Fas ligand–Fas receptor pathway (CD95L–CD95) (FasL–Fas (CD95L–CD95))

The Fas ligand–Fas pathway comprises the Fas receptor (CD95/APO-1), a type-I transmembrane TNF receptor superfamily member with a cytoplasmic death domain, and its physiological ligand Fas ligand (FasL/CD95L), a type-II transmembrane TNF superfamily cytokine; engagement of Fas by trimeric membrane FasL clusters Fas and assembles the death-inducing signaling complex (DISC) via FADD, recruiting and activating caspase-8 (and caspase-10 in humans) to initiate the extrinsic apoptosis cascade; in some cells (e.g., hepatocytes) death signals may be amplified via BID cleavage linking to mitochondrial pathways; beyond apoptosis, Fas–FasL can initiate non-apoptotic signaling (NF-κB, MAPK) and under certain contexts necroptosis, contributing to roles in immune homeostasis (negative selection, AICD), cytotoxic lymphocyte function, immune privilege, and diseases including autoimmunity, cancer, infection, and liver injury; mutations in Fas or FasL cause lymphadenopathy and SLE-like autoimmunity in mice and humans, underscoring their importance and highlighting therapeutic opportunities and safety liabilities for pharmacologic modulation of this pathway.

Other names

Fas–FasL pathwayCD95–CD95L pathwayAPO-1–APO-1 ligand pathwayTNFRSF6–TNFSF6 pathwayDeath receptor 6 (Fas) signalingFas/APO-1 signalingFas cell death pathway

Death receptor agonism: Multimerization of Fas by membrane FasL or agonistic biologics induces DISC formation, recruiting FADD and pro–caspase-8/10 to trigger caspase cascade and apoptosis; Inhibition/decoy: Blocking Fas–FasL interaction (e.g., soluble Fas) prevents DISC assembly and downstream apoptosis (investigational); Non-apoptotic signaling modulation: Through c-FLIP/TRAFs/RIP recruitment, Fas engagement can activate NF-κB/ERK/MAPK leading to proliferation/inflammation; therapeutic modulation could tilt outcomes