Year: 2025
Type: article
Abstract: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with no effective curative therapies. Necroptosis, a regulated necrotic cell death pathway controlled by receptor-interacting protein kinase 1 (RIPK1), has emerged as a potential driver of inflammation and fibrosis in chronic liver disorders. We investigated the role of necroptosis in PSC and whether RIPK1 inhibition could modify disease course and progression. Spatial profiling of human PSC biopsies revealed that necroptosis primarily affects cholangiocytes, while apoptosis was more frequent in hepatocytes and nonbiliary cells. In vitro, necroptosis inhibition protected cholangiocytes, and RIPK1 deletion conferred resistance to TNF-mediated cytotoxicity. In a murine model of PSC, pharmacological RIPK1 inhibition reduced cholestatic injury, hepatic inflammation, and biliary fibrosis. Multiomic analyses comprehensively demonstrated reprogramming toward wild-type–like profiles following treatment. These findings identify necroptosis as a critical effector in PSC and highlight RIPK1 inhibition as a promising disease-modifying approach, opening the door to targeted necroptosis-based therapies for this otherwise untreatable disease.
Source: Science Advances
Authors: Pierre-Antoine Soret, Virginie Steunou, Julien Hedou, Juliette Tokgozoglu, Valeria Pistorio, Amine Majdi, Nadia Darwane, Jean-Louis Delaunay, Siham Benyahia, Laetitia Dinard, Tatiana Ledent, Inès Metatla, Chiara Guerrera, Marie Lhomme, Maharajah Ponnaiah, Jérôme Galon, Patrick Soussan, Lawrence Serfaty, Christophe Corpechot, Chantal Housset, Tounsia Aït-Slimane, Franck Verdonk, Olivier Chazouillères, Dominique Wendum, Vlad Ratziu, Sara Lemoinne, Axelle Cadoret, Nicolas Chignard, Jérémie Gautheron
Institutions: Inserm, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Hôpital Saint-Antoine, Centre de Recherche Saint-Antoine, Fondation pour l’innovation en Cadiométabolisme et Nutrition, Université Paris Cité, Centre de Recherche des Cordeliers, Structure fédérative de recherche Necker, Fédération Hospitalo-Universitaire, Paris Center for Microbiome Medicine
Language: English
Topic: Liver Diseases and Immunity
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
Funders: Fondation de l'Avenir pour la Recherche Médicale Appliquée, Fondation Maladies Rares, Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, Ligue Contre le Cancer, Institut National Du Cancer, Association Française pour l'Etude du Foie, Société Francophone du Diabète, Sorbonne Université
OpenAlex ID: W4417439389