilled water (i.p.); group B had 1% CMC + 200 mg/kg TAA i.p. (three times weekly); group C had 50 mg/kg silymarin + 200 mg/kg TAA; group D had 30 mg/kg Ombuin + TAA; group E had 60 mg/kg Ombuin + mg/kg TAA. The non-toxic effects of Ombuin were evidenced by the lack of any toxicity incidence in rats ingested with up to 500 mg/kg. The TAA inoculation provoked significant hepatic intoxication confirmed by histopathological indications, alteration of tissue architecture, cellular proliferation, endothelial injury, enlarged hepatic nucleus, cytoplasmic vacuolation, collagen deposition, and elevated necrotizing tissues. The oxidative stress and inflammation process was noticeably initiated following TAA delivery to rats evidenced by down-regulation of SOD, CAT, GPx, and IL- 10, while, up-regulating the MDA and TNF-α and IL- 6 cytokines. TAA injection stimulated cellular proliferation and apoptotic actions in injured liver tissues, indicated by increased proliferating cell nuclear antigen (PCNA) and elevated expression of Bcl- 2-associated X (Bax) proteins. Ombuin supplementation showed significant resistance against TAA-mediated hepatotoxicity, reversed those cellular alterations, and restored liver functions. These results demonstrate significant ameliorative effects of Ombuin in TAA hepatotoxic rats, which could be attributed to its anti-apoptotic, antioxidant, and anti-inflammatory potentials, making it a possible viable hepatoprotective agent for inflammatory-related hepatitis.

Background: Chronic liver disease (CLD) is a major global health concern, contributing significantly to morbidity and mortality. Cirrhosis and liver cancer are the leading causes of liver-related deaths, with various etiological factors, such as metabolic disorders and alcohol-related and viral hepatitis, driving its global prevalence. Non-invasive biomarkers and scoring systems have emerged as key tools for assessing liver disease severity and differentiating CLD from cirrhosis. This study evaluates biomarkers and non-invasive scores and their utility in distinguishing CLD from cirrhosis. Methods: This retrospective observational study included 250 adult patients hospitalized between January 2021 and December 2023 at Cluj County Emergency Clinical Hospital, Romania. Patients were diagnosed with either cirrhosis or CLD of viral, autoimmune, or primary biliary cholangitis (PBC) etiology. Non-invasive biomarkers, scores, and various hemogram-derived ratios were evaluated. Statistical analysis involved descriptive statistics, comparative tests, and receiver operating characteristic (ROC) curve analysis. Results: Among the 250 patients, 137 had liver cirrhosis (54.8%) and 113 had CLD without cirrhosis (45.2%). Significant differences were observed in laboratory parameters, with cirrhosis patients showing lower hemoglobin, platelet count, and albumin levels alongside higher liver enzymes and INR values. Non-invasive scores such as APRI, FIB-4, and NFS demonstrated higher values in the cirrhosis group, indicating more advanced liver damage. Hemogram-derived ratios, particularly the neutrophil-to-lymphocyte ratio (NLR), were higher in cirrhosis patients. ROC analysis revealed that the Lok index had the highest discriminatory power (AUC 0.89), followed by the King score (AUC 0.864) and the Fibrosis index (AUC 0.856), which effectively distinguished cirrhosis from CLD. Conclusions: This study underscores the utility of non-invasive biomarkers and scoring systems in differentiating CLD from cirrhosis. The Lok index, King score, and Fibrosis index demonstrated excellent diagnostic accuracy, while hemogram-derived ratios, such as NLR, offer insights into systemic inflammation associated with liver disease progression. These findings support the integration of non-invasive markers into clinical practice for improved risk stratification and management of liver diseases.

The incidence and prevalence of chronic liver diseases (CLD) and liver cancer are increasing worldwide.

This study aimed to evaluate the associations between the intake levels of high-fat and low-fat dairy products and CLD mortality and liver cancer incidence.

This study included eligible participants from the NIH-American Association of Retired Persons Diet and Health Study cohort established between 1995 and 1996. Epidemiological data, including dietary factors, were collected using a self-administered validated questionnaire. Portion size and frequency of intake of dairy products were recorded. Cox proportional hazard models were used to examine the associations.

