The roof plate-specific spondin-leucine-rich repeat-containing G-protein coupled receptor 4/5 (LGR4/5)-zinc and ring finger 3 (ZNRF3)/ring finger protein 43 (RNF43) module is a master regulator of hepatic Wnt/β-catenin signaling and metabolic zonation. However, its impact on nonalcoholic fatty liver disease (NAFLD) remains unclear. The current study investigated whether hepatic epithelial cell-specific loss of the Wnt/β-catenin modulator Lgr4/5 promoted NAFLD. The 3- and 6-month-old mice with hepatic epithelial cell-specific deletion of both receptors Lgr4/5 (Lgr4/5dLKO) were compared with control mice fed with normal diet (ND) or high-fat diet (HFD). Six-month-old HFD-fed Lgr4/5dLKO mice developed hepatic steatosis and fibrosis but the control mice did not. Serum cholesterol-high-density lipoprotein and total cholesterol levels in 3- and 6-month-old HFD-fed Lgr4/5dLKO mice were decreased compared with those in control mice. An ex vivo primary hepatocyte culture assay and a comprehensive bile acid (BA) characterization in liver, plasma, bile, and feces demonstrated that ND-fed Lgr4/5dLKO mice had impaired BA secretion, predisposing them to develop cholestatic characteristics. Lipidome and RNA-sequencing analyses demonstrated severe alterations in several lipid species and pathways controlling lipid metabolism in the livers of Lgr4/5dLKO mice. In conclusion, loss of hepatic Wnt/β-catenin activity by Lgr4/5 deletion led to loss of BA secretion, cholestatic features, altered lipid homeostasis, and deregulation of lipoprotein pathways. Both BA and intrinsic lipid alterations contributed to the onset of NAFLD.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) constitute an appealing tool for drug discovery, disease modeling, and cardiotoxicity screening. However, their physiological immaturity, resembling CMs in the late fetal stage, limits their utility. Herein, we have developed a novel, scalable cell culture medium designed to enhance the maturation of hPSC-CMs. This medium facilitates a metabolic shift towards fatty acid utilization and augments mitochondrial function by targeting Acetyl-CoA carboxylase 2 (ACC2) with a specific small molecule inhibitor. Our findings demonstrate that this maturation protocol significantly advances the metabolic, structural, molecular and functional maturity of hPSC-CMs at various stages of differentiation. Furthermore, it enables the creation of cardiac microtissues with superior structural integrity and contractile properties. Notably, hPSC-CMs cultured in this optimized maturation medium display increased accuracy in modeling a hypertrophic cardiac phenotype following acute endothelin-1 induction and show a strong correlation between in vitro and in vivo target engagement in drug screening efforts. This approach holds promise for improving the utility and translatability of hPSC-CMs in cardiac disease modeling and drug discovery.

Background: Despite an expanding repertoire of advanced therapies for inflammatory bowel disease (IBD), treatment outcomes remain suboptimal, with only 30%–40% of patients achieving sustained remission. Emerging evidence indicates that therapeutic outcomes are shaped by complex interactions between host immune pathways, the gut microbiome and psychosocial factors. However, robust biomarkers to predict individual treatment response are currently lacking. Aims: The Therapy Personalisation using Multiomic Analyses in Inflammatory Bowel Disease (THAMES‐IBD) study aims to address this critical unmet need by identifying predictors that differentiate responders from non‐responders to advanced therapies in ulcerative colitis (UC) using an integrated multiomics approach. Methods: The THAMES‐IBD study is a multicentre, prospective observational cohort study recruiting adults with active UC initiating or switching advanced therapies, alongside patients with inactive UC and non‐IBD controls. Multimodal samples will be collected from recruited participants prior to treatment initiation, including stool (metagenomics and metabolomics), blood (transcriptomics, proteomics and metabolomics) and mucosal biopsies (transcriptomics). Longitudinal blood and stool samples, as well as clinical, demographic, dietary and comprehensive psychosocial data, will be collected at baseline and at 8–14 weeks and 28–32 weeks after commencing a new advanced therapy. Treatment outcomes will be pragmatically defined based on validated patient‐reported outcome (PRO‐2) scores and biochemical measures. Multiomics integration will be performed using complementary unsupervised and supervised approaches. Predictive models will undergo internal cross‐validation and, where feasible, external validation in independent cohorts. Conclusion: Through deep multimodal phenotyping of patients with UC, the THAMES‐IBD study seeks to identify biological mechanisms associated with therapeutic response and resistance. These insights have the potential to inform the development of novel predictive biomarkers to guide precision medicine strategies, minimise ineffective treatment cycling and ultimately improve outcomes for patients with IBD.