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Publications

Journal Article Review Ahead of print

PubMed: 42020362 DOI: 10.1038/s41419-026-08771-5

c-FLIP as a master regulator of immune homeostasis and disease mechanisms.

Cell Death Dis

Authors: Eliana Urbini, Annalisa Adamo, Yushu Hu, Luca Giacobazzi, Silvia Dusi, Francesco De Sanctis, Carmine Carbone, Davide Gibellini, Sara Pilotto, Vincenzo Corbo, Vincenzo Bronte, Fulvia Vascotto, Stefano Ugel

Affiliations

  • Immunology Section, Department of Medicine, University of Verona and Verona University Hospital Trust Verona, Verona, Italy.
  • Department of Medical and Surgical Sciences, Medical Oncology, Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy.
  • Microbiology Section, Department of Diagnostic and Public Health, University of Verona and Verona University Hospital Trust, Verona, Italy.
  • Section of Innovation Biomedicine - Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and Verona University Hospital Trust, Verona, Italy.
  • Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy.
  • ARC-Net Research Centre, University of Verona, Verona, Italy.
  • TRON, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz gGmbH, Mainz, Germany.
  • Immunology Section, Department of Medicine, University of Verona and Verona University Hospital Trust Verona, Verona, Italy.

Abstract

Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) was discovered more than three decades ago and has since emerged as a multifunctional regulator of cell fate. Initially identified through its homology with viral FLIP (v-FLIP) proteins and its ability to inhibit death receptor-induced apoptosis, c-FLIP is now recognized as a pivotal molecule at the crossroads of apoptosis, necroptosis, autophagy, and inflammation. Beyond its classical anti-apoptotic role, c-FLIP modulates key signaling pathways, including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and Wnt/β-catenin, thereby influencing immune cell activation, differentiation, and tolerance. In immune cells, c-FLIP expression determines susceptibility to death receptor signaling and fine-tunes inflammatory responses, contributing to the balance between immune activation and suppression. Aberrant c-FLIP regulation has been implicated in cancer, autoimmunity, and chronic inflammatory diseases, positioning it as both a biomarker and a potential therapeutic target. This review summarizes current understanding of c-FLIP structure, isoforms, and regulation; delineates its roles in apoptosis and non-apoptotic pathways; and discusses its critical function in orchestrating immune homeostasis and disease pathogenesis. By integrating mechanistic and translational perspectives, we highlight c-FLIP as a central hub that links cell death, immunity, and therapeutic opportunities.

MeSH

Cells, Homeostasis, Immunity, Receptors, Death Domain, Therapeutics, Apoptosis, Cell Death