BACKGROUND AND AIMS: Drug development in primary sclerosing cholangitis (PSC) is challenging, giving orphan disease status and variable rates of disease progression. A potential route for new therapies is through attenua...BACKGROUND AND AIMS: Drug development in primary sclerosing cholangitis (PSC) is challenging, giving orphan disease status and variable rates of disease progression. A potential route for new therapies is through attenuation of symptoms. However, the epidemiology of symptomatic presentations and how they inherently fluctuate over time is not known. We conducted a prospective, multicenter study (trial registration: ISRCTN:15518794) to quantify the prevalence, intensity, and variability of pruritus in PSC. APPROACH AND RESULTS: Participants underwent face-to-face symptom assessment through the itch numerical rating scale (NRS) and 5D-itch tool. Clinical, radiological, and biochemical factors associated with pruritus intensity were determined, alongside the impact on health-related quality-of-life [EQ-5D-5L and chronic liver disease questionnaires (CLDQ)] over 12-week intervals (up to 48±4 weeks). In all, 220 patients participated, of whom n=116 reported pruritus, with n=56 scoring NRS worst itch ≥4. Median 5D-itch was greater in people with cirrhosis (11.0 vs. 8.0), transient elastography readings >8.0 kPa (9.5 vs. 5.0), and a history of ascending cholangitis (11.0 vs. 7.0) ( p <0.01; all). 5D-itch correlated positively with serum bilirubin, ALP, ALT, and AST; and negatively with CLDQ and EQ-5D-5L. In patients scoring NRS ≥4, 61.5% reported persistent pruritus intensity over 48 weeks. Reciprocally, 46.2% experienced a spontaneous ≥2 point reduction in NRS without the addition of a new anti-pruritic agent. CONCLUSIONS: One in 4 PSC patients experience moderate-severe pruritus, with greater symptom intensity in those with advanced disease. Our dataset is able to serve as a reference tool to aid future interventional study design, with regard to anti-pruritus therapies in PSC.
Wang X, Zhou Y, Zhang S
… +20 more, Farrar C, Xie X, Li J, Zhang SM, Zhang Z, Yonemura A, Haynes JT, Feng X, Shang R, Xu Z, Wu Y, Qiao Y, Cui G, Liao W, Li R, Calvisi DF, Zhang S, Xu M, Chen X, Wang H
BACKGROUND AND AIMS: Approximately 10% of human hepatocellular carcinomas (HCC) exhibit concurrent c-MET activation and β-catenin gain-of-function mutations, representing a clinically relevant HCC subtype. This study aim...BACKGROUND AND AIMS: Approximately 10% of human hepatocellular carcinomas (HCC) exhibit concurrent c-MET activation and β-catenin gain-of-function mutations, representing a clinically relevant HCC subtype. This study aimed to investigate the role of mTORC2/AKT signaling in this subtype and identify potential therapeutic targets. APPROACH AND RESULTS: The mTORC2/AKT cascade was activated in c-Met/β-cateninΔ90 HCC lesions. Genetic ablation of Rictor , the essential mTORC2 subunit, strongly suppressed c-Met/β-cateninΔ90 -dependent hepatocarcinogenesis. Mechanistically, both the TSC2/mTORC1 axis and FOXO1 transcription factors functioned as critical downstream effectors of mTORC2/AKT in this model. We further identified RNF125 as a direct transcriptional target of FOXO1. RNF125 overexpression significantly inhibited tumorigenesis in the c-Met/β-cateninΔ90 model and suppressed liver cancer cell growth in vitro. Notably, using an in vivo doxycycline-inducible system, we found that inducing RNF125 expression in established c-Met/β-cateninΔ90 HCC suppressed tumor progression, suggesting that activation of RNF125 may have translational implications for HCC treatment. CONCLUSIONS: Our study, for the first time, established the mTORC2/AKT/FOXO1/RNF125 axis as a critical driver and therapeutic vulnerability in c-MET-activated/β-catenin-mutated HCC. Our study filled a critical gap by defining the tumor-suppressive role of FOXO1 specifically in this HCC subtype. Furthermore, our results positioned RNF125 as a promising therapeutic target for this aggressive HCC subtype.
