Hepatic fibrosis lacks effective direct antifibrotic therapy. Human V3–V4 16S rRNA profiling identified a sequence feature provisionally assigned to M. hypermegale that was depleted in hepatic fibrosis; subsequent functional experiments used a cultured M. hypermegale strain. Administered from the onset of fibrosis induction, oral M. hypermegale attenuated CCl₄- and DDC-induced fibrosis in preventive/early-intervention models, reduced liver injury and collagen accumulation, and partially preserved intestinal epithelial integrity. M. hypermegale-conditioned medium suppressed transforming growth factor-β-induced hepatic stellate cell (HSC) activation, with activity retained after heat treatment, proteinase K digestion, and <3-kDa fractionation. Targeted metabolomics and germ-free mono-colonization identified indole-3-lactic acid (ILA) as a prominent M. hypermegale-associated metabolite. Purified ILA reproduced the antifibrotic phenotype and inhibited HSC contractility through aryl hydrocarbon receptor (AHR)-dependent suppression of RhoA/ROCK/p-MLC2 signaling. HSC-selective Ahr knockdown in mice and CRISPR/Cas9-mediated AHR disruption in HSCs weakened these effects. Arabinoxylan increased M. hypermegale abundance and portal ILA availability in association with reduced fibrosis. Circulating ILA was decreased in patients and inversely associated with indices of liver injury and fibrosis. These findings identify an M. hypermegale–ILA–AHR pathway that restrains HSC activation and supports microbiota–metabolite-directed strategies for experimental hepatic fibrosis.

Gastroesophageal variceal bleeding is a life-threatening complication of portal hypertension. This study evaluated the efficacy and safety of endoscopic ultrasound-guided selective variceal devascularization (EUS-SVD) compared with conventional endoscopic cyanoacrylate injection. This retrospective cohort study adhered to the STROBE guidelines. Between August 2022 and June 2024, 107 patients were enrolled and allocated to conventional endoscopy (n = 52) or EUS-SVD (n = 55). Propensity score matching was performed to reduce confounding. Primary outcomes included rebleeding, ulcer formation, and resource utilization. Compared with the conventional group, the EUS group required significantly lower volumes of polidocanol and cyanoacrylate (both P < 0.05). The 6‑month rebleeding rate and 3‑month ulcer formation rate were significantly lower in the EUS group (P < 0.05). Kaplan-Meier analysis demonstrated a reduced cumulative rebleeding incidence in the EUS group (HR 0.38, 95

IMPORTANCE:In Crohn's disease (CD) patients treated with biologics preoperatively, the optimal strategy for postoperative biologic management remains unclear. DESIGN:This was a retrospective multicenter study involving CD patients with ileocolonic anastomosis from 9 medical centers. Patients were divided into "the consistent group" (postoperative biologic previously used before surgery) and "the switched group" (postoperative biologic not used preoperatively). The primary endpoint was postoperative endoscopic recurrence (ER), which was defined as the first endoscopy performed between 6 and 18 months after surgery. Propensity score matching (PSM) was used to minimize baseline differences between groups, and conditional logistic regression was applied to identify factors associated with ER. RESULTS:In total, 227 patients were included in the study, of whom 177 were in the consistent group. No significant difference was observed in the rate of ER between the switched group and the consistent group (30.0% vs 40.7%, P = .170). In patients with ≤2 risk factors defined by established guidelines, the switched group showed a lower ER rate (20.6% vs 40.0%, P = .038). After 1:1 PSM, the switched group had a lower ER rate (29.4% vs 61.8%, P = .027). Conditional logistic regression analysis revealed that switching biologics was associated with a lower risk of ER (odds ratio = 0.31, 95% confidence interval, 0.11-0.85, P = .023). CONCLUSIONS:In CD patients with preoperative biologic exposure, both continuing and switching biologic therapy postoperatively were effective in preventing ER, with switching showing improved endoscopic outcomes after adjustment for confounders.

