Caspase-3 (CASP3)

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.

Recent Publications Summary

Recent studies have examined Caspase-3 (CASP3) as a central apoptosis-related target across cancer, inflammatory injury, and metabolic disease models. In a rat cadmium nephrotoxicity model, aqueous Zingiber officinale extract was evaluated in pre-treatment and post-treatment regimens using histopathology, immunohistochemistry, and molecular assays, including caspase-3 staining, to assess renal protection against oxidative stress, inflammation, and apoptosis 42446780Jul. In a gestational diabetes rat model, placental malformations and apoptotic changes were assessed with caspase-3 staining alongside Azan histology, and ethanolic propolis extract was reported to ameliorate placental structural damage 42223797Jun. resveratrol was also studied in pentylenetetrazol-induced epilepsy, where chronic seizures were associated with increased apoptotic activity involving Casp-3, Casp-9, Bax, and Bcl-2, and resveratrol improved diaphragm muscle function while modulating these pathways 42426356Jul.

Several anticancer studies linked CASP3 to treatment-induced cell death. In human lung adenocarcinoma A549 xenografts, interstitial photodynamic therapy reduced tumor growth and increased apoptotic signaling, with qRT-PCR and western blot analyses showing altered expression of Caspase-3 together with Bax, Bcl-2, Survivin, VEGF, and HIF-1α 42429993Jul. In colorectal cancer, the theranostic agent MF48 suppressed glucose uptake and induced selective cytotoxicity through activation of p53/p21/caspase-3 apoptotic signaling 42315971Jun. In hepatocellular carcinoma, urolithin derivative 11e promoted apoptosis and network pharmacology analyses identified CASP3 among the key predicted targets 41855633Mar. A brominated betulin derivative was likewise predicted by molecular docking to bind CASP3 and BRAF, and biological testing showed apoptosis and reactive oxygen species generation in melanoma cells 42019410Apr.

CASP3 was also implicated in pyroptosis-oriented cancer strategies, reflecting its role as a cleavage node linking apoptosis and inflammatory cell death. A Prussian blue nanocube formulation co-loaded with JQ1 and doxorubicin induced robust pyroptotic death in MDA-MB-231 triple-negative breast cancer cells through the CASP3/NF-κB/IL-1β pathway 42299821Jun. Mitochondria-targeted zwitterionic nanogels triggered photopyroptosis after 640 nm irradiation via ROS amplification and activation of the caspase-3/GSDME axis 42143709May. Cauloside A induced pyroptosis in non-small cell lung cancer cells by activating JNK phosphorylation and subsequent caspase-3-dependent GSDME cleavage after interaction with TLR4 42085840May. Saquinavir similarly triggered caspase-3-GSDME-dependent pyroptosis in hepatocellular carcinoma, alongside inhibition of glycolysis and the TCA cycle and degradation of JAK1 41687749Feb. In PD-1-refractory tumors, pan-PKC inhibition was reported to overcome resistance by inducing Caspase-3/GSDME-dependent immunogenic pyroptotic cell death 42234523Jun.

Other publications used CASP3 as a mechanistic marker of cytoprotection or tissue injury. Vitexin ameliorated high-glucose injury in ARPE-19 retinal cells, with bioinformatics and docking supporting CASP3 as the relevant target and experimental data showing reduced oxidative stress, apoptosis, and inflammation 42345537Jun. Ex vivo donor-organ pretreatment with siRNA nanoparticles targeting Caspase-3, complement C3, and NF-κB was developed to attenuate cold ischemia-reperfusion injury in cardiac transplantation 42339737Jun. In a radiobiology study, high-dose-rate flattening filter-free radiotherapy produced stronger early inflammatory and apoptotic responses in heart and lung tissues, with elevated cleaved caspase-3 indicating apoptotic activation 42411639Jul. Across these reports, CASP3 was consistently positioned as a key effector in apoptosis and, in several settings, as a switch point for pyroptosis or tissue-protective interventions.

What Changes, What Holds

1. Caspase-3 remains a broadly used apoptosis readout, now extended into injury and metabolic models
REINFORCES These studies do not alter the core account of CASP3 as an executioner protease or biomarker of apoptosis; they simply show it being used in additional preclinical settings to track renal, placental, and seizure-associated injury and response 42446780Jul42223797Jun. The main implication is practical rather than conceptual: caspase-3 staining continues to function as a general indicator of cell death and tissue stress across diverse disease models.

2. Treatment-induced caspase-3 activation continues to mark anticancer efficacy, with added target-prediction work
REINFORCES The new cancer papers fit the established view that CASP3 is a downstream effector of apoptosis and a common readout of therapeutic response, rather than redefining its role 42429993Jul42315971Jun. Docking and network-pharmacology predictions that place CASP3 among candidate targets are supportive but do not change the baseline understanding; they mainly reinforce its use as a mechanistic node in drug-response studies.

3. Caspase-3 is increasingly being used as the cleavage switch that links apoptosis to pyroptosis
NEW DIRECTION This extends the Overview’s statement that caspase-3 cleaves gasdermin proteins such as GSDME by showing that, in several cancer models, that cleavage is being exploited as an intentional route to inflammatory cell death rather than only as a marker of apoptosis 42299821Jun42143709May. The baseline does not discuss pyroptosis as a functional role, so these reports add a new use of CASP3 while leaving its apoptotic function intact.

4. Caspase-3 is also being pursued as a protective intervention target in tissue injury models
NEW DIRECTION Ex vivo silencing strategies and organ-protection studies move CASP3 beyond its established use as a biomarker and effector of apoptosis, toward a target whose inhibition may reduce ischemia-reperfusion or radiation-associated damage 42339737Jun42411639Jul. That does not contradict the Overview, which is silent on therapeutic suppression of CASP3; it does suggest a growing split between using caspase-3 as a readout of injury and trying to blunt it to preserve tissue.

Overview update candidates: caspase-3 as a functional switch into GSDME-linked pyroptosis; caspase-3 inhibition as a tissue-protective strategy in injury models.