A total of 485,931 eligible participants, 59.8% male, with an average age of 61.5 y (SD = 5.4 y) at baseline were included in this analysis after excluding those with pre-existing cancer diagnoses or extreme caloric intakes. During a median follow-up of 15.5 y, 993 deaths from CLD and 940 incident liver cancer cases occurred. CLD mortality was positively associated with intake of high-fat dairy [hazard ratio (HR)21+ compared with 0-<3.5 serv/wk = 1.51, 95% confidence interval (CI): 1.24, 1.84, Ptrend = 0.009] and high-fat milk (HR14+ compared with 0 serv/wk = 2.03, 95% CI: 1.31, 3.14, Ptrend <0.001), and was inversely associated with low-fat dairy (HR21+ compared with 0-<3.5 serv/wk =0.62, 95% CI: 0.46, 0.84, Ptrend = 0.002), low-fat milk (HR14+ compared with 0 serv/wk =0.54, 95% CI: 0.41, 0.70, Ptrend = 0.028) and yogurt (HR4+ compared with 0 serv/wk = 0.60, 95% CI: 0.37, 0.97, Ptrend = 0.057). Total dairy intake (HR21-<28 compared with 0-<7 serv/wk = 1.26, 95% CI: 0.99, 1.59, Ptrend = 0.040) and high-fat dairy (HR14-<21 compared with 0-<3.5 serv/wk = 1.35, 95% CI: 1.07, 1.70, Ptrend = 0.14) showed marginally positive association with liver cancer risk. Milk intake was positively associated with risk of hepatocellular carcinoma (HCC).

High-fat dairy intake is positively associated with CLD mortality, and low-fat dairy shows an inverse association. Total dairy intake is marginally positively associated with liver cancer, and milk intake is positively associated with HCC.

Liver fibrosis is a critical precursor to the progression of cirrhosis and liver cancer. However, the development of precision therapies for this condition has been impeded by incompletely elucidated molecular mechanisms. Activin receptor like kinase 5 (ALK5), termed TGF-β type I receptor (TGF-βRI), has been identified as a promising therapeutic target for antifibrotic drug development. In this study, we designed and synthesized two novel thiazole derivatives (J-1155 and J-1156) featuring enantiomeric amino acid moieties to selectively target ALK5 for hepatic fibrosis treatment. Our data demonstrated that both compounds effectively attenuate hepatic fibrosis and associated inflammation through dual inhibition of the TGF-β/Smad signaling pathway and blockade of the P2X7R-NLRP3 inflammasome axis. In comparison, J-1156 demonstrated superior overall therapeutic efficacy to J-1155 in terms of anti-fibrotic efficacy, while J-1155 exhibited superior modulation of Smurf2. Collectively, our observations demonstrate the potential of J-1155 and J-1156 as dual novel therapeutic agents targeting hepatic fibrosis.

Advances in nucleic acid delivery have positioned the liver as a key target for gene therapy, with adeno-associated virus vectors showing long-term effectiveness in treating hemophilia. Steatotic liver disease (SLD), the most common liver condition globally, primarily results from metabolic dysfunction-associated and alcohol-associated liver diseases. In some individuals, SLD progresses from simple steatosis to steatohepatitis, cirrhosis, and eventually hepatocellular carcinoma, driven by a complex interplay of genetic, metabolic, and environmental factors. Genetic variations in various lipid metabolism-related genes, such as patatin-like phospholipase domain-containing protein 3 (PNPLA3), 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13), and mitochondrial amidoxime-reducing component 1 (MTARC1), impact the progression of SLD and offer promising therapeutic targets. This review largely focuses on genes identified through clinical association studies, as they are more likely to be effective and safe for therapeutic intervention. While preclinical research continues to deepen our understanding of genetic factors, early-stage clinical trials involving gene-based SLD therapies, including transient antisense and small-molecule approaches, are helping prioritize therapeutic targets. Meanwhile, hepatocyte gene editing technologies are advancing rapidly, offering alternatives to transient methods. As such, gene-based therapies show significant potential for preventing the progression of SLD and enhancing long-term liver health.