Ulcerative colitis (UC) is characterized by intestinal barrier dysfunction and chronic inflammation, yet its underlying mechanisms remain incompletely understood. This study investigates the role of Six-transmembrane epithelial antigen of the prostate 4 (STEAP4), a metalloreductase linked to redox regulation, in UC pathogenesis. Using clinical samples from IBD patients, a dextran sulfate sodium (DSS)-induced murine colitis model, and lipopolysaccharide (LPS)-treated intestinal epithelial cells (NCM460 and HT-29), we demonstrated that STEAP4 expression was significantly upregulated in inflamed mucosa across human, murine, and in vitro models. H&E staining, and Western blot analyses verified the successful modeling of DSS-induced colitis mice. STEAP4 knockdown via siRNA restored tight junction protein claudin-1 expression (p < 0.05; n=3), increased TEER value (p < 0.001; n=3), decreased the permeability of FITC-D (p < 0.01, p < 0.001; n=3) and suppressed LPS-induced pro-inflammatory cytokines (TNF-α, IL-6) (p < 0.05; n=3) by attenuating NF-κB phosphorylation (p65, IκBα) (p < 0.05, p < 0.01, p < 0.001; n=3). These findings position STEAP4 as a critical regulator of mucosal inflammation, bridging redox homeostasis, epithelial barrier function, and NF-κB-driven immune responses. Our study highlights STEAP4 as a potential therapeutic target for restoring intestinal homeostasis in UC, warranting further exploration of its molecular interactions and translational applications.

The gut commensal bacterium Akkermansia muciniphila (AKK) has emerged as a candidate for treating liver disorders, yet its therapeutic potential in liver fibrosis remains poorly defined. Here, using a carbon tetrachloride (CCl4)-induced murine model, we show that AKK administration markedly attenuates collagen deposition, inflammation, and hepatic injury. AKK restored intestinal barrier integrity, reshaped microbial composition, and enhanced propionic acid transport from the gut to the liver, leading to suppression of hepatic stellate cell activation. Multi-omics profiling revealed that AKK enriched propionate-producing taxa and upregulated key metabolic enzymes, thereby elevating hepatic propionate levels. Supplementation with propionic acid alone recapitulated AKK's benefits, improving liver function, alleviating extracellular matrix accumulation, and activating the Keap1-Nrf2 antioxidant pathway. Together, our findings identify a microbiota-metabolite axis in which AKK counters liver fibrosis by enhancing propionate-mediated antioxidant regulation, highlighting its therapeutic promise for chronic liver disease.

PurposeTo provide a detailed pooled analysis of the diagnostic accuracy of microRNAs (miRNAs) in predicting the response to transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC).MethodsA comprehensive literature search was conducted across PubMed, Embase, Cochrane Library, and Web of Science to identify studies assessing the diagnostic performance of miRNAs in predicting TACE response in HCC. Two independent reviewers performed quality assessment and data extraction using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristic (SROC) curve were calculated using a bivariate random-effects model. Subgroup analyses and meta-regression were performed to explore potential sources of heterogeneity, including sample size, response criteria, specimen source, response evaluation methods, TACE efficacy interval window, and geographical location.ResultsSeven studies, comprising 320 HCC responders and 187 non-responders, were included in this meta-analysis. The miRNAs studied included miR-373, miR-210, miR-4492, miR-1271, miR-214, miR-133b, and miR-335. The pooled sensitivity of miRNAs in predicting recurrence after TACE was 0.79 [95% CI: 0.72-0.84], and the pooled specificity was 0.82 [95% CI: 0.74-0.88]. The DOR was 17 [95% CI: 9-33], and the pooled area under the SROC curve (AUC) was 0.85 [95% CI: 0.81-0.88], indicating excellent diagnostic accuracy. Subgroup analyses revealed significant differences in diagnostic performance based on response criteria and geographical location. Meta-regression did not identify any significant sources of interstudy heterogeneity.ConclusionMiRNAs show promise as diagnostic tools for predicting TACE response in HCC patients. However, their clinical application requires further validation in larger cohorts. Future research should focus on standardizing RNA extraction methods, selecting consistent endogenous controls, and adopting uniform response evaluation criteria to improve reliability and reduce variability.

