Coexistence of metabolic dysfunction-associated steatotic liver disease (MASLD) increases hepatocellular carcinoma (HCC) risk after HCV cure. The specific impacts of steatosis grade and cardiometabolic burden on HCC risk among patients with MASLD remain unclear. We enrolled 700 patients who underwent biannual HCC surveillance after HCV cure. Steatosis was graded by vibration-controlled transient elastography using controlled attenuation parameter cut-offs of 248-267, 268-279 and ≥280 dB/m, corresponding to S1, S2 and S3, respectively. Cardiometabolic risk factors (CMRFs) were assessed at the time of viral cure. Cumulative HCC incidence was compared across steatosis grades and cardiometabolic burdens using the log-rank test. Multivariable Cox proportional hazards models with Akaike Information Criterion-based selection evaluated the effects of steatosis grade, cardiometabolic burden and individual CMRFs on HCC risk, expressed as adjusted HRs (aHRs) with 95% CIs. Fine-Gray subdistribution hazard models were used for sensitivity analyses. Cumulative HCC incidence differed significantly across steatosis grades (p=0.035) but not across cardiometabolic burdens (p=0.62). In multivariable analysis adjusted for age, sex, liver stiffness and alpha-fetoprotein, advanced steatosis remained independently associated with HCC risk (S3 vs S1: aHR 2.15, 95% CI 1.25 to 3.69, p=0.005). Among individual CMRFs, pre-diabetes or type 2 diabetes was significantly associated with HCC risk (aHR 2.33, 95% CI 1.38 to 3.94, p=0.002). Fine-Gray analyses confirmed these associations. Advanced hepatic steatosis and glycaemic abnormalities, rather than overall cardiometabolic burden, are independently associated with increased HCC risk after HCV cure.

Genetic studies of stool frequency (SF), an indirect proxy for gastrointestinal transit, may reveal therapeutically tractable pathways relevant to IBS and other dysmotility disorders. To identify genes and mechanisms involved in gut motility, providing a foundation for clinical translation. We performed a multiancestry genome-wide association study (GWAS) meta-analysis of SF in 268 606 European and East Asian individuals. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS signals were fine-mapped and functionally annotated to prioritise candidate genes and pathways. Findings implicating thiamine metabolism were followed-up with dietary interaction analyses in UK Biobank (UKB). SF heritability was comparable in Europeans (7.0%) and East Asians (5.6%). We observed strong genetic correlations with gastrointestinal and psychiatric disorders (rg=0.18-0.47), and causal effects on IBS. Novel correlations with cardiovascular traits (rg=0.12-0.14) were supported by drug signature enrichment analyses. We identified 21 independent loci, including 10 novel signals implicating bile acid synthesis (KLB) and cholinergic signalling (COLQ). Fine-mapping converged on vitamin B1 metabolism, highlighting single-variant causal effects at SLC35F3 (a thiamine transporter) and XPR1 (phosphate exporter essential for thiamine activation). In 98 449 UKB participants, thiamine intake was positively associated with SF (p<0.0001), and a combined SLC35F3/XPR1 genotype score significantly modulated this effect (p<0.0001). We identify therapeutically tractable mechanisms involved in the control of gut motility, including a previously unrecognised role for vitamin B1. These findings warrant mechanistic and clinical studies to evaluate their translational potential in IBS and other dysmotility syndromes.

IBD is characterised by recurrent flares, but evidence on whether modifiable dietary factors influence flare risk is limited. The PREdiCCt study was designed to examine demographic, clinical and dietary factors associated with disease flare among patients with IBD in self-reported remission. Multicentre, prospective cohort study conducted across 47 UK centres. Patients with Crohn's disease (CD), ulcerative colitis (UC) or IBD unclassified (IBDU) in self-reported remission were prospectively followed up. The baseline diet was assessed using a validated food frequency questionnaire. The primary outcome was time to patient-reported flare (captured by monthly IBD-Control) and objective flare (clinical flare plus C-reactive protein >5 mg/L and/or faecal calprotectin (FC) >250 µg/g with treatment escalation). Associations were evaluated using Cox frailty models adjusted for demographic, clinical and biochemical variables, including baseline FC. Between November 2016 and March 2020, 2629 participants (1370 CD; 1259 UC/IBDU) were enrolled and followed up for a median of 4.1 years (IQR 3.0-5.0). Baseline FC was strongly associated with patient-reported flares (FC ≥250 µg/g: adjusted HR (aHR) 2.22; FC 50-250 µg/g: aHR 1.52 (reference <50 µg/g)) and objective flares (FC ≥250 µg/g: aHR 3.25; FC 50-250 µg/g: aHR 1.98). In UC, higher total meat intake was associated with increased risk of objective flares (highest versus lowest quartile: aHR 1.95, 95% CI 1.07 to 3.56). No consistent associations were observed for ultraprocessed foods, fibre or polyunsaturated fatty acids and flare. Higher habitual meat intake was associated with increased risk of objective flare in UC, suggesting diet may contribute to flare susceptibility in specific patient groups. NCT03282903.

