Hepatotropic viruses naturally have narrow host and tissue tropisms, challenging the development of robust experimental models. The advent of organoid technology provides a unique opportunity for moving the field forward. Here, we demonstrate that three-dimensional cultured organoids from fetal and adult human liver with cholangiocyte or hepatocyte phenotype support hepatitis E virus (HEV) replication. Inoculation with infectious HEV particles demonstrates that human liver–derived organoids support the full life cycle of HEV infection. By directing organoids toward polarized monolayers in a transwell system, we observed predominantly apical secretion of HEV particles. Genome-wide transcriptomic and tRNAome analyses revealed robust host responses triggered by viral replication. Drug screening in organoids identified brequinar and homoharringtonine as potent HEV inhibitors, which are also effective against the ribavirin resistance variant harboring G1634R mutation. Thus, successful recapitulation of HEV infection in liver-derived organoids shall facilitate the study of virus-host interactions and development of antiviral therapies.

Summary Background Treatment of chronic drug‐induced liver injury (DILI) or herb‐induced liver injury(HILI) is an important and unresolved challenge. There is no consensus regarding the indications for corticosteroids for chronic DILI/HILI. Aims To investigate the efficacy and safety of corticosteroid plus glycyrrhizin for patients with chronic DILI/HILI. Methods This was a randomised open‐label trial. Eligible patients with causality assessment using the updated RUCAM were randomly assigned (1:1) either to the steroid treatment group (48‐week stepwise dose reduction of methylprednisolone plus glycyrrhizin) or control group (glycyrrhizin alone). Liver biopsies were performed at baseline and at the end of the 48‐week treatment period. The primary outcome was the proportion of patients with sustained biochemical response (SBR). The secondary outcomes were improvement in liver histology, time to biochemical normalisation and safety. Results Of 80 participants, 70 (87.5%) completed the trial. The patients were predominantly female (77.5%), aged >40 years (77.5%) and had a hepatocellular injury pattern of DILI (71.2%). Compared to the control group, the treatment group showed a higher proportion of SBR (94.3% vs. 71.4%, p = 0.023), shorter biochemical normalisation time and histological improvements in both histological activity and fibrosis. The DILI and HILI subgroups, as well as the autoimmune hepatitis (AIH)‐like DILI and non‐AIH‐like subgroups, showed comparable responses. No severe adverse events were observed during the trial. Conclusion This study provides the first clinical evidence that corticosteroid plus glycyrrhizin therapy for chronic DILI with or without AIH‐like features can achieve both biochemical response and histological improvements with good safety. (http://clinicaltrials.gov, NCT 02651350).

The cover image is based on the Randomised Clinical Trial Corticosteroid plus glycyrrhizin therapy for chronic drug‐ or herb‐induced liver injury achieves biochemical and histological improvements: A randomised open‐label trial by Jia‐Bo Wang et al., https://doi.org/10.1111/apt.16902.

We would like to thank Rolf Teschke and Axel Eickhoff for their interest in our work investigating the efficacy and safety of corticosteroid (CS) plus glycyrrhizin (GC) therapy for chronic drug-or herb-induced liver injury (DILI/HILI). 1,2 Cessation of the suspected agent(s) is widely recommended and convincingly proved to reverse 80% DILI in the acute phase, 3,4 but this strategy seemed not contributable for patients in our study. It is worth to note that all the participants in two groups of this study have experienced drug cessation at least 6 months prior to therapy, suggesting they had already been patients with chronic DILI and drug cessation alone is not sufficient for DILI intervention. In addition, our study aimed to compare treatment outcome between strategies with and without CS in DILI patients with similar basal conditions, thus the drug cessation is unlikely a confounding factor that would influence our final conclusion. This clinical study is based on a prospectively registered and performed trial (NCT02651350), with randomised and open-labeled design, rather than a retrospective study. We started to recruit