Caspase-Dependent Mechanisms in Cell Death and Disease

Caspases are a family of cysteine proteases central to the regulation of programmed cell death and inflammatory processes. They exist as inactive zymogens that are activated via proteolytic cleavage in response to intrinsic or extrinsic signals. Initiator caspases (such as caspase-8 and caspase-9) respond to death-receptor engagement or mitochondrial cytochrome c release, respectively, assembling into multiprotein platforms (the death-inducing signalling complex or apoptosome). These in turn activate executioner caspases (such as caspase-3, ‑6 and ‑7), which orchestrate the demolition phase of apoptosis by cleaving structural, regulatory and repair proteins. Beyond apoptosis, certain caspases (notably caspase-1) mediate pyroptosis, an inflammatory cell death that facilitates cytokine processing and release. Emerging evidence highlights non-lethal roles for executioner caspases in tissue regeneration, cell proliferation and oncogenic transformation, as well as the ability of cells to reverse late-stage apoptotic events in a process termed anastasis. Dysregulated caspase activity contributes to a range of human pathologies, including neurodegeneration, autoimmunity, cancer and ischaemic injury. Selective chemical inhibition and novel biosensors now enable precise interrogation of individual caspase isoforms, illuminating their diverse physiological and pathological functions and opening avenues for targeted therapeutic interventions.

Research from Nature Portfolio

A dual-colour biosensor system has been developed to track caspase activity in living organisms and to identify cells that survive apoptotic triggering. This approach revealed that many cells sustain caspase activation without progressing to irreversible cell death, indicating widespread anastasis during normal development and following environmental stress. The study demonstrated both transient and persistent reporter expression in distinct tissues, underscoring non-apoptotic roles for caspases in physiological contexts. Functional recovery after late-stage caspase engagement suggests potential targets for modulating tissue repair and limiting unintended survival of damaged or pre-malignant cells.

Caspase-Dependent Mechanisms in Cell Death and Disease publication trend

The graph below shows the total number of articles in caspase-dependent mechanisms in cell death and disease across all publications each year (not limited to Nature Index journals).

Technical terms

Apoptosis: Programmed cell death characterised by membrane blebbing, chromatin condensation and formation of apoptotic bodies.

Pyroptosis: Inflammatory form of programmed cell death driven by caspase-1 and gasdermin-mediated pore formation.

Anastasis: Reversal of apoptotic processes, enabling cells to recover after initiation of caspase activation.

Initiator caspase: Protease that responds to upstream signals and activates executioner caspases.

Executioner caspase: Downstream protease that cleaves substrates to execute cell dismantling.

Caspase zymogen: Inactive precursor form of a caspase requiring proteolytic cleavage for activation.

Covalent inhibitor: Small molecule that irreversibly binds to an enzyme active site, blocking its function.

Chemoproteomic probe: Reactive compound used to profile enzyme activities and selectivity across complex proteomes.

Endonuclease G (EndoG): Mitochondrial nuclease that translocates to the nucleus to facilitate DNA fragmentation during cell death.

References

1. Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase‑6. Journal of the American Chemical Society (2023).
2. Cell survival following direct executioner-caspase activation. Proceedings of the National Academy of Sciences of the United States of America (2023).
3. Executioner Caspase-3, -6, and -7 Perform Distinct, Non-redundant Roles during the Demolition Phase of Apoptosis*. Journal of Biological Chemistry (2000).
4. Caspase-1: is IL-1 just the tip of the ICEberg?. Cell Death & Disease (2012).
5. Paracrine control of tissue regeneration and cell proliferation by Caspase-3. Cell Death & Disease (2013).
6. In vivo CaspaseTracker biosensor system for detecting anastasis and non-apoptotic caspase activity. Scientific Reports (2015).
7. Caspase-3 promotes oncogene-induced malignant transformation via EndoG-dependent Src-STAT3 phosphorylation. Cell Death & Disease (2024).