The pathogenesis of liver fibrosis centres on the activation of hepatic stellate cells (HSCs). Adenosine-to-inosine RNA editing, primarily catalysed by adenosine deaminase acting on RNA1 (ADAR1), is the most prevalent post-transcriptional modification that increases transcriptome diversity. This study aims to elucidate the role of ADAR1-imposed RNA editome in HSC activation and to determine the therapeutic potential of targeting ADAR1 for liver fibrosis. ADAR1 expression was measured in fibrotic human and mouse livers, as well as in primary human and mouse HSCs. Adar1 loss-of-function effect was evaluated in Adar1f/f /Cre-ER, Adar1△HSC and Adar1i△HSC mice, whereas viral infection with Ad-Adar1 was employed in gain-of-function studies. Adar1△HSCIfih1-/-- and Adar1△HSCIfnar△HSC mice were used for mechanistic studies. An ADAR1 inhibitor and HSC-selective RNAi were used for therapeutic evaluations. ADAR1 is decreased in human and mouse fibrotic livers and activated HSCs. HSC-specific ablation or pharmacological inhibition of ADAR1 ameliorated HSC activation and liver fibrosis. In contrast, forced expression of ADAR1, but not its editing-deficient mutant, exacerbated HSC activation. Mechanistically, ADAR1 ablation accumulated double-stranded RNA and activated HSC-intrinsic innate immunity in a melanoma differentiation-associated gene 5-dependent manner. Interferon-β was identified as a key antifibrotic effector via the activation of the JAK1/2 pathway. RNA editome analysis revealed the Col3a1 3' UTR as a novel ADAR1 editing target, leading to increased collagen production. ADAR1-imposed RNA editome suppresses HSC-intrinsic innate immunity and promotes collagen production, leading to aggravated HSC activation and liver fibrosis. Targeting ADAR1 with its pharmacological inhibitor or HSC-selective RNAi shows great promise in treating liver fibrosis.

Oncological principles favour en bloc R0 excision for curative endoscopic resection. In Barrett's neoplasia, endoscopically curable cancers include T1a and selected early T1b disease. Although endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are established treatments, optimal lesion selection remains debated. To evaluate the oncological impact of two selective resection strategies: (1) prioritising ESD for suspected Barrett's cancers >15 mm and (2) a historical approach reserving ESD mainly for advanced cancers. Multicentre retrospective observational study comparing an ESD-first strategy (period 2, 2017-2024) with a historical selective ESD approach (period 1, 2004-2016). Lesion allocation was based on endoscopic assessment of invasion in both periods. Outcomes included basal R0 resection, curative resection, recurrence and adverse events. A total of 581 resections were performed in 542 patients (median lesion size 20 mm). Cancer was present in 271 cases (178 T1a and 93 T1b). Period 2 had a higher cancer burden (52.3% vs 34.9%) and greater ESD use (77.1% vs 21.2%). Basal R0 resection improved from 69.7% to 91.2% (p<0.001), with the greatest benefit in T1b lesions (33.3% to 81.9%, p<0.001). In T1b cancers, curative resection increased (9.5% to 30.5%, p=0.043) and recurrence decreased (55.6% to 23.6%, p=0.043). ESD achieved higher 2-year cancer-free survival than EMR (87.4% vs 50%, p=0.021). Adverse events were infrequent (2.2%) and similar between techniques. Prioritising ESD for Barrett's cancers >15 mm improves basal R0 resection, reduces recurrence and improves short-term survival for T1b disease, supporting routine ESD for all larger Barrett's cancers.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterised by remarkable cellular heterogeneity, which emerges early from the interplay of oncogenic KRAS signalling and inflammatory injury. However, the transcriptional, metabolic and functional properties of these pre-malignant cell states that initiate and drive PDAC progression remain elusive. This study aimed to identify and functionally characterise the critical premalignant cell states that arise from this heterogeneity, to define novel biomarkers and targets for early intervention. Public and in-house scRNA-seq data of pancreatic tumour models were analysed to identify key subpopulations in early cellular heterogeneity. Genetic perturbation in KrasG12D-driven models was performed to assess functional impact. Mechanistic studies used TurboID proximity proteomics, epigenetic profiling and metabolic assays. Clinical relevance was validated in human PDAC cohorts. We identified LY6D as a marker of a distinct, gastric-like cell state that emerges early and persists throughout tumourigenesis. The LY6D+ population exhibits conserved stemness and a unique, pan-stage dependency on oxidative phosphorylation (OXPHOS). Genetic ablation of Ly6d specifically impaired the gastric lineage and delayed tumourigenesis, while its overexpression enhanced tumourigenic and metastatic potential. Mechanistically, the glycosylphosphatidylinositol (GPI)-anchored LY6D protein scaffolds a lipid raft-associated kinase network that drives FOSL1-dependent epigenetic-transcriptional reprogramming. In human PDAC, LY6D+ cells harbour stemness and Epithelial-Mesenchymal Transition (EMT) signatures, and high LY6D expression is an independent prognostic marker of poor survival. Our work defines the LY6D+ gastric-like cell state as a key driver linking early pre-malignant heterogeneity to PDAC initiation and progression. LY6D represents a pan-stage therapeutic target and a candidate biomarker for early detection and therapeutic targeting.

