Caspase-2, a highly conserved member of the caspase family, is considered an initiator caspase that triggers apoptosis in response to some cellular stresses. Previous studies suggest that an intracellular multi-protein complex PIDDosome, induced by genotoxic stress, serves as a platform for caspase-2 activation. Due to caspase-2's inability to process effector caspases, however, the mechanism underlying caspase-2-mediated cell death upon PIDDosome activation remains unclear. Here, we conducted an unbiased genome-wide genetic screen and identified that the Bcl2 family protein BID is required for PIDDosome-induced, caspase-2-mediated apoptosis. PIDDosome-activated caspase-2 directly and functionally processes BID to signal the mitochondrial pathway for apoptosis induction. In addition, a designed chemical screen identified a compound, HUHS015, which specifically activates caspase-2-mediated apoptosis. HUHS015-stimulated apoptosis also requires BID but is independent of the PIDDosome. Through extensive structure-activity relationship efforts, we identified a derivative with a potency of ~60 nmol/L in activating caspase-2-mediated apoptosis. The HUHS015-series of compounds act as efficient agonists that directly target the interdomain linker in caspase-2, representing a new mode of initiator caspase activation. Human and mouse caspase-2 differ in two crucial residues in the linker, rendering a selectivity of the agonists for human caspase-2. The caspase-2 agonists are valuable tools to explore the physiological roles of caspase-2-mediated cell death and a base for developing small-molecule drugs for relevant diseases.
Caspase 2/genetics* ; Humans ; BH3 Interacting Domain Death Agonist Protein/metabolism* ; Apoptosis/drug effects* ; Death Domain Receptor Signaling Adaptor Proteins/metabolism* ; Animals ; Mice ; Cysteine Endopeptidases

The co - existence of lower extremity varicose veins and non - thrombotic iliac vein lesions is not uncommon in clinical practice. The clinical manifestations of the two are similar, but there is no linear correlation between their severity. Therefore, a thorough examination is required to individually analyze the causes of patients, and then formulate treatment strategies. Treating the two diseases simultaneously can resolve both superficial and deep venous issues, accelerate the improvement of clinical symptoms, especially the healing of venous ulcers. However, the overall cost is high, and there are issues such as exceeding medical insurance limits. Treating the two diseases in stages allows for a decision on whether to treat the other disease after close follow - up, but there is a risk of disease progression. This article reviewed the literature on the etiology, diagnosis, grading, and treatment of lower extremity varicose veins and non - thrombotic iliac vein lesions, and explored the optimal treatment strategies.