Duan X, Li S, Li Q
… +19 more, Wen W, Mezzetti O, Warner C, Xu M, Jeyarajan AJ, Li Y, Shi Y, Jiang N, Li W, Yang C, Yang Y, Xu J, Xu M, Xie H, Li S, Chung RT, Wang X, Chen L, Lin W
BACKGROUND AND AIMS: Chronic hepatitis B (CHB) is a major etiology of liver cirrhosis. We previously found that pyruvate, a key intermediate in many metabolic pathways, increases HBV replication. However, the mechanism b...BACKGROUND AND AIMS: Chronic hepatitis B (CHB) is a major etiology of liver cirrhosis. We previously found that pyruvate, a key intermediate in many metabolic pathways, increases HBV replication. However, the mechanism by which pyruvate mediates HBV-induced liver fibrosis is not well characterized. We hypothesize that HBV induces liver fibrosis through a pyruvate-peroxisome proliferator-activated receptor α (PPARα)-reactive oxygen species (ROS) pathway. APPROACH AND RESULTS: We evaluated HBV-induced fibrogenesis in HepAD38, HBV-infected NTCP-HepG2, primary human hepatocytes (PHHs), and HSC lines (LX2) in mono-culture and co-culture models and in patient sera. We also evaluated the effects of PPARα agonist/antagonist and ROS inhibition on HBV-induced liver fibrosis in cell culture, HBV carrier mouse, HBV-Transgenic mouse (HBV-Tg), humanized liver mouse, and human precision-cut liver slice (PCLS) models. We found that HBV increased pyruvate levels and fibrosis-related gene expression in both HBV-infected hepatocytes and patient sera. Supernatants from HBV-infected cells (HBVsup) and pyruvate supplementation independently and additively increased expression of profibrotic genes (TGF-β1, TIMP-1, COL1A1, and α-SMA), activated ROS production, and inhibited PPARα expression. Notably, PPARα inhibition and siRNA knockdown increased ROS production and profibrogenic gene expression, while activation of PPARα blocked HBVsup-induced and pyruvate-induced ROS generation and fibrogenesis. ROS was confirmed to be downstream of PPARα-related fibrogenesis, as ROS inhibition abrogated HBVsup-induced, pyruvate supplementation-induced, or PPARα inhibition-induced liver fibrosis. CONCLUSIONS: HBV infection induces pyruvate production and decreases PPARα expression, leading to increased ROS generation and liver fibrosis. Pyruvate and PPARα represent novel targets for antifibrotic therapeutic development in CHB.
BACKGROUND AND AIMS: The relative contributions of alcohol-associated and cardiometabolic drivers to liver-related events (LREs) remain unknown. We aimed to evaluate their relative contributions to LREs and examine possi...BACKGROUND AND AIMS: The relative contributions of alcohol-associated and cardiometabolic drivers to liver-related events (LREs) remain unknown. We aimed to evaluate their relative contributions to LREs and examine possible interactions. APPROACH AND RESULTS: A total of 329,526 UK Biobank participants were included. Alcohol consumption was self-reported and categorized by weekly consumption as low (<140 g for females, <210 g for males), intermediate (140-350 g for females, 210-420 g for males), and high (>350 g for females, >420 g for males). Five cardiometabolic risk factors (CMRFs) were identified using diagnostic criteria for metabolic dysfunction-associated steatotic liver disease. Over a median follow-up of 12.8 years, 1809 LREs were documented. Alcohol consumption showed the strongest association with LREs. Among participants with low alcohol intake, pre-diabetes/diabetes (HR: 1.87, 95% CI: 1.64-2.14), low HDL cholesterol (1.79, 1.53-2.10), overweight/obesity (1.68, 1.40-2.01), hypertension (1.27, 1.06-1.53), and overall CMRF burden (5.61, 3.66-8.62) were associated with increased risk of LREs. The corresponding values for intermediate alcohol consumption were 2.00 (1.64-2.43), 1.47 (1.16-1.86), 1.19 (0.92-1.54), 1.90 (1.36-2.64), 5.95 (2.84-12.45); and for high consumption, 1.48 (1.17-1.87), 1.47 (1.11-1.95), 0.88 (0.66-1.18), 1.30 (0.88-1.94), 1.17 (0.58-2.34), respectively. A multiplicative interaction was observed between high alcohol consumption and CMRFs, but not between intermediate consumption and CMRFs. CONCLUSIONS: Excessive alcohol use appears to be the strongest factor associated with LREs. Associations between CMRFs and LREs seem similar among individuals with low and intermediate alcohol intake. Reducing alcohol intake, alongside targeted management of CMRFs, may improve strategies for preventing severe liver disease.
