caspase-3
caspase-3
Overview
Caspase-3 is a central executioner protease in the apoptotic cascade and belongs to the cysteine-aspartic acid protease family. It is synthesized as an inactive zymogen and becomes activated by upstream initiator caspases, most notably caspase-8 and caspase-9, in response to intrinsic or extrinsic death signals. Once activated, caspase-3 cleaves a broad range of cellular substrates, including poly(ADP-ribose) polymerase (PARP) and gasdermin family proteins such as GSDME, thereby driving the biochemical and morphological features of programmed cell death.
Because of this role, caspase-3 is widely used as a biomarker of apoptosis in biomedical research and is frequently measured alongside Bax, Bcl-2, cytochrome c, PARP, and related pathway components such as PI3K/Akt, MAPK, p53, and TGF-β/SMAD signaling. In cancer, neurodegeneration, liver injury, reproductive biology, and inflammatory disease models, changes in caspase-3 activity or cleavage are commonly interpreted as evidence of altered cell survival, tissue injury, or treatment response.
Focus of Latest Publications
Recent publications have continued to examine caspase-3 as a marker and mediator of apoptosis across diverse disease models, with several studies linking changes in caspase-3 to the effects of natural products and candidate therapeutics. In diabetic retinopathy-related work, vitexin was reported to protect high-glucose-challenged ARPE-19 retinal cells by targeting CASP3. The study combined cell viability assays, flow cytometry, biochemical measurements of oxidative stress and inflammatory mediators, western blotting, bioinformatics, and molecular docking. Vitexin reduced malondialdehyde and reactive oxygen species, improved superoxide dismutase and glutathione peroxidase activity, lowered TNF-α and IL-6 while increasing IL-10, and ultimately reduced apoptosis. CASP3 overexpression weakened these protective effects, supporting a role for caspase-3 in the observed cytoprotection.
Caspase-3 was also implicated in placental injury during gestational diabetes. In a streptozotocin-induced diabetic rat model, placental histology showed structural disorganization, trophoblastic degeneration, fibrosis, and increased oxidative stress, accompanied by increased caspase-3 expression. Treatment with ethanolic propolis extract improved metabolic and hematological parameters, restored antioxidant defenses, attenuated placental damage, and reduced caspase-3 expression, suggesting decreased apoptosis. In a separate diabetes-related neuroinflammation study, the iminoguanidine derivative FuBIG reduced neuronal apoptosis in LPS-induced BV2 and SH-SY5Y cells by upregulating B-cell lymphoma 2 and downregulating Bax and caspase-3, alongside activation of AMPK and suppression of inflammatory and oxidative stress-related changes.
Other recent studies used caspase-3 as part of broader apoptosis profiling in cancer and immune resistance models. In triple-negative breast cancer cells, Otostegia fruticosa ethanol extract induced ROS-associated apoptosis and reduced migration and invasion of MDA-MB-231 cells, with gene and protein analyses showing altered expression of caspase-3, caspase-8, caspase-9, Bcl2, Bax, Bid, cytochrome c, PTEN, and matrix metalloproteinase-9. In hepatocellular carcinoma, a urolithin derivative, compound 11e, inhibited proliferation, induced G2/M arrest, and promoted apoptosis in HepG2 cells; network pharmacology and docking identified CASP3 among key targets, together with EGFR, Akt1, and MAPK1, consistent with involvement of PI3K/Akt and MAPK signaling pathways. In an immuno-oncology study, pan-PKC inhibition in anti-PD-1-refractory tumors induced caspase-3/GSDME-dependent immunogenic pyroptotic cell death and helped resensitize tumors to checkpoint blockade, linking caspase-3 to tumor cell death and immune remodeling.
Not all recent work supported a direct pro-apoptotic role for caspase-3. In erythrocytes exposed to tobacco heating product aerosol, caspase-3 inhibition had no effect on eryptosis, indicating that the observed phosphatidylserine exposure and cell shrinkage were driven instead by calcium- and PKC-dependent mechanisms involving prostaglandin E2, calpain activity, and cytoskeletal changes. Overall, these publications portray caspase-3 as a recurring readout and mechanistic node in apoptosis-related injury, therapeutic protection, and cell death regulation across retinal, placental, neuronal, cancer, and immune-refractory tumor contexts.