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

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.