Targeting Interferon-Gamma (IFN-γ)-Related Signalling Pathways in Inflammatory Bowel Disease: Emerging Inhibitors and Therapeutic Advances

Abstract

Inflammatory bowel disease (IBD) encompasses a group of chronic and relapsing inflammatory disorders of the gastrointestinal tract, driven by a multifaceted interplay between genetic predisposition, environmental factors and dysregulated immune responses. Central to its immunopathogenesis is the aberrant activation of pro-inflammatory cytokine networks, among which interferon-gamma (IFN-γ) has been increasingly recognised as a critical mediator of mucosal damage and disease perpetuation. IFN-γ exerts pleiotropic effects on both innate and adaptive immune compartments, orchestrating a pathogenic immune milieu that disrupts intestinal epithelial integrity and sustains chronic inflammation. Recent therapeutic advances have focused on the modulation of IFN-γ signalling as a targeted approach to restoring intestinal homeostasis. A growing repertoire of IFN-γ inhibitors-including neutralising monoclonal antibodies (MAbs), small-molecule Janus kinase (JAK) inhibitors and bioactive phytochemicals-are being explored for their capacity to attenuate IFN-γ-driven inflammatory cascades. These agents offer distinct mechanistic profiles, targeting various nodes of the IFN-γ axis, and hold significant promise for addressing therapeutic gaps in refractory IBD. This review provides a comprehensive evaluation of emerging IFN-γ-targeted therapies, detailing their mechanisms of action, preclinical and clinical efficacy and translational potential. By elucidating the therapeutic landscape of IFN-γ modulation, this study aims to inform the development of more effective and personalised treatment strategies for patients with IBD.

Keywords: IBD; IFN-γ; cytokines; inflammation; inhibitors.