Dysosmobacter welbionis is a recently discovered butyrate producer whose presence in stool correlates with improved metabolic health. Whether its abundance is reduced in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unknown. Mechanistic insight into its butyrate production from myo-inositol, a dietary compound from fruits, beans, grains and nuts with metabolic benefits, is also limited. To assess population-level distribution, relative abundance and strain diversity of D. welbionis in humans, and to elucidate its metabolic capacity to ferment myo-inositol into butyrate. We analysed several human cohorts for associations with liver health and evaluated D. welbionis J115T supplementation in a diet-induced steatosis mouse model. An antibody-guided anaerobic cell-sorting strategy enabled isolation of distinct strains. We combined 13C-labelled inositol isotopes with NMR, mass spectrometry, genomics and proteomics. We found that D. welbionis and two related species (D. hominis and D. segnis) are prevalent gut bacteria in the human gut. D. welbionis abundance was reduced in MASLD across two cohorts and inversely correlated with fibrosis score in a third cohort. Treatment with D. welbionis J115T improved glycaemia and hepatic steatosis in high-fat diet fed mice. We identified a non-canonical myo-inositol-to-butyrate fermentation pathway. 19 human strains were isolated, comparative genomics of 23 strains revealed an open pangenome (about 2100 core genes) including the full myo-inositol fermentation pathway. D. welbionis possesses a unique, conserved route to convert dietary myo-inositol into butyrate, distinguishing it from other commensals and supporting its potential as a next-generation probiotic for metabolic and liver health.

Why alcohol-associated liver disease (ALD) resolves after abstinence in most people but progresses to liver failure in others remains poorly understood. Experimental models show that increased exposure to proinflammatory cytokines exacerbates ALD, yet clinical trials targeting these cytokines have failed. The tumour necrosis factor alpha (TNFα)-inducible zinc finger protein 36 (ZFP 36) family of RNA binding proteins controls the outcomes of TNFα exposure by destabilising suites of messenger RNAs (mRNAs) that execute the pleiotropic downstream actions of TNFα. To investigate the role of RNA binding protein ZFP36 ring finger protein like 1 (ZFP36L1) in regulating hepatocyte fate and its contribution to the progression of ALD. We selectively deleted ZFP36L1 in mouse hepatocytes to assess its impact on ALD progression, transcriptional reprogramming, senescence and direct mRNA targets. In parallel, we analysed human liver explants to evaluate ZFP36L1 in relation to hepatocyte senescence, disease severity and zinc-dependent regulation. Deletion of ZFP36L1 exacerbated experimental ALD and activated transcriptional programmes driving ductal transdifferentiation, inflammation and senescence. Mechanistically, ZFP36L1 directly destabilised cyclin-dependent kinase inhibitor 1A (Cdkn1a)(p21) and jagged canonical notch ligand 1 (Jag1) mRNAs, thereby suppressing hepatocyte senescence and JAG1-NOTCH signalling. In human liver explants, ZFP36L1 activity declined in parallel with increasing hepatocyte senescence and ALD severity and was closely associated with impaired zinc-dependent signalling. Manipulation of zinc availability altered ZFP36L1 activity and expression of its direct targets. These findings uncover a zinc-dependent ZFP36L1-regulon that governs hepatocyte fate by repressing p21- and JAG1-driven senescence and NOTCH activation and highlight ZFP36L1 as a promising therapeutic target in ALD.

Accumulating evidence has demonstrated that distinct tumour-promoting and tumour-restraining cancer-associated fibroblast (CAF) subtypes coexist in pancreatic ductal adenocarcinoma. To develop targeted CAF therapeutic strategies by reprogramming tumour-promoting CAF subtypes. We leveraged multiomics technologies to systematically identify and characterise CAF subtypes transcriptionally, epigenetically and spatially and correlate them with clinicopathological features. We found that complement-secreting CAFs (csCAFs), initially identified by our group and inflammatory CAFs (iCAFs) share significant overlap in their transcriptional profiles and chromatin accessibility. iCAFs specifically express transcription factors from the heme and oxidative homeostasis pathway and the activator protein 1 family, which are both involved in cellular response to oxidative stress. Notably, the composition of csCAFs among all CAFs declined during pancreatic carcinogenesis, while trajectory analysis showed that csCAFs could potentially differentiate into iCAFs. Spatially resolved analysis indicated that tumour regions with a higher csCAF composition were associated with lower levels of TGF-β ligands, fewer M2 tumour-associated macrophages and increased levels of lipid mediators. Additionally, we identified a spatially defined CXCL12-CXCR4 ligand-receptor interaction between csCAFs and T cells, but in distinct patterns between different metastatic organs. Patients with a higher composition of csCAFs have significantly longer overall survival and recurrence-free survival through multiplex immunohistochemistry and bulk RNA-seq deconvolution. Our study demonstrates that csCAFs may represent an early-stage iCAF subtype and suggests a promising strategy for reprogramming iCAFs into csCAFs.