The immunoproteasome regulatory component proteasome activator subunit beta (PSME2) plays a crucial role in immune regulation, yet its impact on intestinal barrier integrity in ulcerative colitis (UC) remains unclear. This study aimed to elucidate the involvement of PSME2 in UC pathogenesis. Clinical samples from UC patients and healthy controls were analyzed to assess PSME2 expression. A dextran sulfate sodium-induced colitis mouse model was employed to evaluate disease progression, colon histology, and PSME2 levels. In vitro, colonic cells were treated with lipopolysaccharide (LPS) to examine tight junction protein (claudin-1) expression and inflammatory mediators (IL-6, IL-10, TNF-α). Autophagy modulation was investigated using PSME2 silencing and chloroquine (CQ) treatment. PSME2 upregulation in UC and colitis mice correlated with disease severity. In vitro, LPS suppressed claudin-1 expression, while PSME2 knockdown restored claudin-1 levels and reduced inflammatory cytokines. PSME2 depletion enhanced autophagy, as indicated by an increased LC3-II/LC3-I ratio, reduced p62, and elevated LC3B puncta. CQ treatment reversed the protective effects of PSME2 silencing, confirming autophagy’s role in barrier integrity. PSME2 exacerbates intestinal inflammation by promoting cytokine release and disrupting epithelial barrier function through autophagy dysregulation. Suggesting its potential as a therapeutic target.

INTRODUCTION:Hepatocellular carcinoma (HCC) is one of the most common malignant tumors globally. Macrophages, as essential components of the immune system, play crucial roles in immune regulation, inflammation modulation, and antitumor activity. However, it remains unclear whether tumor-associated macrophages can serve as prognostic markers for HCC. METHODS:First, we identified tumor-associated macrophages based on single-cell data from GSE140228. Then, using a machine learning approach with a combination of 101 module genes, we constructed an optimal prognostic model. Subsequently, we compared our constructed model with other published prognostic models for HCC. Finally, we utilized the generated model score to predict the response to chemotherapy and immune therapy. RESULTS:First, we identified clusters of tumor-associated macrophages using single-cell data. Subsequently, we calculated the tumor-associated macrophage score based on module genes from the previous step. Compared to traditional clinical indicators, tumor-associated macrophage signature (TAMS) exhibits significant advantages. The TAMS C-index not only predicts overall survival, but also recurrence-free survival in HCC patients. Additionally, there was a higher prevalence of TP53 mutations in HCC patients with high TAMS. Furthermore, patients with low TAMS showed greater sensitivity to immunotherapy compared to those with high TAMS. Notably, the number and intensity of interactions between TAM and other T lymphocytes were significantly higher than those involving other cell populations. Interestingly, the high TAMS group exhibited significantly elevated levels of immune checkpoint markers and M2 macrophage markers. CONCLUSION:TAMS can serve as a novel and potent tool, offering improved treatment options and prognostic assessment for patients with HCC.

Auricularia auricula, esteemed in Chinese culture for their culinary and medicinal properties, exhibits notable metabolic and immunomodulatory effects. The principal active constituents are indigestible fermentable polysaccharides, which not only exhibit anti-inflammatory activities but also facilitate the proliferation of beneficial gut microbiota. However, the influence of gut-derived components on liver-regulated metabolic products remains insufficiently understood. This item offers insights into the therapeutic potential of wood ear mushrooms for treating hepatic fibrosis and the associated mechanisms. Following 8 weeks of treatment, a substantial reduction in ECM deposition was recorded, linked to modulation of the NLRP3 inflammasome activation. This study aims to reveal the potential microbiome-mediated mechanisms behind its therapeutic effects. Insights from antibiotic combination treatments indicate that the protective effects against ECM deposition rely on the presence of specific gut microbiota. This fecal microbiota intervention enhances key physiological mechanisms, underscoring the contributions of Lactobacillales, Rikenellaceae, and Bacteroidaceae in potentially mitigating fibrosis. Collectively, these findings suggest that interventions utilizing wood ear mushrooms may reduce inflammation and ECM deposition, mediated by the TLR4/NF-κB pathway.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and remains a global health challenge. The biological process of HCC is very complex, involving the imbalance of tumor suppressor genes and oncogenes, abnormal activation of molecular signaling pathways, and the differentiation of HCC cells. Standard clinical approaches for HCC treatment encompass surgery, chemotherapy, and radiation therapy. However, treatment options for advanced HCC are constrained, primarily due to an incomplete understanding of its underlying mechanisms. Cellular senescence is a crucial mechanism that influences the pathophysiological processes of HCC and serves as a potent barrier to tumor development. Our research identified the biological functions and mechanisms of Mitochondrial Ribosomal Protein L23 (MRPL23) in relation to cellular senescence in HCC. Results demonstrated that MRPL23 was upregulated in both tumor tissues and hepatoma cells. Additionally, the inhibition of MRPL23 resulted in decreased cell proliferation and promoted cellular senescence. Moreover, MRPL23 deficiency protected against HCC progression in a mouse model. Finally, we confirmed that MRPL23 regulated cellular senescence by targeting HMGB1 using the inhibitor NecroX-7. These findings laid the foundation for developing potential therapies for HCC by inhibiting MRPL23 or inducing senescence.

