Several second-generation farnesoid X receptor (FXR) agonists are being developed to reproduce the histological benefit demonstrated with obeticholic acid, but with an improved safety profile. MET409 is one of these novel, non-biliary FXR agonists with altered PK and PD properties that allow once daily dosing. Harrison and coworkers present a proof-of-concept trial where 58 patients with biopsy-proven non-alcoholic steatohepatitis (NASH), MRI-proven steatosis and abnormal ALT values were randomised to receive 80 mg, 50 mg or placebo for 12 weeks. The drug clearly reduced liver fat content, with relative reductions of 55% (high dose) and 38% (lower dose) vs. only 6% with placebo. It also reduced ALT, though some individuals experienced transient ALT elevations on therapy. Importantly, the drug induced pruritus and increases in LDL which were both dose related. This new molecule appears to be a very powerful FXR agonist and further studies need to identify an effective dose with acceptable toxicity. However, hopes that a next-generation FXR agonist could maintain high efficacy without causing pruritus and lipid changes seem to be fading away. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many cancers, but activating anti-tumoral immune responses with ICIs carries the risk of immune-related side effects including immune-mediated hepatitis. Gudd and coworkers meticulously analysed blood and liver samples of patients undergoing ICI therapy for malignancies in order to define characteristic immune activation patterns associated with ICI-related hepatitis. Myeloid and lymphoid populations were drastically changed in blood and livers, with inflammatory monocytes and cytotoxic, effector-type CD8+ T-cells becoming dominant in patients with hepatitis. These data may build the foundation for a better risk stratification of patients undergoing ICI therapy, early diagnosis of ICI-related hepatitis and possibly also new therapeutic or preventive interventions. Hepatocyte homeostasis is severely disturbed in NASH, characterised by lipotoxicity, mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Simón and coworkers now demonstrate that this is accompanied by drastic changes in magnesium (Mg2+) homeostasis, because the Mg2+ transporter cyclin M4 (CNNM4) is upregulated in NASH and acts as a Mg2+ exporter in the liver. Using patient samples, primary hepatocyte cultures and rodent NASH models, downregulating CNNM4 in hepatocytes restored hepatic magnesium levels and reduced ER stress, which translated into improved steatosis, lower inflammation and reduced fibrosis. While these data indicate that inhibiting CNNM4 in hepatocytes could be attractive to treat NASH, the extrahepatic consequences of interfering with Mg2+ levels warrant further investigation. In hepatic steatosis, “ER stress” activates the unfolded protein response (UPR) and disturbs hepatocyte homeostasis. Liu and coworkers identified that ER stress and the UPR induce Forkhead box A3 (FOXA3) transcription in hepatocytes, which controls lipid synthesis via PER1/SREBP1c. Genetic FOXA3 deletion or siRNA-mediated suppression ameliorated chronic ER stress, steatosis and insulin resistance in rodent non-alcoholic fatty liver disease (NAFLD) models. The next step is translating these basic findings into strategies to reduce excessive FOXA3 in patients with NASH. He and coworkers uncovered the role of IL-20, another cytokine of the IL-10 family, in response to injury signals in the liver. Using a novel IL-20-deficient mouse model, IL-20 was found to exacerbate acute hepatitis and hepatocyte responses to bacterial infection, by upregulating NAD(P)H: quinone oxidoreductase 1 (NQO1) and subsequently promoting the protein degradation of the transcription factor IκBζ. This then inhibits IL-6 and LCN2 in hepatocytes, which is an important hepatic defence mechanism against bacteria and sterile injury. The finding that IL-20 opposes IL-22 and aggravates hepatitis could potentially be leveraged to develop new therapies to control acute hepatitis and bacterial infections. About 15–30% of patients with hepatocellular carcinoma (HCC) have gain of function mutations in the CTNNB1 gene and distinct pathological features. Liang and coworkers report that T-box transcription factor 3 (TBX3), a known target of the Wnt pathway implicated in hepatocarcinogenesis, is in fact a tumour suppressor gene and restricts tumour growth induced by activated CTNNB1 mutants. Based on the analysis of gene expression profiles in large public datasets, experiments in murine models of liver cancer and in human HCC cell lines, TBX3 was found to function by regulating the YAP/TAZ pathway and likely drives specific pathological phenotypes observed in CTNNB1-mutant human HCCs. These data suggest that therapeutic strategies to increase TBX3 expression could be effective in HCC, but this requires further clinical exploration. Hypoxia-inducible factors (HIFs) are a hallmark of inflammation and are key regulators of hepatic immunity and metabolism and yet their role in HBV replication is poorly defined. HBV replicates in hepatocytes within the liver, a naturally hypoxic organ, however, most studies of viral