Orchestrated cell death pathways in cholangiopathies.

Abstract

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.