Topic: Genetic Mechanisms and Gene Therapy in Liver Disease

The liver plays a central role in metabolism, detoxification, immune regulation, and nutrient homeostasis. Consequently, genetic alterations affecting hepatic function can lead to a wide spectrum of diseases, ranging from rare monogenic metabolic disorders to complex, multifactorial conditions such as fatty liver disease and hepatocellular carcinoma. In recent years, advances in genomics, molecular biology, and gene-editing technologies have significantly deepened our understanding of the genetic mechanisms underlying liver disease and opened new avenues for precision therapies.

High-throughput sequencing technologies have enabled the identification of pathogenic variants responsible for inherited liver disorders such as Wilson disease, alpha-1 antitrypsin deficiency, progressive familial intrahepatic cholestasis, and urea cycle disorders. At the same time, genome-wide association studies and multi-omics approaches have uncovered genetic risk factors that contribute to common liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), viral hepatitis progression, and liver cancer. These discoveries are transforming our understanding of disease pathogenesis and enabling the development of targeted therapeutic strategies.

Parallel to these advances, gene therapy has emerged as one of the most promising approaches for treating liver diseases. The liver is an especially attractive target for gene-based therapies due to its accessibility through systemic delivery, high regenerative capacity, and central metabolic role. Recent breakthroughs in adeno-associated viral (AAV) vectors, lipid nanoparticle-mediated nucleic acid delivery, and genome-editing technologies such as CRISPR/Cas systems have accelerated the translation of gene-based interventions from experimental models to clinical trials. These strategies include gene replacement, gene silencing, genome editing, and RNA-based therapeutics, many of which have demonstrated encouraging results in preclinical studies and early-phase clinical trials.

Despite this progress, several challenges remain. These include achieving efficient and durable gene delivery, avoiding immune responses, ensuring genomic safety, and addressing ethical and regulatory considerations. Furthermore, translating genetic discoveries into clinically effective therapies requires interdisciplinary collaboration among geneticists, hepatologists, molecular biologists, and clinical researchers.

This Special Issue, “Genetic Mechanisms and Gene Therapy in Liver Disease,” aims to provide a comprehensive overview of recent advances in the field. We welcome original research articles, reviews, perspectives, and methodological studies that explore the genetic basis of liver disease and the development of innovative gene-based therapeutic approaches. By bringing together insights from basic science and translational research, this collection seeks to highlight emerging discoveries, identify remaining challenges, and accelerate the development of effective genetic therapies for liver disorders.

Suggested Topics for the Special Issue

● Genetic architecture of inherited liver diseases;

● Molecular mechanisms of monogenic liver disorders;

● Genomics and multi-omics approaches in liver disease;

● Genetic modifiers and susceptibility loci in MASLD/NAFLD;

● Epigenetic regulation in liver disease development and progression;

● Gene-environmental interactions in liver pathogenesis;

● Advances in viral vectors for liver-directed gene therapy (e.g., AAV, lentiviral vectors);

● Non-viral delivery systems for hepatic gene therapy (e.g., lipid nanoparticles);

● CRISPR/Cas and next-generation genome-editing technologies in liver diseases;

● Base editing and prime editing applications in hepatology;

● RNA-based therapeutics (siRNA, antisense oligonucleotides, mRNA therapies);

● Gene therapy for inherited metabolic liver diseases (e.g., Wilson disease, PFIC, OTC deficiency);

● Gene-based strategies for alpha-1 antitrypsin deficiency;

● Genetic and gene therapy approaches for cholestatic liver diseases;

● Gene therapy in viral hepatitis and liver fibrosis;

● Genetic drivers and gene-targeted therapies for hepatocellular carcinoma;

● Preclinical models for gene therapy in liver disease;

● Safety, immunogenicity, and long-term efficacy of liver-directed gene therapies;

● Biomarkers and patient stratification for genetic therapies;

● Ethical, regulatory, and clinical translation challenges in gene therapy for liver diseases;

● Precision medicine and personalized genetic treatment strategies in hepatology.