replication are performed under conditions of atmospheric oxygen, where HIFs are inactive. Wing and coauthors investigated the impact of hypoxia on the HBV life cycle. Culturing liver cell-based model systems under low oxygen uncovered a new role for HIFs in binding HBV DNA and activating the basal core promoter, leading to increased pre-genomic RNA and de novo HBV particle secretion. Identifying a role for this conserved oxygen sensor in regulating HBV transcription suggests that this virus has evolved to exploit the HIF-signalling pathway to persist in the low oxygen environment of the liver. Most primary HBV infections during host adulthood do not lead to disease, thus, highlighting the self-restrictive feature of HBV-host interactions. Besides the well-defined open reading frames, it is interesting to ask whether and how the HBV genome might possess extra coding potential. Yuan and coworkers identified an EnhI-SL (Enhancer I-stem loop) as a new cis element in the HBV genome, and mutations disrupting EnhI-SL were found to elevate viral polymerase expression. Furthermore, while rediscovering HpZ/P’, a previously under-explored isoform of the HBV polymerase, they also identified HBxZ as a novel short isoform of HBX and confirmed their existence and functionally characterized them as potent suppressors of HBV gene expression or genome replication. Mechanistically, HpZ/P’ was found to repress HBV gene expression partially through interacting with and sequestering SUPV3L1. The abundance of HBV mutants with deficient HpZ/P’ or disrupted EnhI-SL seemed to be diminished upon activation of the host immune system. Finally, SRSF2, an HBV-downregulated host protein in the RNA spliceosome, was found to promote the splicing of viral pre-genomic RNA and HpZ/P’ biogenesis. The authors conclude that SRSF2-HpZ/P’ appears to constitute another negative feedback mechanism in controlling the HBV life-cycle. Targeting the host splicing machinery might represent an under-explored strategy to intervene with HBV-host interactions. HEV replication outside of the liver has been proven in vitro in experimentally infected neuronal and placental cell lines, as well as in cerebrospinal fluid, the kidney, placenta, intestine, lymph nodes and tonsils. Various viruses have been detected in the ejaculate and can outlast the duration of viremia, indicating replication beyond the blood-testis barrier. Horvatits and coworkers aimed to determine the occurrence, features and morphology of HEV in the ejaculate. While none of the 6 ejaculate samples from patients with acute HEV infection and none of the pig testis samples tested positive, in 2 of the 3 chronically HEV-infected patients, the authors observed HEV-RNA (genotype-3c) in seminal plasma and semen with viral loads >2 logs higher than in the serum. Genomic sequencing showed significant differences between viral strains in the ejaculate compared to stool. Under ribavirin-treatment, HEV shedding in the ejaculate outlasted the duration of viremia for >9 months. The authors conclude that the male reproductive system may be a niche of HEV persistence in chronic, but not in acute HEV infection. We already knew that high-fructose intake increases hepatic de novo lipogenesis and hepatic fat content and decreases hepatic insulin sensitivity independently from weight gain. This study attempted a comprehensive evaluation of the metabolic effects of fructose not only on hepatic lipogenesis but also on adipose tissue lipolysis and fatty acid oxidation. Moreover, the respective impact of fructose alone (usual beverage sweetener in the US), of sucrose (fructose with glucose, the usual beverage sweetener in Europe) and of glucose alone were compared. Geidl-Flueck and coworkers randomized 94 healthy lean men to receive, during 7 weeks, diets supplemented with these 3 types of carbohydrates vs. a control group with no carbohydrates but equivalent caloric intake. Using tracer-based methodology, the study elegantly shows that fructose-based sweeteners increase hepatic lipogenesis contrary to glucose, and enhance VLDL production. There was also a significant change of the LDL particle distribution towards smaller, more atherogenic particles. Moreover, microbial fermentation of fructose also feeds hepatic lipogenesis through acetate. Fructose or sucrose, however, did not increase peripheral lipolysis nor fatty acid oxidation. This “metabolic switch” in hepatocytes is an adaptive process to recurrent fructose loads and could pave the way to diseases such as metabolic steatosis or type 2 diabetes. Stephens et al. presented a comprehensive analysis of 843 patients with drug-induced liver injury (DILI) enrolled into the Spanish DILI Registry over a 20-year time period (up to 2018). Cases were identified, diagnosed and followed prospectively for clinical features, drug information and outcomes. Patients had a mean age of 54 years (48% females). Anti-infective agents represented the most common therapeutic class followed by the central nervous system, musculoskeletal drugs and cardiovascular agents. Hepatocellular injury was the predominant phenotype (57%) in all age groups except for patients ≥80 years in whom cholestatic injury predominated. Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years-old and in patients with underlying liver disease. Independent predictors of liver-related death/transplantation outcome included new Ratio (nR = ALT or AST, whichever was the highest × ULN/ALP × ULN) – based definition of hepatocellular injury, female sex, higher onset AST and bilirubin values. Thus, the authors concluded that AST elevation at onset is a strong predictor of poor outcome and should be performed routinely in DILI evaluation and that older patients with hepatocellular damage and patients with underlying hepatic conditions have a higher mortality. Golexanolone, a novel small molecule GABA-A receptor modulating steroid antagonist, was proved to restore spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and to mitigate the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. In this paper Montagnese et al. reported data on the safety and PK of golexanolone, and its affect on the electroencephalogram (EEG) as well as the subjective sleepiness and cognitive performance in adult patients with cirrhosis. Golexanolone exhibited a satisfactory safety and PK profile. Baseline characteristics were similar between patients randomized to placebo or to golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in measures of subjective sleepiness and cognitive performance. Considering the variability and improvement in cognitive measures observed between screening and baseline, post hoc analyses suggested signals of efficacy. The authors concluded that golexanolone was well tolerated and associated with improvement in cognitive performance. They also stated that the results of the study implicate a GABA-A receptor modulating neurosteroids in the pathogenesis of HE and suggest that golexanolone holds promise as a therapeutic option. Taiwan has introduced a number of population-wide interventions to reduce the burden of HCC over the last decades, providing a natural opportunity to evaluate to what extent changes in HCC incidence and case-fatality impact mortality at a population level. Liao et al. have studied this topic using registry data before and after universal hepatitis B vaccination, universal health care, and viral hepatitis therapy. According to age, mortality trends dropped in all but the elderly group. Both the reduced incidence and a remarkable decline in case-fatality rate attributed to universal health care contributed to the declining trends in mortality. Hepatitis B vaccination led to a 36% reduction of incidence for those aged 30 years or below and antiviral therapy resulted in around 15% reduction for those aged 30 to 69 years. These results confirm the benefits of providing universal access to vaccination and antiviral therapy. Screening patients with cirrhosis for HCC using ultrasound every 6 months is recommended in all guidelines. However, the overall sensitivity of the procedure is suboptimal and abbreviated MRI (AMRI) could be an alternative. Gupta et al. have performed a systematic review to determine the diagnostic accuracy of AMRI in HCC screening and compare it to ultrasound. Fifteen studies including a total of 2,807 patients and 917 HCC cases were included in a meta-analysis. AMRI performed well with a pooled per-patient sensitivity and specificity of 86% and 94%, irrespective of screening setting. Importantly, the sensitivity of AMRI for the detection of very early HCC (<2 cm) was 69%. The sensitivity and specificity of non-contrast AMRI was comparable to those of contrast-enhanced AMRI and the diagnostic performance of the protocols was comparable. AMRI is therefore a valuable tool for HCC screening. It is well known that patients with cirrhosis and significant coronary artery disease (CAD) are at risk for peri-liver transplantation cardiac events. Rachwan and coworkers analysed data on 1,771 patients who underwent pre-liver transplant cardiac evaluation at a single US Center, including stress echocardiography (SE) and cardiac catheterization (CATH). Risk-adjusted predictors of significant CAD at CATH were older age, male gender, diabetes, hypertension, tobacco use, family history of CAD, and personal history of CAD. The authors created a score and stratified the CAD risk as low (≤2%), intermediate (3% to 9%), and high (≥10%). Among patients who underwent CATH, the risk-based testing algorithm compatible with high risk, would have identified 97% of all significant CAD and potentially avoided unnecessary testing. The authors concluded that the CAD-liver transplant score and algorithm effectively stratify pre-liver transplant risk for significant CAD. Patrizia Burra at Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy. Frank Tacke at Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany Vlad Ratziu at Insitute for Cardiometabolism and Nutrition, Sorbonne Université and Hospital Pitié Salpêtrière, Paris, France. Stefan Zeuzem at Department of Medicine I, Goethe University Hospital, Frankfurt, Germany. Bruno Sangro at Liver Unit, Clinica Universidad Navarra and CIBEREHD, Pamplona, Spain. Paolo Angeli at Unit of Internal Medicine and Hepatology, University of Padua, Padua, Italy.