Disulfidptosis is a newly discovered programmed cell death pathway that may be connected to tumorigenesis and development, showing promise as a novel treatment strategy for cancer. This study aims to construct a prognostic model of disulfidptosis-related Long non-coding RNAs (DRLRs) within the Asian HCC population and to investigate the impact of DRLRs on HCC.

Utilising a combination of univariate Cox, Lasso-Cox, and multivariate Cox analyses, five pivotal DRLRs (AC099850.3, ZNF337-AS1, LINC01138, AL031985.3, AC131009.1) were identified, forming a robust prognostic signature. Subsequent validations included Receiver Operating Characteristic (ROC) and Concordance Index analyses, alongside Principal Component Analysis. Comprehensive bioinformatics analysis was performed on the hub DRLRs, followed by experimental validation using quantitative real-time polymerase chain reaction and cellular functional assays.

The risk score independently predicted prognosis, outperforming traditional clinical-pathological factors across varying ages, tumour stages, and pathological classifications in the cohort. A nomogram integrating these variables demonstrated capability in forecasting survival. Multivariate analysis confirmed that the risk score and AJCC TNM staging are independent prognostic factors for predicting overall survival (OS) in Asian HCC patients (both P < 0.001). The prognostic model's ROC area under the ROC values for 1-, 3-, and 5-year predictions were 0.837, 0.794, and 0.783, respectively, indicating its strong diagnostic and prognostic value. Pathway and immune landscape analyses elucidated the biological underpinnings and immune modulations associated with the high-risk group. Immune landscape analysis indicated that both immunescore (P < 0.001) and estimatescore (P < 0.05) were significantly decreased in the high-risk group, with both specific and non-specific immune responses being significantly suppressed, while the tumour immune dysfunction and exclusion score was notably increased (P < 0.001). Tumour mutational burden (TMB) analysis revealed a significantly higher TMB in the high-risk group (P = 0.033) and shorter OS for HCC patients in the high TMB subgroup (P = 0.002). Notably, Potential chemotherapeutic agents (PFI3, 5-Fluorouracil, BPD-00008900, GDC0810, and AZ6102) were identified for high-risk group. Experimental validations through quantitative PCR and in vitro assays confirmed the deregulation of these DRLRs in HCC, with functional studies highlighting the potential of ZNF337-AS1 silencing in curtailing tumour invasiveness.

Our investigations validate a DRLR-based risk scoring model as an effective prognostic tool for Asian HCC. This model not only enhances understanding of disulfidptosis's role in HCC but also facilitates personalised treatment strategies, potentially improving patient outcomes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with adverse clinical outcomes, impaired health-related quality of life, and large economic burden. The growing burden of MASLD and MASH has led to the publication of a large number of MASLD/MASH guidelines by national and international societies. However, important differences among the recommendations have created confusion, contributing to a low rate of implementation and suboptimal management of MASLD and MASH. Creating a consensus recommendation has become more important since the approval of a partial agonist of thyroid hormone β receptor (resmetirom) for MASH treatment in the United States. We built a consensus among the most recently published recommendations for MASLD/MASH.

A comprehensive search for MASLD and MASH guidelines, guidance, or similar documents from January 2018 to January 2025 using PubMed, Embase, Web of Science, and society websites was conducted. Each selected document was assessed across 8 specific domains with 145 variables. Variables with <50% concordance were used for the Delphi statement development. A supermajority of 67% was set for Delphi statement acceptance.

There were 61 documents published from 2018 through January 2025. Four rounds of Delphi were conducted: 46 statements were generated for Round 1, 32 statements for Round 2, 16 statements for Round 3, and 8 statements for Round 4, whereby 100% of statements achieved a greater than 90% agreement. All final consensus recommendations were summarized in tables and algorithms.

Our study provides an extensive set of recommendations generated based on a comprehensive review of the most recent MASLD/MASH guidelines and a consensus-building process.

