In this issue of the Journal, de Franchis et al. report the findings of the latest Baveno workshop on portal hypertension. The main fields of discussion were the relevance and indications for measuring the hepatic venous pressure gradient as a gold standard, the use of non-invasive tools for the diagnosis of compensated advanced chronic liver disease (ACLD) and clinically significant portal hypertension, the impact of aetiological and non-aetiological therapies on the course of cirrhosis, the prevention of the first episode of decompensation, the management of an acute bleeding episode, the prevention of further decompensation, as well as the diagnosis and management of splanchnic vein thrombosis and other vascular disorders of the liver. For each of these 9 topics, a thorough review of the medical literature was performed, and a series of consensus statements/recommendations were discussed and agreed upon. Long-chain omega-3 fatty acids, e.g., eicosapentaenoic acid (EPA), are considered part of a healthy diet in fatty liver disease, but clinical trials did not demonstrate a specific benefit of EPA for patients with non-alcoholic steatohepatitis (NASH). Fraser and coworkers developed an engineered EPA derivative (icosabutate), which promoted beneficial effects on human hepatocyte lipid metabolism and oxidative stress in vitro and translated into reduced NASH and fibrosis in mouse models in vivo. Encouragingly, a post hoc analysis of overweight and dyslipidaemic volunteers treated for up to 12 weeks with icosabutate demonstrated a reduction in liver enzymes and improvement in the FIB-4 score. These data support the further clinical development of chemically modified fatty acids, such as icosabutate, for the treatment of aberrant metabolic pathways in NASH. The ductular reaction (DR) is commonly observed in liver injury, particularly in biliary disease, and is characterised by injury-induced proliferation of bile ducts, leading to bile duct hyperplasia. Navarro-Corcuera and coworkers uncovered the molecular mechanisms underlying the DR in cholangiocytes, by using cholangiocyte-specific knockout mice and inhibitor molecules, primary cholangiocytes from mouse and human livers, as well as organoids. They demonstrate that the interaction of the epigenetic modifiers p300 and ELK1 with the long non-coding RNA, ACTA2-AS1, drives histone acetylation and regulates expression of the growth factor PDGFB, leading to subsequent proliferative and fibrogenic responses in cholangiopathies. It will be interesting to analyse the potential therapeutic implications of these findings, including in non-biliary diseases such as non-alcoholic fatty liver disease (NAFLD), in future studies. Hepatic ischaemia-reperfusion injury, as observed during liver transplantation (LT), causes acute inflammation and hepatocyte injury. Kadono and coworkers now identified that 2 transcriptional regulators in macrophages termed SIRT1 and Ikaros have important functions in balancing inflammasome-pyroptotic cell death and hepatocellular damage in stressed livers. These insights into macrophage activation during acute sterile liver injury may enable the identification of novel biomarkers and targets in ischaemia-reperfusion injury. Cirrhosis, the end-stage of chronic liver diseases, is characterised by multiple structural and functional changes, including altered bile acid (BA) transporters and stellate cell activation. Garrido and coworkers characterised the histone acetylation regulator MCRS1 in the development of liver fibrosis and cirrhosis. In hepatocyte-specific Mcrs1 knockout mice, the BA transporter NTCP is downregulated due to increased histone acetylation of BA transporter genes, ultimately causing accumulation of BAs in the sinusoids, activation of hepatic stellate cells and progressive liver disease up to cirrhosis in mice. Strikingly, associations of reduced MCRS1 and NTCP expression were also observed in human cirrhosis samples. The genetic ablation of Mcrs1 in mouse hepatocytes appears to represent a novel genetic mouse model of cirrhosis, which will enable the study of interactions between BA signalling and fibrogenesis, as well as of therapeutic interventions. The identification of active steatohepatitis with fibrosis (Fibro-NASH) is a major challenge that current fibrosis biomarkers cannot overcome. Recently a blood-based biomarker (NIS4) and an elastometry+aspartate aminotransferase (AST)-based algorithm (FAST) became available. In this study, Noureddin et al. tested an MRI-based algorithm, which combines elastometry and proton density fat fraction (PDFF) with AST, in a derivation cohort (n = 103) and a validation cohort (n = 244) of patients with NAFLD. MAST exhibited slightly higher AUROCs than FAST, FIB-4 and NFS. MAST demonstrated similar positive predictive value and specificity and overall higher sensitivity and negative predictive value at the 90% sensitivity cut-off. The proportion of patients in the grey zone was similar between MAST and FAST. Overall, the performance of MAST and FAST is rather similar and future studies in independent cohorts will need to determine if there is a real difference in diagnostic accuracy between the algorithms. Meanwhile MAST is a useful addition, particularly for early phase therapeutic trials. In trying to understand the state of NAFLD awareness around the globe, Lazarus et al. collected data from 102 countries, on NAFLD policies, guidelines, civil society engagement, clinical management, and epidemiology then developed a preparedness index based on policies, guidelines, civil awareness, epidemiology and data on NAFLD detection and management which were categorised as