Special Issue “Liver Fibrosis: Mechanisms, Targets, Assessment and Treatment”

Liver fibrosis is a significant challenge in hepatology, as it represents the common pathway of chronic liver injury due to various causes such as viral hepatitis, metabolic dysfunction-associated steatotic liver disease (MASLD), intoxication, alcohol-related liver disease, autoimmune conditions, and genetic disorders [1,2]. The progression of fibrosis not only indicates worsening organ dysfunction but also warns of serious complications, such as cirrhosis and hepatocellular carcinoma. The latter is the fourth-leading cause of cancer death worldwide [3]. Despite advancements in our understanding, effective antifibrotic treatments are limited, and many aspects of fibrogenesis remain unclear. This highlights the pressing need for ongoing research on the molecular mechanisms behind hepatic fibrosis, as well as improved methods for early detection and targeted intervention [4]. Given the clinical importance and biological complexity of liver fibrosis, research on the mechanisms driving fibrogenesis, new diagnostic biomarkers, and emerging therapeutic approaches is more crucial than ever [5,6].

The Special Issue “Liver Fibrosis: Mechanisms, Targets, Assessment and Treatment” was conceived to provide a comprehensive platform for cutting-edge research in this rapidly evolving field. This issue includes 10 original articles, reviews and case reports contributed by over 60 authors from a variety of countries, including Denmark, Germany, Greece, Japan, Lebanon, Poland, Sweden, Turkey, the United Kingdom, and the United States. This diversity emphasizes both the global impact of liver fibrosis and the international dedication to addressing the disease through collaborative science.

The collection begins with an Editorial by Ralf Weiskirchen and Tilman Sauerbruch, who discuss the dual nature of fibrosis as both reparative scar tissue after inflammation and a driver of progressive organ failure. They invite researchers worldwide to tackle mechanistic questions and translational challenges. Their introduction underscores how multifactorial triggers, from metabolic syndrome to infections or monogenic diseases, require equally multifaceted scientific approaches (Contribution 1).

One notable original contribution comes from Vorona et al., who present a compelling case report on MASLD arising from familial partial lipodystrophy, a rare genetic disorder. This paper not only outlines diagnostic challenges, but also showcases significant improvement following leptin replacement therapy. By summarizing current diabetes treatment options in MASLD contexts alongside their case experience, they offer valuable insights into personalized medicine for rare forms of fatty liver disease (Contribution 2).

On the immunological frontlines of fibrogenesis research is the paper of Tsomidis et al., whose extensive review dissects immune checkpoint pathways, such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), in both innate and adaptive immunity during hepatic fibrosis progression. They highlight how advancements in immunotherapy may soon lead to antifibrotic treatments targeting these regulatory axes (Contribution 3).

Advances in non-invasive diagnostics are exemplified by Villanueva Raisman et al., who leverage targeted mass-spectrometry-based proteomics to identify plasma protein panels capable of stratifying patients across different stages of liver fibrosis. Their approach holds promise for early detection, potentially reducing invasive biopsy, and supporting precision medicine through robust biomarker discovery (Contribution 4).

Innovations in technology are further addressed by Pyka et al., who describe their development of elastography measuring caps optimized for ex vivo assessment using porcine models. Their numerical simulations, validated with preclinical data, demonstrate improved accuracy in mechanical wave propagation analysis while minimizing tissue damage during assessment procedures relevant to transplantation medicine (Contribution 5).

Pedersen et al. compare proteomic profiles between visceral adipose tissue (VAT) and liver samples from obese individuals at various MASLD stages. While no direct MASH-specific signature emerged in VAT, several immunomodulatory proteins correlated between both tissues, suggesting shared inflammatory circuits that may influence disease trajectory (Contribution 6).

From Japan comes an important clinical study by Nagaoki et al., which addresses outcomes after hepatitis C virus eradication using direct-acting antivirals (DAAs). Through long-term follow-up they identify key risk factors—including platelet count < 11 × 10⁴/μL, high liver stiffness measurement, elevated bile acids, and an enlarged left gastric vein diameter—for the aggravation of esophagogastric varices despite virological cures. These findings offer practical guidance for surveillance protocols tailored to individual risk profiles (Contribution 7).

Kamoua et al., based in North America, deliver an up-to-date review on cutaneous manifestations associated with advanced liver dysfunction, including spider angiomas, palmar erythema, jaundice, and pruritus. They stress the value of these visible markers in aiding diagnosis and prognosis at the bedside. This article highlights the urgent need for increased clinical awareness in managing patients with liver diseases (Contribution 8).

The review by El Khoury et al. bridges basic science with cardiovascular epidemiology by examining the role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) deficiency in linking insulin resistance-driven steatohepatitis/fibrosis with endothelial dysfunction that underlies atherosclerosis. Drawing on animal models they propose CEACAM1 not only as a mechanistic bridge but also as a promising therapeutic target at the intersection of hepatic and vascular disease (Contribution 9).

Finally, Chandrasekaran and Weiskirchen provide an authoritative synthesis on MBOAT7, a lipid remodeling enzyme whose genetic variants have recently been implicated in MASLD susceptibility and progression through human association studies and mouse models. They discuss how targeting enzymes like MBOAT7 could open new avenues for future fatty liver disease therapies beyond classical targets such as PNPLA3 or TM6SF2 (Contribution 10).

Taken together, these ten contributions reflect not only scientific excellence but also remarkable international collaboration, from leading European academic centers to institutions across Asia, North America, and the Middle East. Each article offers new perspectives on fundamental biology or translational approaches toward assessment and treatment.

We express our sincere gratitude to all contributing authors whose expertise has made this Special Issue possible. We particularly recognize early-career scientists whose innovative ideas are pushing boundaries forward. Our hope is that readers will find inspiration within these pages to continue exploring one of the most pressing challenges in hepatology: understanding and ultimately reversing the complex process of liver fibrogenesis.

With ongoing advances in molecular biology, immunology, diagnostics, technology, and clinical management now converging more closely than ever before, we look forward with optimism to future breakthroughs that will transform healthcare for millions living with chronic liver disease worldwide.