Hepatocellular carcinoma (HCC) is one of the primary liver tumors with high incidence and mortality. RNA G-quadruplexes (rG4) are nucleic acid structures involved in gene expression and genome duplication. rG4 exerts its function by interacting with rG4-binding proteins. The carboxypyridostatin (cPDS), a specific ligand of rG4, are widely studied in numerous tumors. However, the role of cPDS in HCC and its regulatory mechanisms are not yet fully understood. Our study aimed to discuss the regulatory mode of cPDS on Baculoviral IAP Repeat Containing 3 (BIRC3) expression and its impact on proliferation, apoptosis, and other biologic functions in HCC. We conducted colony formation, CCK8, Edu incorporation, scratch healing, and cell spheroid formation assays to analyze the function of cPDS on cell proliferation and migration. Additionally, we explored the role of cPDS in regulating BIRC3 expression by Western blot and qRT-PCR. Furthermore, we evaluated the impact of BIRC3 on cell proliferation and subcutaneous tumor formation in nude mice. Finally, we analyzed the regulatory mechanisms of cPDS on cell apoptosis by Western blot, qRT-PCR, flow cytometry, and Annexin V-FITC staining. Our results demonstrated that cPDS inhibited HCC cells proliferation and migration. Moreover, cPDS elevated the mRNA level while inhibiting the protein expression of BIRC3 in HCC cells. Overexpression of BIRC3 significantly enhanced the proliferation of HCC cells. In the nude mice model, BIRC3 significantly increased the tumor volume and weight. Mechanistically, cPDS promoted cell apoptosis via inhibiting BIRC3-mediated anti-apoptotic effect. Our findings revealed a critical role of rG4 ligand cPDS in HCC progression and indicate that cPDS may be used for HCC treatment considering its tumor inhibitory properties by regulating cell apoptosis.

ABSTRACT Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited treatment options. This study investigated the therapeutic potential and mechanisms of Everolimus (Eve), a selective mTORC1 inhibitor, in experimental UC. Dextran sulfate sodium (DSS)‐induced colitis mice were used to assess Eve's effects on clinical outcomes, histopathology, inflammation, barrier integrity, and signaling pathways. CLEC4E agonist rescue and antibiotic‐mediated microbiota depletion clarified mechanistic roles. Fecal microbiota transplantation (FMT), 16S rRNA sequencing, and untargeted metabolomics evaluated microbiota‐ and metabolite‐driven effects. A Caco‐2/THP‐1 coculture model was applied to validate the functions of CLEC4E and propionic acid. Eve alleviated DSS‐induced colitis by reducing weight loss, colon shortening, tissue injury, cytokine overproduction, and barrier disruption. Mechanistically, Eve suppressed macrophage CLEC4E/Syk/NF‐κB signaling, while CLEC4E activation abolished these benefits. Eve reshaped gut microbiota, enriching Bacteroides_acidifaciens and elevating propionic acid. FMT confirmed transferable protection, whereas microbiota depletion negated Eve's efficacy. In vitro , propionic acid reproduced Eve's anti‐inflammatory and barrier‐protective effects. Eve protects against UC via a dual mechanism: inhibiting CLEC4E‐driven inflammation and remodeling the gut microbiota‐metabolite axis, notably propionic acid. These findings highlight Eve's therapeutic promise and potential for clinical translation in UC.