high, medium, and low. A minority of countries were categorised as high-level while the majority were categorised as low-level. A third of countries scored zero out of 100. No country had a national or sub-national strategy for NAFLD and <2% of the different strategies for related conditions included any mention of NAFLD. National NAFLD clinical guidelines were present in only 32 countries. The authors conclude that although NAFLD is a pressing public health problem, no country was found to be well prepared to address it. An accompanying editorial further discusses the interpretation and limitations of these findings. Studies on the microbiome have largely focused on bacteria, whereas little is known about commensal fungi. Demir et al. characterised faecal fungi in 78 patients with NAFLD, 16 controls and 73 patients with alcohol use disorder (AUD) and investigated their role in a faecal microbiome-humanised mouse model of Western diet-induced steatohepatitis. They demonstrated a distinct faecal mycobiome signature in patients with NASH and significant fibrosis. The faecal mycobiome composition was also different between patients with NASH or AUD despite similar fibrosis stages. The faecal mycobiome composition was different according to histological activity or the presence of diabetes. Plasma anti-C. albicans IgG was increased in patients with NAFLD and advanced fibrosis. Gnotobiotic mice, colonised with human NASH faeces and treated with amphotericin B were protected from Western diet-induced steatohepatitis and fibrosis. The authors speculate that targeting the faecal mycobiome may be an attractive therapeutic option. The diagnostic criteria for autoimmune hepatitis (AIH) have been well described but there is a need to update and precisely define the criteria for both treatment response and treatment-induced remission. Pape et al., on behalf of the International Autoimmune hepatitis group (IAHG), performed a systematic review of the literature and identified different possible response criteria. They then used a Delphi method amongst IAHG members (34% responders) to consensually redefine the response criteria in AIH. Non-response was defined as a reduction of <50% in aminotransferase activity within 4 weeks of treatment initiation. Complete biochemical response was defined as normalisation of aminotransferase and IgG values after 6 months. Remission was defined histologically if the activity index was <4/18. These definitions were then tested in a dataset of 293 patients with clinical data available; 83% of treated patients were responders at 1 month and these patients experienced less LT or death than non-responders (2.4% vs. 21.4%); 46% had a complete biochemical response with LT or death occurring less frequently than in those without (0% vs. 7.5%). There were not enough follow-up biopsies to test for remission criteria. These definitions provide a simple and reproducible framework for treatment response and non-response, irrespective of the therapeutic intervention and should be useful for reporting study results and allowing comparisons between clinical trials. Antiepileptic drugs (AEDs) are a common cause of drug-induced liver injury (DILI). Over the last few decades, several newer AEDs were approved for marketing in the United States, and they are being increasingly prescribed for indications other than seizures. Since AEDs are a common cause of DILI, Chalasani et al. aimed to describe the trends, clinical characteristics, and outcomes of patients with AED DILI enrolled into the DILIN prospective study between 2004 and 2020. Among 1,711 participants with definite, highly likely, or probable DILI, 66 (3.9%) had AED DILI. The frequency of AED DILI significantly decreased during the study period (from 8.5% of cases during 2004-2007 to 2.6% during 2015-2020, p = 0.01). Compared to other agents, patients with AED DILI were younger (mean age 38.5 vs. 50.1 years-old, p <0.001) and more likely African American (27% vs. 12%, p = 0.008). Drug reaction with eosinophilia and systemic symptoms was commonly associated with liver injury caused by lamotrigine, phenytoin, and carbamazepine, but not valproate or gabapentin. Liver injury severity was moderate to severe in the majority: 5 died, and 3 underwent LT. None of the patients with lamotrigine-related DILI, including 13 with hepatocellular jaundice, died or needed LT, compared to 3 out of 16 (19%) with phenytoin-related DILI. In conclusion, the frequency of AED DILI significantly decreased over the last two decades. AED DILI has several distinctive features, including preponderance in African American patients with outcomes depending on the type of AED involved. Interleukin- (IL)-26 has been assigned to the IL-10 subfamily of cytokines. High serum IL-26 concentrations and IL-26 expression at sites of inflammation have been reported in patients with chronic inflammatory diseases, such as Crohn's disease, rheumatoid arthritis and vasculitis. IL-26 has emerged as a link between cell death and persistent inflammation and has been implicated in the pathophysiology of chronic inflammatory disorders. In addition to this harmful role, IL-26 might have protective physiological functions, particularly in antiviral protection. Beaumont, Larochette and coworkers investigated the possibility that IL-26 controls HCV infection independently of the immune system. They show that IL-26 penetrates HCV-infected hepatocytes, where it interacts directly with HCV double-stranded RNA replication intermediates, thereby inhibiting viral replication. Furthermore, IL-26 interferes with viral RNA-dependent RNA polymerase activity, preventing the de novo synthesis of