Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease characterized by progressive inflammation, fibrosis, and stricturing of the intrahepatic and/or extrahepatic bile ducts. This process leads to cholestasis, hepatic dysfunction, progression to biliary cirrhosis, and an increased risk of hepatobiliary malignancies 1, 2.

PSC displays a bimodal age distribution, with a first peak in adolescence and a more pronounced one in early adulthood 3, 4. It predominantly affects males (male-to-female ratio ∼2:1) and is strongly associated with inflammatory bowel disease (IBD), particularly ulcerative colitis, present in more than half of patients 5, 6.

The pathogenesis of PSC is complex, multifactorial, and incompletely understood. Genetic predisposition accounts for less than 10% of disease liability, while environmental factors are estimated to contribute to over 50% [7]. Central to the disease pathogenesis is the gut–liver axis: dysbiosis, mucosal inflammation, and increased intestinal permeability allow microbial products and lymphocytes to reach the liver, triggering both innate and adaptive immune responses [7]. These antimicrobial immune-mediated mechanisms damage innocent bystander epithelial cells, leading to cholestasis, which amplifies inflammation and drives cellular senescence. Simultaneously, peribiliary glands expand, and peribiliary mesenchymal cells differentiate into myofibroblasts, resulting in progressive bile duct fibrosis [8].

There are currently no approved pharmacological therapies for PSC (Figure 1), as the drugs tested so far have not shown a clear benefit in altering the natural history of the disease. Liver transplantation remains the only definitive treatment, yet disease recurrence occurs in up to 38% of patients post-transplantation 9, 10.

The therapeutic landscape of PSC is rapidly expanding with numerous clinical trials exploring promising novel agents. However, trial design remains challenging due to disease’s clinical heterogeneity and variable progression [11]. Clinical end points can take years to develop, and none of the surrogate end points have yet to be validated, further complicating risk stratification, further complicating risk stratification [12]. The concomitant use of IBD treatments includes anti-inflammatory drugs, antibiotics, and ursodeoxycholic acid (UDCA), which may act as confounding factors [13]. Moreover, competing end points involving both liver, biliary tree, and gut increase the complexity of result interpretation [14]. Finally, the combination of disease heterogeneity and low prevalence, typical of rare conditions, the lack of approved therapies, difficulties in recruiting of patients into clinical trials, and results that are not generalizable to the broader PSC population [15]. A potential strategy to mitigate these challenges may involve reducing phenotypic heterogeneity by studying patients at an early disease stage or by focusing on populations in which disease onset can be more precisely defined, such as those with post-transplant recurrence. While these approaches may enhance the interpretability of therapeutic effects, they also restrict the eligible patient pool in an already rare disease. Therefore, efforts to promote patient referral to tertiary centers and to facilitate enrollment in clinical trials remain essential to ensure feasibility and representativeness.