As the major driving factor of hepatic fibrosis, the activated hepatic stellate cells (aHSCs) rely on active glycolysis to support their aberrant proliferation and secretion of the extracellular matrix. Sorafenib (Sor) can combat liver fibrosis by suppressing HIF-1α and glycolysis, but its poor solubility, rapid metabolism, and low bioavailability restrict such a clinical application. Here, Sor was loaded onto polydopamine nanoparticles and then encapsulated by a retinoid-decorated red blood cell membrane, yielding HSC-targeted Sor nanovesicles (PDA/Sor@RMV-VA) with a high Sor-loading capacity and photothermally controlled drug release for antifibrotic treatment. These Sor RMVs not only exhibited a good particle size, dispersity and biocompatibility, prolonged circulation time, enhanced aHSC targetability, and hepatic accumulation both in vitro and in vivo, but also displayed a mild photothermal activity proper for promoting sorafenib release and accumulation in CCl4-induced fibrotic mouse livers without incurring phototoxicity. Compared with nontargeting Sor formulations, PDA/Sor@RMV-VA more effectively downregulated HIF-1α and glycolytic enzyme in both cultured aHSCs and fibrotic mice and reversed myofibroblast phenotype and amplification of aHSCs and thus more significantly improved liver damage, inflammation, and fibrosis, all of which could be even further advanced with NIR irradiation. These results fully demonstrate the antifibrotic power and therapeutic potential of PDA/Sor@RMV-VA as an antifibrotic nanomedicine, which would support a new clinical treatment for hepatic fibrosis.

Chronic liver disease affects over a billion people worldwide. Liver fibrosis is the key driver of liver-related complications and mortality. Elastography has been a transformative tool in hepatology, allowing for the diagnosis and staging of liver fibrosis noninvasively, and is evolving beyond these purposes into a prognostication tool. By measuring tissue stiffness, elastography techniques such as shear-wave and magnetic resonance elastography offer critical insights into liver fibrosis, portal hypertension, and the progression of disease. Magnetic resonance elastography stands out for its reliability across fibrosis stages and robustness in obese patients affected by metabolic liver disease. Spleen stiffness measurement complements liver assessments, enhancing the identification of portal hypertension and refining patient risk stratification. This review covers current clinical applications but also anticipates future innovations such as artificial intelligence-based algorithms that could expand elastography's clinical impact, thereby improving patient outcomes.

The global prevalence of Metabolic Dysfunction-Associated Steatohepatitis (MASH) has been rising sharply, closely mirroring the increasing rates of obesity and metabolic syndrome. MASH exhibits a strong sexual dimorphism where females are affected with more severe forms after menopause. Hexokinase domain-containing protein 1 (HKDC1) has recently been recognized for its role in liver diseases, where its expression is minimal under normal conditions but significantly increases in response to metabolic stressors like obesity and liver injury. This selective upregulation suggests HKDC1's potential specialization in hepatic glucose and lipid dysregulation, linking it closely to the progression of MASH. This study aims to clarify the role of HKDC1 in Western diet-induced MASH in female mice by examining its impact on hepatic glucose and lipid metabolism, offering insights into its potential as a therapeutic target and addressing the need for sex-specific research in liver disease. This study reveals that HKDC1 expression is elevated in obese women with MASH and correlates with liver pathology. In a mouse model, liver-specific HKDC1 knockout (HKDC1LKO) protected against Western diet-induced obesity, glucose intolerance, and MASH features, including steatosis, inflammation, and fibrosis. Transcriptomic analysis showed that HKDC1 deletion reduced pro-inflammatory and pro-fibrotic gene expression, while gut microbiome analysis indicated a shift toward MASH-protective bacteria. These findings suggest that HKDC1 may exacerbate MASH progression through its role in metabolic and inflammatory pathways, making it a potential therapeutic target.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by metabolic triggers and genetic predisposition. Among the genetic MASLD risk variants identified today, the common PNPLA3 148M variant exerts the largest effect size of MASLD heritability. The PNPLA3 148M protein is causatively linked to the development of liver steatosis, inflammation and fibrosis in experimental studies and is therefore an appealing target for therapeutic approaches to treat this disease. Several PNPLA3 targeted approaches are currently being evaluated in clinical trials for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), the most severe form of MASLD and promising proof of principle data with reduced liver fat content in homozygous PNPLA3 148M risk allele carriers has been reported from phase 1 trials following hepatic silencing of PNPLA3. Thus, targeting PNPLA3, the strongest genetic determinant of MASH may hold promise as the first precision medicine for the treatment of this disease. A histological endpoint-based phase 2b study has been initiated and several more are expected to be initiated to evaluate treatment effects on histological MASH and liver fibrosis in participants being homozygous for the PNPLA3 148M risk allele variant. The scope of this mini-review is to briefly describe the PNPLA3 148M genetics, function and preclinical experimental evidence with therapeutic approaches targeting PNPLA3 as well as to summarise the PNPLA3 based therapies currently in clinical development.

