CFLAR (CASP8 and FADD-like apoptosis regulator) is a crucial anti-apoptotic regulator that functions as a critical link between cell survival and cell death pathways 1. Its primary mechanism involves inhibiting extrinsic apoptosis by producing a proteolytic fragment (p43) that blocks caspase-8 recruitment and activation at the death-inducing signaling complex (DISC) 2. CFLAR acts as a checkpoint in TNF receptor signaling: when NF-κB activation occurs via complex I signaling, CFLAR(L) accumulates in cytoplasmic complex II, promoting cell survival; conversely, CFLAR downregulation sensitizes cells to death 3. Beyond apoptosis inhibition, CFLAR regulates multiple cell death pathways. It permits caspase-8-dependent necroptosis inhibition while preventing apoptosis induction 4. CFLAR stability is regulated through ubiquitination by E3 ligase ITCH and de-ubiquitination by USP40, with GMEB1 serving as a stabilizing bridge protein 1. PRMT1 and PRMT5 distinctly control CFLAR degradation through arginine methylation, modulating chemotherapy sensitivity 5. Clinically, CFLAR overexpression correlates with aggressive tumors and poor prognosis 67. Beyond cancer, CFLAR suppresses nonalcoholic steatohepatitis by inhibiting ASK1/JNK signaling, with therapeutic potential for NASH treatment 8. These findings establish CFLAR as a multifunctional regulator controlling tumor progression, metabolic disease, and immune responses.