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Publications

Journal Article Review Ahead of print

PubMed: 42593061 DOI: 10.1080/13543784.2026.2717160

Receptor interacting protein kinase 1 as a potential therapeutic target in inflammatory bowel disease: biological rationale and emerging clinical evidence.

Expert Opin Investig Drugs

Authors: Sailish Honap, Axel Dignass, Vipul Jairath, Fernando Magro, Silvio Danese, Laurent Peyrin-Biroulet

Affiliations

  • Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK.
  • Infection and Immunity Research Institute, City St George's, University of London, London, UK.
  • Department of Medicine I, Agaplesion Markus Hospital, Goethe University, Frankfurt, Germany.
  • Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada. Department of Epidemiology and Biostatistics, Western University, London, ON, Canada.
  • CINTESIS@RISE Department, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.
  • Department of Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy.
  • Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada.

Abstract

INTRODUCTION

Inflammatory bowel disease (IBD) remains a major cause of morbidity, with many patients failing to achieve sustained remission and mucosal healing. Receptor-interacting protein kinase 1 (RIPK1) is a potential therapeutic target that links tumor necrosis factor receptor signaling to inflammation, apoptosis, and necroptosis, processes relevant to epithelial injury and barrier dysfunction in IBD.

AREAS COVERED

This narrative review summarizes the biological rationale and translational and clinical evidence for targeting RIPK1 in IBD. MEDLINE was searched from database inception to March 2026 to identify relevant articles. Preclinical studies across cell systems, human tissue, and murine colitis models, suggest that RIPK1 kinase activity contributes to inflammatory signaling, epithelial injury, and necroptosis, while selective inhibition attenuates these processes and ameliorates experimental colitis. However, RIPK1 also has kinase-independent scaffolding functions important for epithelial homeostasis, highlighting the complexity of therapeutic targeting. GSK2982772 did not demonstrate convincing efficacy, whereas clinical efficacy data for newer RIPK1 inhibitors, including ABBV-668 and eclitasertib, have not yet been reported.

EXPERT OPINION

RIPK1 remains a compelling but clinically unvalidated target in IBD. Future progress will depend on improved patient selection, confirmation of mucosal target engagement, and better recognition of patients in which RIPK1 signaling is a key driver.

MeSH

Colitis, Protein Kinases, Necroptosis, Protein Kinase Inhibitors, Inflammatory Bowel Diseases, Therapeutics, Colitis, Ulcerative