Anwar, Abid A

Cholangiocytes are specialized epithelial cells that line the intrahepatic and extrahepatic biliary tree and play a critical role in bile modification, liver homeostasis, and response to injury. Cholangiocytes exhibit notable heterogeneity and plasticity, and their dysfunction is central to a spectrum of diseases targeting the bile ducts, collectively called cholangiopathies. These disorders include genetic, infectious, immune-mediated, and malignant diseases, with primary sclerosing cholangitis (PSC) representing one of the most complex and enigmatic of these disorders. PSC is a progressive, fibro-inflammatory disease of the bile ducts that is closely linked to inflammatory bowel disease, carries a heightened risk of cancer, and lacks any approved therapies. This review explores the biology of cholangiocytes, including their development, functional plasticity, and roles in secretion, absorption, and cellular signaling. We provide a detailed examination of cholangiopathies, particularly PSC, a complex cholangiopathy characterized by a paradoxical state of cholangiocyte senescence and hyperproliferation. We describe how immune cell dysfunction, the gut microbiome, genetic predispositions, and environmental factors converge to mediate PSC pathogenesis. We revisit the foundational technologies that empowered early discoveries and shaped the field as we know it today. We also explore how newer techniques such as organoid cultures, single-cell transcriptomics, epigenomics, and spatialomics have transformed our modern understanding of biliary pathophysiology. Finally, we provide an overview of existing rodent models of cholangiopathies and discuss their relevance to human disease. PSC remains therapeutically unaddressed, and thus ongoing multidisciplinary efforts are essential to developing targeted interventions. This review serves as a comprehensive resource for researchers and clinicians navigating the rapidly evolving landscape of cholangiocyte-centered liver disease research.

The field of ribonucleic acid (RNA) biology has revealed an array of noncoding RNA species, particularly long noncoding RNAs (lncRNAs), which play crucial roles in liver disease pathogenesis. This review explores the diverse functions of lncRNAs in liver pathology, including metabolic-associated steatotic liver disease, hepatocellular carcinoma, alcohol-related liver disease, and cholangiopathies such as primary sclerosing cholangitis and cholangiocarcinoma. We highlight key lncRNAs that regulate lipid metabolism, inflammation, fibrosis, and oncogenesis in the liver, demonstrating their diagnostic and therapeutic potential. Emerging RNA-based therapies, such as mRNA therapy, RNA interference, and antisense oligonucleotides, offer approaches to modulate lncRNA activity and address liver disease at a molecular level. Advances in sequencing technologies and bioinformatics pipelines are simultaneously enabling the identification and functional characterization of novel lncRNAs, driving innovation in personalized medicine. In conclusion, this review highlights the potential of lncRNAs as biomarkers and therapeutic targets in liver disease and emphasizes the need for further research into their regulatory mechanisms and clinical applications.