Cellular FLICE-inhibitory protein (c-FLIP)

Cellular FLICE-inhibitory protein (c-FLIP, encoded by CFLAR) is a structurally and functionally conserved apoptosis regulator, best known for its role as an endogenous inhibitor of death receptor (extrinsic) apoptosis. It acts as a competitive inhibitor at the death-inducing signaling complex (DISC), preventing the activation of caspase-8 and thereby hindering the transmission of apoptotic signals initiated by death receptors such as Fas/CD95 and TRAIL receptors. In humans, c-FLIP has multiple isoforms, notably c-FLIP_L (long), c-FLIP_S (short), and c-FLIP_R (Raji), which vary in their regulatory functions and interact with FADD and procaspase-8 through their N-terminal death effector domains (DEDs). c-FLIP not only blocks apoptosis but also modulates NF-κB and Wnt signaling pathways, autophagy, and immune responses, making it critical for cell survival, inflammation, immune modulation, and cancer progression. Overexpression of c-FLIP contributes to treatment resistance in multiple cancers, and decreased c-FLIP can sensitize cells to immune-mediated apoptosis and certain chemotherapeutics. While there are no approved drugs directly targeting c-FLIP in the clinic, it remains an active subject of research as a therapeutic target and biomarker, especially in oncology.

Other names

CFLARCaspase-8 and FADD-like apoptosis regulatorFLICE-like inhibitory proteinCLARPFLAME-1I-FLICECasperCASHUsurpin

Drugs targeting c-FLIP aim to inhibit c-FLIP expression or function to remove its blockade on caspase-8 activation at the death-inducing signaling complex (DISC), thus promoting apoptosis in tumor cells and overcoming resistance to death receptor-targeted therapies (e.g., TRAIL agonists, anti-Fas therapies)