Background:Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality with limited therapeutic options. Solute carrier family 25 member 10 (SLC25A10), a mitochondrial transporter linked to metabolic regulation and tumor progression, has unclear roles in HCC pathogenesis. This study aimed to elucidate the functional and mechanistic contributions of SLC25A10 to HCC development. Methods:The International Cancer Genome Consortium (ICGC) database, GAO et al. dataset, quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB), and immunohistochemistry (IHC) staining were used to explore the expression levels of SLC25A10 in HCC tissues and cell lines. Functional assays [cell counting kit-8, colony formation, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, SA-β-galactosidase staining, and flow cytometry] and a subcutaneous xenograft mouse model were employed to assess the effects of SLC25A10 knockdown on proliferation, senescence, and tumorigenesis. Finally, NecroX-7, a high mobility group box 1 (HMGB1) inhibitor, was used to delineate the underlying molecular mechanisms involved in cell senescence caused by SLC25A10 knockdown. Results:The protein and messenger RNA (mRNA) levels of SLC25A10 in HCC tissues were higher than those in adjacent normal tissues. Knockdown of SLC25A10 suppressed cell proliferation, induced senescence-associated β-galactosidase activity, and triggered G1 phase arrest by downregulating cyclin-dependent kinase 4 (CDK4)/Cyclin D1 and upregulating cyclin-dependent kinase inhibitor 2A (CDKN2A). In vivo, SLC25A10 silencing reduced tumor growth and decreased KI67/proliferating cell nuclear antigen (PCNA) expression, while enhancing HMGB1, a senescence-associated secretory phenotype (SASP) marker. Mechanically, pharmacological inhibition of HMGB1 with NecroX-7 partially reversed the anti-proliferative and pro-senescent effects of SLC25A10 knockdown, restoring cell cycle progression. Conclusions:SLC25A10 promotes HCC progression by suppressing cellular senescence. Pharmacological or genetic inhibition of SLC25A10 triggers tumor suppression through HMGB1-mediated SASP signaling, positioning SLC25A10 as a promising therapeutic target for HCC intervention.

Despite few studies focusing on the OAZ2 gene in colorectal cancer, its potential role in colon adenocarcinoma (COAD) prognosis and immune modulation remains underexplored. This study examines the expression and mechanistic involvement of OAZ2 in COAD using data from The Cancer Genome Atlas (TCGA) and additional laboratory experiments. We employed uni- and multivariate Cox hazard regression analyses to evaluate its prognostic significance and gene set enrichment analysis (GSEA) to identify related signaling pathways. Our findings demonstrate significantly lower OAZ2 expression in COAD tissues compared to normal counterparts (P < 0.05) and establish its value as an independent prognostic indicator (P < 0.05). Laboratory experiments further revealed that the protein and mRNA levels of OAZ2 are significantly diminished in COAD compared to adjacent normal tissues, while its antagonist AZIN2 shows elevated expression, suggesting a competitive interaction that may regulate tumor behavior. Overexpression of OAZ2 in RKO colorectal cancer cells significantly reduced their proliferation rate and impaired migration, confirming the functional impact of OAZ2 dysregulation in COAD. Gene Set Enrichment Analysis (GSEA) highlighted the involvement of OAZ2 in cardiac muscle contraction and oxidative phosphorylation pathways. Additionally, OAZ2’s association with immune features such as tumor mutational burden (TMB), microsatellite instability (MSI), and immune infiltration underscores its integral role in the tumor microenvironment. These comprehensive findings position OAZ2 as a promising biomarker for COAD prognosis and a potential target for therapeutic intervention, with evidence supporting its regulatory effects on cell dynamics and tumor aggressiveness.

