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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月22日

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  • 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

摘要

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.