DIABLO (diablo IAP-binding mitochondrial protein), also known as Smac, is a pro-apoptotic mitochondrial protein that functions as a critical antagonist of inhibitor of apoptosis proteins (IAPs). Upon apoptotic stimulation, DIABLO is released from the mitochondrial intermembrane space into the cytosol, where it binds to and inactivates IAPs, thereby allowing caspase activation and apoptosis progression 1. DIABLO operates through multiple apoptotic pathways: it can be released in response to chemotherapeutic drugs and genotoxic stress 1, and its release involves mitochondrial outer membrane permeabilization triggered by BAX translocation 2. Additionally, DIABLO functions in TNF-alpha-induced apoptosis by facilitating the degradation of cIAP1/2, which enables caspase-8 activation through formation of a RIPK1-FADD-caspase-8 complex 3. Therapeutically, synthetic DIABLO mimetics (SMs) have been developed to enhance cancer cell apoptosis in solid tumors by recapitulating DIABLO's IAP-antagonizing function 4. Decreased DIABLO expression correlates with chemotherapy resistance in certain cancers, particularly colorectal cancer 5. Clinically, mutations in DIABLO are associated with autosomal dominant deafness type 64, though the mechanism remains incompletely characterized in provided abstracts.