Strain R, Edmans M, Montalvo Zurbia-Flores G
… +11 more, Frumento N, Brown A, Hutchings C, Board C, Knight C, Flyak AI, Bailey J, Lauer G, Cox A, Klenerman P, Barnes E
BACKGROUND AND AIMS: An effective vaccine against hepatitis C virus (HCV) infection is required to achieve viral eradication. A previous viral vectored vaccine encoding a genotype-1b T cell antigen suppressed peak viral...BACKGROUND AND AIMS: An effective vaccine against hepatitis C virus (HCV) infection is required to achieve viral eradication. A previous viral vectored vaccine encoding a genotype-1b T cell antigen suppressed peak viral RNA but failed to prevent chronic infection. Previous studies showed dominant vaccine-induced T cell responses were not cross-reactive with common HCV strains, possibly contributing to vaccine failure. To address this, we evaluated 2 novel HCV vaccine strategies designed to elicit T cells targeting multiple HCV genotypes. APPROACH AND RESULTS: HCV genetic segments highly conserved between genotypes 1-6 were encoded in chimpanzee adenoviral (ChAd-Gt1-6) and Modified Vaccinia virus Ankara (MVA-Gt1-6) vectors and tested in prime-boost regimens. This was compared with vaccinating with an ancestral genotype-1a non-structural antigen encoded in ChAd (ChAd-Bole1a-NS) boosted with a genotype-3a non-structural antigen encoded in MVA (MVA-Gt3a-NS). Immunogenicity was evaluated in C57BL/6 and transgenic HLA-A*02:01 mice. Splenocytes were stimulated with genotype-1a, genotype-1b, or genotype-3a peptide pools in ex vivo IFNγ ELISpot and intracellular cytokine assays. Priming with ChAd-Gt1-6 elicited broad T cell responses toward all genotypes, whereas ChAd-Bole1a-NS generated a focused response to genotype-1a. Boosting ChAd-Bole1a-NS with MVA-Gt3a-NS generated cross-reactive T cells targeting multiple genotypes, though some responses were genotype-specific. In contrast, ChAd-Gt1-6 and MVA-Gt1-6 prime-boost generated high-magnitude responses that were all cross-reactive between genotypes. CONCLUSIONS: Vaccinating with conserved regions of genotypes 1-6 or sequentially vaccinating with genotype-1a and genotype-3a immunogens are 2 novel approaches to generate cross-reactive T cells. The proportion of intergenotypic cross-reactive T cells generated was higher using the conserved region antigen.
Zapata-Pavas LE, Serrano-Macia M, Merlos Rodrigo MÁ
… +27 more, Barrenechea-Barrenechea JA, Peña-SanFelix P, Del Río-Álvarez Á, Gil-Pitarch C, Rejano-Gordillo CM, Goikoetxea-Usandizaga N, González-Recio I, Michalkova H, Mercado-Gómez M, Lachiondo-Ortega S, Castañeda A, Asensio M, Murti A, Lelou E, Nogueiras R, Mayor U, Heger Z, Sancho-Bru P, Delgado TC, Calvisi DF, Xirodimas DP, Wang B, Marin JJG, Fernandez-Barrena MG, Armengol C, Ávila M, Martínez-Chantar ML
BACKGROUND AND AIMS: Hepatoblastoma (HB) is the most common malignant liver tumor in children. Despite advances in multimodal treatment, chemoresistance and relapses remain major clinical challenges. NEDDylation, a post-...BACKGROUND AND AIMS: Hepatoblastoma (HB) is the most common malignant liver tumor in children. Despite advances in multimodal treatment, chemoresistance and relapses remain major clinical challenges. NEDDylation, a post-translational modification involving the ubiquitin-like molecule NEDD8, has been implicated in cancer, but its role in HB remains poorly understood. This study investigates the functional relevance of the deNEDDylase NEDP1 and its downstream target CAND1 in HB progression and therapy response. APPROACH AND RESULTS: Transcriptomic and proteomic analyses of HB patient samples, cell lines, patient-derived xenograft (PDX) cells, and transgenic mouse models revealed a significant reduction in NEDP1 expression and activity, accompanied by global hyper-NEDDylation. Functional studies demonstrated that NEDP1 overexpression restored deNEDDylation, induced apoptosis, impaired tumor cell proliferation and metabolism, and significantly restrained tumor growth and metastasis in both in vivo mouse models and in the chorioallantoic membrane (CAM) assay. Proteomic profiling identified CAND1 as a key NEDDylated substrate regulated by NEDP1. High CAND1 expression was associated with aggressive molecular HB subtypes (C2-pure, Epi-CB) and poor clinical outcomes, including reduced overall survival. Rescue experiments confirmed that CAND1 overexpression counteracted the antitumor effects of NEDP1. CONCLUSIONS: NEDP1 acts as a tumor suppressor in HB by modulating the NEDDylation status of key regulatory proteins, particularly CAND1. Restoration of NEDP1 activity suppresses tumorigenesis and metastasis, underscoring the NEDDylation pathway as a promising therapeutic target. CAND1 is proposed as a potential prognostic biomarker and actionable oncogenic driver in HB.