viral genomic single-stranded RNA. These results identify IL-26 as a novel antiviral molecule. A considerable proportion of patients with sustained virological response (SVR) remain at risk of developing complications of ACLD. While the incidence of hepatic decompensation seems to be low, de novo hepatocellular carcinoma (HCC) development remains a major concern. Several risk-prediction models have been proposed, however, all of these previously published scores have yet to undergo external validation. Thus, no recommendation regarding the identification of a low-risk subgroup of patients with ACLD in whom HCC surveillance is not cost-effective has been implemented in recent guidelines on the management and follow-up of chronic hepatitis C. Semmler and coworkers developed risk stratification algorithms for de novo HCC development after SVR and validated them in an independent cohort. During a median follow-up of 41 months, 4.6% of patients with compensated ACLD developed de novo HCC. Post-treatment values showed a higher discriminative ability than pre-treatment values or absolute/relative changes. Approximately two-thirds of patients with compensated ACLD were identified as having an HCC risk <1%/year in both the derivation and validation cohort, thereby falling below the cost-effectiveness threshold for HCC surveillance. The mechanisms of carcinogenesis in NASH are being actively investigated. TAZ is a gene regulator increased in both mice and humans during the transition from steatosis to steatohepatitis. Wang et al. studied whether TAZ might have an independent role in activating molecular events in pre-tumour NASH hepatocytes that could eventually lead to HCC. The authors demonstrate that TAZ, by inducing the pro-oxidant gene Cybb, promotes oxidative DNA damage in pre-tumour NASH, leading to eventual HCC tumour formation. Silencing of hepatocyte TAZ in pre-tumour NASH suppressed subsequent HCC development and this anti-carcinogenic effect appeared to be distinct from the inhibitory effect on NASH progression. It was mainly explained by induction of the NOX2-encoding gene Cybb, which led to NADPH-mediated oxidative double strand DNA damage. The relevance to the human disease was confirmed by showing strong correlations between TAZ, NOX2 and oxidative DNA damage in tumour-surrounding tissue from human NASH-HCC livers. These data shed light on the earliest molecular-cellular processes of tumour formation in NASH and suggest that targeting TAZ could help prevent NASH-HCC. The IMbrave150 clinical trial showed improved overall survival (OS) and progression-free survival with atezolizumab plus bevacizumab vs. sorafenib in patients with unresectable HCC at the primary analysis, after a median 8.6 months of follow-up, when median OS in the combination arm had not been reached. Cheng et al. report on the updated results after 12 months of additional follow-up of this cohort of 501 patients randomized 2:1 to the combination or sorafenib. The median OS was 19.2 months with atezolizumab plus bevacizumab and 13.4 months with sorafenib (hazard ratio 0.66; 95% CI 0.52-0.85). The median progression-free survival was 6.9 and 4.3 months in the respective treatment groups. Treatment-related grade 3/4 adverse events occurred in 43% and 46%, while treatment-related grade 5 events occurred in 2% and <1% of patients. This late analysis confirms atezolizumab plus bevacizumab as a preferred first-line option for patients with advanced HCC in need of systemic therapy, provided they meet the inclusion criteria of the trial. Extracellular vesicles (EVs) are membrane-derived tiny vesicles able to transfer bioactive molecules from donor cells to neighbouring or distant recipient cells, thus helping shape the tumour microenvironment. Tey et al. have studied the role of EVs in the modulation of aggressive features like cancer stemness, tumorigenesis and metastasis of HCC. The polymeric immunoglobulin receptor (pIgR) is widely expressed in mucosal epithelial cells and aberrantly expressed in tumour tissues. Circulating EVs from patients with more advanced HCC had significantly elevated pIgR expression, and pIgR blockade hampered the stimulating effect that HCC EVs had on cancer stemness and tumorigenesis, while EVs enriched with pIgR promoted cancer stemness and cancerous phenotypes. Such induction of cancer aggressiveness occurred via PDK1/Akt/GSK3β/β-catenin signalling cascades and was abrogated by Akt and β-catenin inhibitors. In mice implanted with patient-derived tumour xenografts, an anti-pIgR neutralizing antibody attenuated tumour growth, revealing a potential therapeutic application of these findings. The presence of indeterminate or non-characterised liver nodules at the start of direct-acting antiviral (DAA) treatment is associated with an increased risk of HCC. Sanduzzi-Zamparelli et al. prospectively studied the risk of developing HCC in patients with advanced fibrosis or cirrhosis who were free from non-characterised liver nodules both before DAAs and at the time when SVR was reached. A total of 185 patients (122 with cirrhosis, 43% of whom had clinically significant portal hypertension) were included. The screening adherence dropped progressively over time, from 98.4% at 6 months to 80% at 2 years. With a median follow-up of 52 months, 10 patients developed HCC after a median time of 28.1 months from SVR. This resulted in an HCC incidence of 1.46 per hundred persons-year (95% CI 0.79–2.71) in the whole cohort and 2.24 per hundred persons-year (95% CI 1.21–4.17) among patients with cirrhosis. No patient with F3 fibrosis developed HCC in this period. 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.