BIRC2 is a multi-functional E3 ubiquitin-protein ligase that regulates apoptosis, NF-κB signaling, and innate immunity. As an inhibitor of apoptosis protein, BIRC2 suppresses caspase activation and protects cells from death through ubiquitination of caspases and death-domain proteins 1. BIRC2 regulates both canonical and non-canonical NF-κB signaling: it positively regulates canonical NF-κB while suppressing the non-canonical pathway by ubiquitinating NIK (NFκB-inducing kinase) 1. This NF-κB inhibition decreases MHC-I expression, enabling immune evasion in hepatocellular carcinoma cells 1. BIRC2 also regulates cell-cycle progression and DNA damage response through histone H3 binding via its BIR domains 2. Clinically, elevated BIRC2 expression correlates with poor prognosis across multiple cancers including HCC, head and neck squamous cell carcinoma, and pancreatic cancer 134. BIRC2 mediates drug resistance by suppressing apoptosis through interactions with upstream regulators like CITED4 and NAP1L1 45. BIRC2 blockade enhances anti-PD-1 immunotherapy efficacy by sensitizing tumor cells to T-cell killing and improving T-cell function 1. Small-molecule BIRC2 inhibitors like LCL161 disrupt histone binding and induce cancer cell death 2, representing promising therapeutic strategies.