Drug development in primary biliary cholangitis (PBC) has led to the conditional approval of three second-line therapies, yet the transition to full regulatory approval remains challenging due to (1) the reliance on liver biochemistry and non-invasive measures of liver fibrosis as biomarkers of clinical outcomes, which are not accepted by regulatory authorities as validated efficacy endpoints; (2) the limited integration of real-world data and real-world evidence to complement clinical trials; and (3) the absence of harmonised and standardised use of patient-reported outcomes (PROs). To address these limitations, the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) commissioned an international, multi-stakeholder consensus panel to conduct a modified Delphi process to review current evidence, identify unmet research needs, and create a framework aligned with regulatory expectations to guide ongoing and future research in PBC. A total of 62 panellists, including clinicians, methodologists, regulators, industry partners, and patient representatives, were divided into three working groups and participated in regular online meetings, one in-person conference, and two online Delphi voting rounds. Response rates across the two voting sessions were 88% and 60%, respectively. The Delphi process resulted in agreement on 16 statements and 42 recommendations across the three thematic domains. Collectively, these consensus recommendations provide a comprehensive and pragmatic framework to support and expand the existing regulatory pathway for the development and approval of new therapies in PBC.

Despite remarkable advances in diagnostics, pharmacotherapy, and transplantation, conventional hepatology often falls short in addressing the persistent symptoms, impaired quality of life, and broader health needs of people living with chronic liver disease. Integrative Hepatology—rooted in the principles of integrative medicine—offers a holistic, evidence-informed approach that combines conventional hepatology with complementary modalities to address the biological, nutritional, physical, psychosocial, behavioral, and environmental determinants of liver health. This framework emphasizes multimodal, patient-centered care aimed at improving both liver-specific and overall health outcomes. We outline 3 models for implementation: (1) foundational knowledge for all hepatologists, incorporating core skills in nutrition, physical activity, and mind-body practices; (2) collaborative referral networks to integrative health providers; and (3) specialized hepatologists with advanced training in integrative medicine. Examples of application to fatigue, cramps, falls, and mental health in chronic liver disease illustrate the potential for non-pharmacologic and complementary strategies to enhance patient well-being. Implementation faces challenges, including evidence gaps, limited training, time constraints, reimbursement barriers, and inequitable access, but opportunities exist through education, interdisciplinary collaboration, group medical visits, and digital health delivery. By expanding the scope of liver care to include whole-person health, Integrative Hepatology seeks not to replace established therapies but to augment their impact—supporting patients in achieving optimal health across the disease spectrum.

Hepatic stellate cells (HSCs) represent a highly heterogeneous mesenchymal cell population with multifaceted roles in liver homeostasis and disease. Beyond their well-established roles in vitamin A storage and scar formation, there is increasing evidence for HSCs in the regulation of hepatic metabolism, regeneration, immunity, and carcinogenesis. Here, we will review the heterogeneity of HSCs in the healthy, aging, and diseased liver, focusing on cell–cell interactions and their contributions to fibrosis, liver zonation and function, regeneration, and cancer. We explore the spatiotemporal diversity of HSCs, highlighting their subpopulations and their specialized roles, as well as the complex bidirectional communications between HSCs, hepatocytes, endothelial cells (ECs), macrophages/monocytes, T cells, and tumor cells. By integrating insights from single-cell sequencing, spatial transcriptomics, preclinical data, and clinical data, this review aims to provide an updated understanding of how HSC heterogeneity contributes to liver homeostasis and disease and can be targeted for therapeutic purposes.

Chronic liver disease affects over a billion people worldwide. Liver fibrosis is the key driver of liver-related complications and mortality. Elastography has been a transformative tool in hepatology, allowing for the diagnosis and staging of liver fibrosis noninvasively, and is evolving beyond these purposes into a prognostication tool. By measuring tissue stiffness, elastography techniques such as shear-wave and magnetic resonance elastography offer critical insights into liver fibrosis, portal hypertension, and the progression of disease. Magnetic resonance elastography stands out for its reliability across fibrosis stages and robustness in obese patients affected by metabolic liver disease. Spleen stiffness measurement complements liver assessments, enhancing the identification of portal hypertension and refining patient risk stratification. This review covers current clinical applications but also anticipates future innovations such as artificial intelligence-based algorithms that could expand elastography’s clinical impact, thereby improving patient outcomes.

DILI is rare in clinical practice, but when it occurs, it can lead to acute liver failure and death. Drug developers and regulators undertake a series of steps to identify the DILI potential of a medication before it is approved for marketing. Preclinical testing by drug developers typically involves a multitude of in vitro assays and in vivo animal experiments before a compound is moved into first-in-human phase 1 testing. Over the last 2 decades, there have been a number of advances in preclinical screening for DILI potential of a new chemical entity, but these approaches tend to be overly sensitive with insufficient positive predictive value. Once in clinical trials, the DILI potential of an investigational agent and risks to a participant are carefully managed through patient selection, DILI monitoring paradigms, and drug interruption and discontinuation criteria, in close concert with the regulators. Recent developments in quantitative systems toxicology offer promising and complementary in silico approaches to predict the compound’s risk for DILI via multifaceted systems biology. When a drug developer submits a New Drug Application for marketing approval, regulators review the preclinical and clinical trial data in a structured fashion to assess the DILI risk. While these approaches have been successful in dramatically reducing the marketing approval of medications eventually associated with hepatotoxicity, many challenges remain in identifying the risk for DILI during preclinical and early-to-late clinical development stages for genetic medicines, biological agents, and immunotherapies. In this review, we discuss current preclinical, in-silico, and clinical development approaches to screen for the DILI potential of an investigational agent and provide a high-level description of regulators’ approach for assessing DILI risk in a New Drug Application.