Elevated lactate levels increase the risk of liver cancer progression. However, the mechanisms by which lactate promotes liver cancer progression remain poorly understood. Epithelial-mesenchymal transition (EMT), characterized by the loss of epithelial cells polarity and cell-cell adhesion, leading to the acquisition of mesenchymal-like phenotypes, is widely recognized as a key contributor to liver cancer progression. TWIST1 (Twist Family BHLH Transcription Factor 1) plays a central role in inducing EMT. Here, we investigated the role of lactate in promoting EMT in liver cancer and the underlying regulatory mechanisms. High levels of lactate significantly promoted EMT progression in liver cancer cells. Mechanistically, lactate-induced lactylation of TWIST1 in vivo and in vitro. Mutation assay confirmed that Lysine 33 (K33) is the major site of TWIST1 lactylation. Moreover, cell fractionation & luciferase reporter assay results identified that TWIST1-K33R mutant impaired the EMT process via inhibiting nuclear import and the transcriptional activity. Thus, our findings provide novel insights into the regulatory role of lactate in EMT in liver cancer pathogenesis. Additionally, targeting of lactate-driven lactylation of TWIST1 may boost the therapeutic strategy for liver cancer.

PANoptosis is a multimodal form of cell death that involves inflammatory, apoptotic, and necroptotic pathways, playing a key role in the development of liver diseases. This article first outlines the definition and characteristics of PANoptosis, and then explores its mechanisms of action in different types of liver diseases, including acute liver injury, liver failure, metabolic dysfunction-associated fatty liver disease, and hepatocellular carcinoma. Furthermore, this article analyses the molecular regulatory network of PANoptosis and potential therapeutic targets. Finally, this article summarises the current research on PANoptosis in liver diseases and future research directions, and it reviews the role of the emerging cell death mechanism of PANoptosis in liver diseases.

Lipid-based nanoparticles have emerged as promising drug delivery systems for a wide range of therapeutic agents, including plasmids, mRNA, and proteins. However, these nanoparticles still encounter various challenges in drug delivery, including drug leakage, poor solubility, and inadequate target specificity. In this comprehensive review, we present an in-depth investigation of four distinct drug delivery methods: liposomes, lipid nanoparticle formulations, solid lipid nanoparticles, and nanoemulsions. Moreover, we explore recent advances in lipid-based nanomedicines (LBNs) for organ-specific delivery, employing ligand-functionalized particles that specifically target receptors in desired organs. Through this strategy, LBNs enable direct and efficient drug delivery to the intended organs, leading to superior DNA or mRNA expression outcomes compared to conventional approaches. Importantly, the development of novel ligands and their judicious combination holds promise for minimizing the side effects associated with nonspecific drug delivery. By leveraging the unique properties of lipid-based nanoparticles and optimizing their design, researchers can overcome the limitations associated with current drug delivery systems. In this review, we aim to provide valuable insights into the advancements, challenges, and future directions of lipid-based nanoparticles in the field of drug delivery, paving the way for enhanced therapeutic strategies with improved efficacy and reduced adverse effects.

The distribution of major causes of liver cancer (LC) in the United States (US) has changed significantly over time. This study analyzes recent temporal trends in the causes of LC in the US from 1990 to 2021 and predicts future trends.

We obtained detailed data on LC in the US from the Global Burden of Disease (GBD) 2021 study. Estimated annual percentage change (EAPC) values for LC in the US were then calculated using linear regression models. An exponential smoothing (ES) projection model and Bayesian Age-Period-Cohort (BAPC) projection model were then used to predict the future disease burden of LC. Risk factors for LC were also assessed.