Heat shock proteins (HSPs) are evolutionarily conserved molecular chaperones that maintain cellular proteostasis under physiological and stress conditions. HSPH1 (Heat Shock Protein Family H Member 1, also known as HSP105 or HSP110) belongs to the HSP110 family and functions as a nucleotide exchange factor for HSP70, enhancing its folding activity. Beyond its canonical role, HSPH1 is increasingly recognized for its involvement in tumor progression. It has been reported to regulate cell proliferation, invasion, metastasis, and resistance to therapy in several cancers, including breast, lung, and liver cancer. Pan-cancer transcriptomic analyses have identified HSPH1 as frequently overexpressed and correlated with poor prognosis. In hepatocellular carcinoma (HCC), while other HSPs such as HSP70 and HSP90 are well-studied, the biological role of HSPH1 remains unclear. In this study, we systematically analyzed HSPH1 expression in HCC using TCGA and GEO datasets, and validated its clinical relevance in patient samples. HSPH1 was significantly upregulated in HCC tissues and associated with advanced tumor stage and worse overall survival. Functional enrichment and immune infiltration analyses suggested that HSPH1 participates in oncogenic pathways (e.g., p53, cell cycle) and modulates the tumor immune microenvironment. Knockdown of HSPH1 in HCC cell lines inhibited proliferation and colony formation. Together, our findings highlight HSPH1 as a potential prognostic biomarker and therapeutic target in HCC.

Aims/Background Gastroesophageal reflux disease (GERD) is a widespread upper esophagogastric disease with incompletely understood biological mechanisms. Emerging evidence supports a complex link between GERD and metabolic markers. Therefore, Mendelian randomization (MR), an innovative genomic approach, was used to evaluate the causal impacts of serum metabolites on GERD, aiming to identify novel biomarkers and elucidate underlying metabolic pathways. Methods A two-sample MR framework was employed to examine causal relationships between circulating metabolites and GERD. Genetic instruments for 486 metabolic traits were derived from a comprehensive metabolomics genome-wide association study (GWAS), with disease outcome data from GERD cohorts. Primary causal inference was conducted using the inverse variance weighted (IVW) method, supported by complementary and sensitivity analyses to validate the reliability of the findings. The analytical framework incorporated multiple validation approaches, including replication, meta-analysis, linkage disequilibrium score regression, colocalization analysis, reverse MR analysis, and multivariable MR analysis. Systematic pathway analysis was employed to elucidate associated pathways and underlying disease mechanisms. Results The IVW analysis identified 32 causal associations between serum metabolites and GERD. Through subsequent sensitive analyses, robust causal links were identified between 13 metabolites and GERD. By applying several advanced approaches, such as replication, meta-analysis, linkage disequilibrium score regression, colocalization analyses, reverse MR analysis, and multivariable MR analysis, two metabolites, adrenate (22:4n6) and 2-palmitoylglycerophosphocholine, were confirmed to have stable and independent impacts on GERD. Pathway analysis revealed that three metabolic pathways, such as tryptophan metabolism, bile acid biosynthesis, and carnitine synthesis, exhibited significant association with GERD. Conclusion Using integrative genomics and metabolomics approaches, this study provides evidence supporting the causal influence of two serum metabolites and three metabolic pathways on GERD, highlighting the potential of these metabolites as promising biomarkers for early screening, diagnosis, and targeted treatment strategies. Moreover, these findings underscore the significance of integrating genomics and metabolomics in understanding disease pathophysiology.

BACKGROUND:Liver fibrosis, characterized by the progressive accumulation of excessive extracellular matrix (ECM), remains a major global health issue with limited treatment options. The gut-liver axis, particularly the dynamics of gut microbiota and bile acids (BAs), plays a pivotal role in modulating hepatic fibrogenesis. Alpha-tocopheryl quinone (TQ), a vitamin E metabolite, exhibits antioxidative and anti-inflammatory properties; however, its impact on liver fibrosis remains unexplored. METHODS:A murine fibrosis model was induced using carbon tetrachloride (CCl4), coupled with gut microbiota depletion via antibiotic cocktail (Abx) and fecal microbiota transplantation (FMT) from cirrhotic donors, to evaluate TQ's therapeutic effects. Biochemical and histological analyses assessed liver injury and fibrosis, while 16S rRNA sequencing determined gut microbiota composition. BAs profiles were quantified using LC-MS/MS. Glycine-β-muricholic acid (Gly-MCA), a gut-restricted farnesoid X receptor (FXR) antagonist, was employed for investigating mechanistic pathways. RESULTS:TQ treatment significantly alleviated liver damage and fibrosis in CCl4-treated mice, with a notable reshaping of the gut microbiota, particularly an increased abundance of Christensenella minuta (C. minuta). Mechanistically, TQ activated the intestinal FXR/FGF15 pathway, resulted in reduced hepatic BAs synthesis and enhanced fecal excretion. Abx and FMT experiments confirmed the microbiota-dependent antifibrotic effects of TQ, with C. minuta identified as a key mediator. Co-treatment with Gly-MCA abrogated the protective effects of C. minuta, highlighting the critical role of intestinal FXR signaling. CONCLUSIONS:TQ attenuates liver fibrosis via modulation of gut microbiota, particularly enriching C. minuta abundance, and regulating BAs metabolism via activation of the intestinal FXR/FGF15 axis. These results establish TQ as a promising therapeutic targeting the gut-liver axis, with C. minuta identified as a pivotal mediator in BAs metabolism and fibrotic resolution. This study lays the groundwork for microbiota-centered therapeutic strategies against hepatic fibrosis.

