cFLAR

cFLAR, short for cellular FLICE-like inhibitory protein-related, refers to a family of proteins encoded by the CFLAR gene in humans. The gene produces several isoforms through alternative splicing, the most studied being c-FLIP_S (short), c-FLIP_L (long), and c-FLIP_R. All isoforms share N-terminal death effector domains that enable interactions at the death-inducing signaling complex (DISC), but c-FLIP_L contains an additional caspase-like region that is catalytically inactive. Together, these proteins regulate programmed cell death in response to death receptor signaling.

The primary role of cFLAR proteins is to inhibit caspase-8 activation at the DISC, thereby blocking apoptosis triggered by receptors such as Fas (CD95) and TRAIL receptors. By competing with procaspase-8 for binding to FADD, cFLIP proteins prevent full caspase-8 activation. In some contexts, however, the c-FLIP_L isoform can form heterodimers with caspase-8 that promote limited caspase-8 activity, potentially influencing other signaling pathways and cell fate decisions. Consequently, cFLAR acts as a critical modulator of cell survival and death, with outcomes shaped by isoform expression levels and cellular context.

Expression of CFLAR is widespread, with regulation by NF-κB signaling and various stimuli in immune and non-immune cells. Post-translational modifications influence stability and function. Clinically, overexpression or dysregulation of CFLAR/c-FLIP has been linked to resistance to apoptosis in several cancers and to altered responses to chemotherapy. As such, cFLAR is often explored as a target to sensitize tumor cells to apoptotic therapies and to understand immune regulation.