In 2021, the disease burden of LC in the US was significantly higher than in 1990. Hepatitis C virus (HCV)-associated LC resulted in the greatest burden of disease. The fastest growing burden of disease was attributed to metabolic dysfunction-associated steatotic liver disease (MASLD)-associated LC. Higher burdens of disease were seen in older and male populations.

In the US, the disease burden of LC from different etiologies continues to rise. As such, targeted prevention and control strategies should be developed to address these unique disease characteristics.

NS5A is a multi-functional phosphoprotein that plays a key role in hepatitis C virus (HCV) genome replication and assembly. The consequences of NS5A phosphorylation for HCV biology remain largely undefined. We previously identified serine 225 (S225) as a major phosphorylation site within the low complexity sequence 1 (LCSI) of NS5A and used a phosphoablatant mutant (S225A) to define the role of this phosphorylation event in genome replication, NS5A-host interactions and sub-cellular localisation. In this study, we investigate this further by raising an antiserum to S225 phosphorylated NS5A (pS225). Western blot analysis revealed that pS225 was predominantly in the hyper-phosphorylated NS5A species. Using a panel of phosphoablatant mutants of other phosphorylation sites in LCSI, we obtained evidence that is consistent with bidirectional hierarchical phosphorylation initiated by phosphorylation at S225. Using super-resolution microscopy (Airyscan and Expansion), we revealed a unique architecture of NS5A-positive punctae in HCV-infected cells; pS225 was present on the surface of these punctae, close to lipid droplets. Although S225 phosphorylation was not specifically affected by treatment with the NS5A-targeting direct acting antiviral agent daclatasvir, this resulted in the condensation of NS5A-positive punctae into larger structures, recapitulating the S225A phenotype. These data are consistent with a key role for S225 phosphorylation in the regulation of NS5A function.

The burden of chronic liver disease (CLD) is dramatically increasing. It is estimated that 20-30% of the population worldwide is affected by CLD. Hepatic fibrosis is a symptom common to all CLDs. Although it affects liver functional activities, it is a reversible stage if diagnosed at an early stage, but no resolutive therapy to contrast liver fibrosis is currently available. Therefore, efforts are needed to study the molecular insights of the disease. Emerging cutting-edge fields in cellular and molecular biology are introducing innovative strategies. Spatial and single-cell resolution approaches are paving the way for a more detailed understanding of the mechanisms underlying liver fibrosis. Cellular models have been generated to recapitulate the in-a-dish pathophysiology of liver fibrosis, yielding remarkable results that not only uncover the underlying molecular mechanisms but also serve as patient-specific avatars for precision medicine. Induced pluripotent stem cells (iPSC) and organoids are incredible tools to reshape the modeling of liver diseases, describe their architecture, and study the residents of hepatic tissue and their heterogeneous population. The present work aims to give an overview of innovative omics technologies revolutionizing liver fibrosis research and the current tools to model this disease.

Hepatocellular carcinoma remains a significant cause of mortality worldwide, particularly among patients with liver cirrhosis. In most cases, surveillance in cirrhotic patients is neglected, leading to a diagnosis when the neoplasm is at an advanced stage. Within this context, Zhou et al carried out a network meta-analysis to demonstrate the effectiveness of hepatic arterial infusion chemotherapy, concluding that it is a superior approach compared to sorafenib and transarterial chemoembolization in the treatment of advanced hepatocellular carcinoma. Unfortunately, the meta-analysis in question lacks methodological rigor, preventing the authors from making more definitive assertions. Additionally, we understand that transarterial chemoembolization, when properly indicated, is a highly effective therapeutic option, and that sorafenib, given the results of new therapies based on immune checkpoint inhibitors, is no longer the recommended drug for the treatment of these patients. Therefore, we believe the use of hepatic arterial infusion chemotherapy is increasingly limited and lacks strong scientific support.

