Caspase-4 is involved in endoplasmic reticulum (ER) stress-induced apoptosis and amyloid-β (Aβ)-induced cell death in humans. The study identifies human caspase-4 as a homolog of mouse caspase-12, which is localized to the ER membrane and is specifically cleaved under ER stress conditions. Caspase-4 is also cleaved by Aβ treatment, suggesting its role in Aβ-induced cell death. The cleavage of caspase-4 is not affected by other apoptotic stimuli such as etoposide, staurosporine, or UV, indicating its specificity to ER stress. Overexpression of Bcl-2, an anti-apoptotic protein, does not prevent caspase-4 cleavage by ER stress, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Knockdown of caspase-4 using small interfering RNA (siRNA) reduces ER stress-induced apoptosis and Aβ-induced cell death, but does not affect apoptosis induced by other stimuli. These findings suggest that caspase-4 functions as an ER stress-specific caspase in humans and may be involved in the pathogenesis of Alzheimer's disease. The study also shows that caspase-4 is localized to the ER and mitochondria, and its cleavage is specific to ER stress and Aβ treatment. The results indicate that caspase-4 plays a key role in ER stress-induced apoptosis and Aβ-induced cell death in human cells.Caspase-4 is involved in endoplasmic reticulum (ER) stress-induced apoptosis and amyloid-β (Aβ)-induced cell death in humans. The study identifies human caspase-4 as a homolog of mouse caspase-12, which is localized to the ER membrane and is specifically cleaved under ER stress conditions. Caspase-4 is also cleaved by Aβ treatment, suggesting its role in Aβ-induced cell death. The cleavage of caspase-4 is not affected by other apoptotic stimuli such as etoposide, staurosporine, or UV, indicating its specificity to ER stress. Overexpression of Bcl-2, an anti-apoptotic protein, does not prevent caspase-4 cleavage by ER stress, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Knockdown of caspase-4 using small interfering RNA (siRNA) reduces ER stress-induced apoptosis and Aβ-induced cell death, but does not affect apoptosis induced by other stimuli. These findings suggest that caspase-4 functions as an ER stress-specific caspase in humans and may be involved in the pathogenesis of Alzheimer's disease. The study also shows that caspase-4 is localized to the ER and mitochondria, and its cleavage is specific to ER stress and Aβ treatment. The results indicate that caspase-4 plays a key role in ER stress-induced apoptosis and Aβ-induced cell death in human cells.