Soret, Pierre‐Antoine

Cholangiopathies comprise a heterogeneous group of chronic liver diseases characterised by progressive bile duct injury, ductular reaction and fibrotic remodelling. Despite distinct aetiologies, these disorders share common cellular stressors that ultimately converge on cholangiocyte dysfunction and loss. In this context, programmed cell death has emerged as a central mechanism linking epithelial stress, immune activation and the development of biliary fibrosis. A range of regulated cell death pathways, including apoptosis, necroptosis, pyroptosis, ferroptosis and autophagy-dependent cell death, can be triggered in cholangiocytes in a disease-dependent and context-dependent manner. Growing evidence suggests that these pathways rarely act in isolation. Instead, they intersect through shared molecular nodes, forming integrated cell death programmes such as PANoptosis. Importantly, it is becoming clear that not only overt cell death but also sublethal activation of death-related signalling can perpetuate cholangiocyte dysfunction and fuel chronic disease progression. Current therapeutic strategies, such as ursodeoxycholic acid and peroxisome proliferator-activated receptor agonists, mainly aim to modify bile composition and improve biochemical parameters. However, they do not directly target the molecular networks governing cholangiocyte death, which may partly explain their limited impact on fibrosis and long-term outcomes. In this review, we synthesise current knowledge on regulated cell death mechanisms in cholangiopathies, highlight key conceptual and technical challenges that complicate their interpretation and therapeutic targeting, and discuss how sublethal death signalling may connect with senescence to sustain cholangiopathy progression and shape therapeutic perspectives.

Background and Aims: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. Approach and Results: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7–21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7–59.9, p < 0.001) when these 2 conditions were met. Conclusions: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.