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Background: 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.

Objective: 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.

Design: 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 Adar1^f/f /Cre-ER, Adar1^△HSC and Adar1^i△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.

Results: 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.

Conclusion: 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.

Background: The efficacy of pharmacological glycogen synthase kinase-3β (GSK3β) inhibition is currently being investigated in unselected cohorts of metastatic pancreatic ductal adenocarcinoma (PDAC). Here, we sought to determine the clinical significance of nuclear GSK3β accumulation in patients with resectable PDAC.

Objective: This study aimed to explore the therapeutic potential and underlying mechanisms of GSK3β pathway disruption in PDAC with enriched nuclear GSK3β levels.

Design: We investigated the activation and function of GSK3β and its downstream transcription factor NFATc1 in tumour recurrence, growth and resistance using human PDAC tissues, patient-derived organoids and tumour cells, PDAC explants, cell lines and murine models. GSK3β signalling was disrupted using genetic and pharmacological approaches. Live-cell imaging, proliferation, homologous recombination (HR) repair and comet assays, messenger RNA sequencing and chromatin immunoprecipitation were used to explore GSK3β-NFATc1 signalling-mediated target gene regulation in DNA repair, growth and resistance.

Results: Nuclear GSK3β accumulates in a subset of resected PDAC and promotes proliferation and DNA repair through NFATc1. The GSK3β^high/NFATc1^high subtype accounts for 14% of resected PDAC and is associated with rapid tumour recurrence and poor survival. The GSK3β-NFATc1 signalling pathway contributes to cisplatin resistance by inducing BRCA genes transcription, which facilitates HR-mediated DNA double-strand breaks (DSBs) repair. Disruption of the GSK3β-NFATc1 axis impairs HR-driven DSB repair, increasing cisplatin sensitivity in vitro and in preclinical PDAC models.

Conclusion: We have identified a highly aggressive GSK3β^high/NFATc1^high subtype that predicts early recurrence, poor survival and cisplatin resistance in PDAC. This subtype reveals new treatment vulnerabilities suggesting that patients with PDAC may benefit from stratification-based tailored treatment strategies.

Background: IBD is characterised by recurrent flares, but evidence on whether modifiable dietary factors influence flare risk is limited.

Objective: The PREdiCCt study was designed to examine demographic, clinical and dietary factors associated with disease flare among patients with IBD in self-reported remission.

Design: 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.

Results: 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.

Conclusion: 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.

Trial registration number: NCT03282903.