mRNA decapping enzyme 2 (DCP2) is a key regulator of mRNA degradation, influencing RNA metabolism and gene expression. While implicated in various diseases, its role in Hepatocellular carcinoma (HCC) remains unclear. This study explores DCP2 as a potential biomarker for HCC through bioinformatics and experimental analyses. Public databases, including The Cancer Genome Atlas (TCGA) and GEPIA2 online database, revealed significant DCP2 upregulation in HCC tissues, correlating with Tumor-Node-Metastasis (TNM) staging, histological grading, platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and alpha-fetoprotein (AFP) levels. Prognostic analysis confirmed high DCP2 expression as an indicator of poor overall survival (OS). Functional enrichment analyses linked DCP2 to cancer-associated pathways, including PI3K/Akt, Hippo signaling, cholesterol metabolism, and oxidative phosphorylation. Immune infiltration analysis showed significant correlations with tumor-associated macrophages (TAMs) and regulatory T cells (Tregs), suggesting a role in immune modulation. Experimental validation via western blot and immunohistochemistry (IHC) confirmed elevated DCP2 expression in HCC cell lines and tissues. These findings suggest that DCP2 may be involved in HCC progression by influencing mRNA degradation, cancer-related signaling, and the immune microenvironment. Although DCP2 shows potential as a diagnostic and prognostic biomarker, as well as a therapeutic target, further functional studies—such as gene knockdown and overexpression experiments—are needed to confirm its mechanistic role in the development of hepatocellular carcinoma (HCC).

Background and aims: Multiple studies have shown that hepatic fibrosis, a progressive condition that represents the endpoint of various chronic liver diseases, is primarily marked by the extensive activation of hepatic stellate cells (HSCs). However, the exact impact of cystic fibrosis transmembrane conductance regulator (CFTR) on HSCs during the development of hepatic fibrosis remains unclear. Methods: In our study, we measured CFTR levels in tissue samples and in HSCs activated by TGF-beta stimulation. We established mouse models of liver fibrosis using carbon tetrachloride (CCl4) and bile duct ligation (BDL). In vitro, we investigated the specific mechanisms of CFTR action in HSCs by exploring aggrephagy. We employed co-immunoprecipitation (co-IP) experiments to identify potential downstream targets of CFTR. Finally, through rescue experiments, we examined the impact of GTPase-activating protein - binding protein 1 (G3BP1) on CFTR-mediated activation of hepatic stellate cells. Result: In activated HSCs induced by TGF-beta, the reduction of CFTR, various liver fibrosis models, and fibrotic tissue samples were identified. In vitro functional experiments confirmed that CFTR promoted the expression of fibrosis-related markers and aggrephagy in HSCs. Mechanistically, we found that CFTR directly interacts with G3BP1, thereby further promoting the TGF-beta/Smad2/3 pathway. The inhibition of G3BP1 caused by CFTR knockdown reduced extracellular matrix deposition, contributing to alleviating liver fibrosis. Conclusion: We emphasize that CFTR activates aggrephagy and promotes HSC activation and hepatic fibrosis by targeting G3BP1, participating in the TGF-beta/Smad2/3 signaling pathway. Overall, CFTR has been identified as a potential therapeutic target for liver fibrosis.

[This corrects the article DOI: 10.3389/fonc.2024.1483196.].