Tryptophan (Trp) is an essential amino acid that must be acquired exclusively through dietary intake. The metabolism of tryptophan plays a critical role in maintaining immune homeostasis and tolerance, as well as in preventing excessive inflammatory responses. Tryptophan-2,3-dioxygenase (TDO2) is a tetrameric heme protein and serves as one of the pivotal rate-limiting enzymes in the first step of tryptophan metabolism. Dysregulation of TDO2 expression has been observed in various digestive system diseases, encompassing those related to the oral cavity, esophagus, liver, stomach, pancreas, and colon and rectum. Digestive system diseases are the most common clinical diseases, with complex clinical manifestations and interrelated symptoms, and have become a research hotspot in the field of medicine. Studies have demonstrated that aberrant TDO2 expression is closely associated with various clinical manifestations and disease outcomes in patients with digestive system disorders. Consequently, TDO2 has garnered increasing recognition as a promising therapeutic target for digestive system diseases in recent years, attracting growing attention. This article provides a brief overview of the role of TDO2 in the tryptophan pathway, emphasizing its significant involvement in diseases of the digestive system. Strategies targeting TDO2 through specific inhibitors suggest considerable promise in enhancing therapeutic outcomes for digestive diseases. Thus, this review concludes by discussing recent advancements in the development of TDO2 inhibitors. We believe that targeted inhibition of TDO2 combined with immunotherapy, the screening of a large number of natural products, and the assistance of artificial intelligence in drug design will be important directions for developing more effective TDO2 inhibitors and improving treatment outcomes in the future.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common form of chronic liver disease, for which only resmetirom has recently received FDA approval. Prevention is crucial, as it can help manage and potentially reverse the progression of MAFLD to more severe stages. Omega-3 fatty acids, which are a type of polyunsaturated fatty acid (PUFA), have numerous beneficial effects in health and disease, including liver disease. Other bioactive lipids, such as furanic fatty acids (FuFA) and hydroxy fatty acid esters (FAHFA), have also demonstrated several benefits on relevant markers of liver dysfunction in animal and cell models. However, the effects of FAHFAs on hepatic steatosis are inconsistent, and studies on the impact of FuFAs in MAFLD are scarce. Further and more extensive research is required to better understand their role in liver health. The aim of this narrative review is to provide a brief overview of the potential effects of omega-3 fatty acids and other bioactive lipids, such as FuFAs and FAHFAs, on liver disease, with a focus on MAFLD.

Hepatic osteodystrophy (HOD) is an important public health issue that severely affects human health. The pathogenesis of HOD is complex, and exposure to environmental pollutants plays an important role. Di-(2-ethylhexyl) phthalate (DEHP) is a persistent environmental endocrine toxicant that is present in many products, and the liver is an important target organ for its toxic effects. Our research aimed to investigate the effects of DEHP on HOD, and to reveal the underlying mechanisms and the potential key preventive approaches.

The daily intake EDI of DEHP and bone density indicators for men and women from 2009 to 2018 were screened and organized from the NHANES database to reveal the population correlation between EDI and BMD; C57BL/6 female and male mice were selected to construct an animal model of DEHP induced HOD, exploring the fuchtions and mechanisms of DEHP on osteoporosis; the novel small molecule inhibitor imICA was used to inhibit the process of DEHP induced osteoporosis, further exploring the targeted inhibition pathway of DEHP induced HOD.

Male and female populations were exposed to a relatively lower concentration of DEHP, and that only the male population exhibited a negative correlation between DEHP exposure and bone mineral density. An in vivo study confirmed that a low dose of DEHP caused liver lesions, disrupted liver function, and induced osteoporosis in male but not female C57BL/6J mice. Regarding the molecular mechanisms, a low dose of DEHP activated the hepatic 14-3-3η/nuclear factor κB (NF-κB) positive feedback loop, which in turn modified the secretory proteome associated with bone differentiation, leading to HOD. Finally, we revealed that targeting the 14-3-3η/ NF-κB feedback loop using our novel 14-3-3η inhibitor (imICA) could prevent DEHP-induced HOD.

A low dose of DEHP activated the hepatic 14-3-3η/ NF-κB positive feedback loop, which in turn modified the secretory proteome associated with bone differentiation and elevated IL-6 and CXCL1 levels, leading to HOD. Targeted 14-3-3η/NF-κB feedback loop using our novel 14-3-3η inhibitor, imICA, prevented DEHP-induced HOD.