Younossi ZM, de Avila L, Petta S
… +85 more, Hagström H, Kim SU, Nakajima A, Crespo J, Castera L, Alkhouri N, Zheng MH, Treeprasertsuk S, Ananchuensook P, Shalimar, Tsochatzis E, Trivikrama SK, Balakumaran LK, Fan JG, Roberts SK, Alswat K, Wong VW, Yilmaz Y, Dunn W, Francque S, Cordie A, Yu ML, Ekstedt M, Goh GB, Oliveira CP, Pessoa MG, Chan WK, Fernandez MIC, Duseja A, Arab JP, Papatheodoridis G, Sebastiani G, Villela-Nogueira C, D'Ambrosio R, Lampertico P, AlNaamani KM, Holleboom AG, Valsan A, Venu A, El-Kassas M, Pennisi G, Shang Y, Liu WY, Lee HW, Kobayashi T, Kakizaki S, Caussy C, Pearlman B, Iruzubieta P, Nadeem R, Cinque F, Neonaki A, Zoncapé M, Yang RX, Song SJ, Dunn N, Gadi Z, Yeh ML, Teh KK, Mahadeva S, Fabian LG, Almohsen A, Leite N, Pugliese N, Vessby J, Xie C, Choudhary NS, Friend E, Poca M, Kawaguchi T, Russo FP, Gadano A, Diaz LA, Singal AK, Segrestin B, Gunn N, Mauricio D, Arrese M, Fracanzani A, Lombardi R, Lam B, Racila A, Alqahtani SA, Stepanova M, Global NASH/MASH Council (GNC)
BACKGROUND AND AIMS: Advanced histologic fibrosis is a major predictor of mortality in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to identify advanced fibrosis clinical determinants across...BACKGROUND AND AIMS: Advanced histologic fibrosis is a major predictor of mortality in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to identify advanced fibrosis clinical determinants across diverse MASLD populations and to assess the prognostic value of noninvasive markers (NITs) of fibrosis for adverse outcomes. APPROACH AND RESULTS: The Global MASLD (G-MASLD) enrolled biopsy-confirmed MASLD patients with clinical, histologic, and noninvasive test (NIT) data. Factors associated with the presence of advanced histologic fibrosis (F3-F4) in MASLD and clinical outcomes were assessed. There were 17,792 patients with MASLD. Advanced fibrosis (≥F3) was present in 35%. The prevalence of type 2 diabetes (T2D) increased stepwise with fibrosis stage, from 28% in F0 to 70% in F4 (trend p <0.0001). Independent predictors of advanced fibrosis included older age, T2D, and obesity, although the association with obesity varied by region. Among patients with follow-up (mean 6.6 y), 6.5% died and 10.1% experienced a clinical event. Older age, male sex, T2D, and obesity were independent predictors of both mortality and clinical events ( p <0.05). Fibrosis severity, whether defined histologically or by NITs, was strongly associated with higher risks of death and liver-related outcomes (all adjusted HR>1.0, p <0.001). Five-year mortality was 2.1% overall, rising to 8.3% in patients with cirrhosis, and exceeded 10% among those with high-risk NIT score values. CONCLUSIONS: In this large global biopsy-based MASLD cohort, advanced fibrosis was highly prevalent and strongly linked to T2D. Both histologic fibrosis and NITs were independent predictors of mortality and clinical outcomes, underscoring the prognostic value of fibrosis assessment with NITs.