Caspase-1 (CASP1)

Overview

CASP1 encodes caspase-1, a cysteine protease best known for its central role in inflammasome signaling and pyroptotic cell death. In canonical innate immune pathways, caspase-1 is activated downstream of inflammasome complexes such as NLRP3, where it processes the pro-forms of interleukin-1 beta (IL-1β) and IL-18 into their mature, bioactive cytokines and can also cleave Gasdermin D (GSDMD) (GSDMD) to drive membrane pore formation and pyroptosis. Through these functions, CASP1 links pathogen sensing, sterile inflammation, and tissue injury responses.

Because of this position in inflammatory signaling, CASP1 is frequently studied in diseases characterized by excessive inflammasome activation, including neuroinflammation, inflammatory bowel disease, rheumatoid arthritis, ischemia-reperfusion injury, cancer-associated inflammatory cell death, and degenerative disorders. In recent work, CASP1 has also been examined as a therapeutic target in combination with pathways involving toll like receptor 4 (TLR4), NF-κB, TXNIP/NLRP3, mitophagy, and SIRT1/HIF-1α, as well as with compounds such as sulforaphane, kaempferol, quercetin, apigenin, salidroside, emodin, and amygdalin.

Recent Publications Summary

Recent studies have continued to place Caspase-1 at the center of inflammasome-driven pyroptosis across diverse disease models. In gallbladder cancer, Caspase-1 was not the primary target but appeared in the broader immune-evasion context of PD-L1 regulation, where splicing-mediated hnRNPD isoform switching altered tumor immune escape 42477458Jul. In ovarian cancer, an intraperitoneal mRNA-based immunotherapy was designed to deliver IL-12, IL-15, pro-IL-18, and Caspase-1 in lipid nanoparticle to reprogram the peritoneal tumor microenvironment 42116169May. In lung adenocarcinoma, CASP1 emerged as one of six core PANoptosis-related genes identified through multi-omics and machine-learning analyses, with the study linking these genes to the tumor microenvironment and therapeutic potential 41935997Apr.

Several publications directly examined Caspase-1 as part of the NLRP3 inflammasome axis in inflammatory and metabolic injury models. In diabetic kidney disease, high glucose increased NLRP3, NF-κB p65, and caspase-1 expression in HK-2 cells, and both MCC950 and irbesartan attenuated these changes along with epithelial-mesenchymal transition markers 42318962Jun. In cerebral ischemia-reperfusion injury, hydromorphone preconditioning was associated with reduced NLRP3-positive expression and lower caspase-1 activity in animal and cell models 42318970Jun, while amygdalin similarly reduced pyroptosis-related marker expression and suppressed the TLR4/NF-κB/NLRP3 axis in vivo and in vitro 42013993Apr. electroacupuncture at ST36 and SP6 alleviated acute gouty arthritis and downregulated NLRP3, caspase-1, and IL-1β in joint tissue 41967209Apr, and a traditional Chinese medicine formulation (“Tianyu”) was reported to modulate the NLRP3/Caspase-1/GSDMD-mediated pyroptosis pathway in rheumatoid arthritis models 42033182Apr.

Caspase-1 was also targeted therapeutically in cancer and tissue-injury settings. In esophageal carcinoma, dexmedetomidine enhanced cisplatin chemosensitivity by activating pyroptosis through the SREBF1/miR-185-5p/Caspase-1 axis; miR-185-5p directly targeted the Caspase-1 3'UTR, and Caspase-1 knockdown reduced the sensitizing effect 41966778Apr. In force-induced root resorption, Caspase-1-dependent pyroptosis was implicated in periodontal ligament stem cell injury, and Caspase-1-targeting siRNA nanoparticles were developed to suppress pyroptosis and prevent disease progression 41850405Mar. In renal cancer stem cells, ARDAP@SPION-PEI nanocomposites induced PANoptosis and altered chromatin accessibility, with the study reporting upregulation of key PANoptosis pathway genes 42138776May. In bovine digital fibroblasts infected with Fusobacterium necrophorum, emodin alleviated pyroptosis via the NLRP3/GSDMD pathway 41819319Mar, and in Parkinson’s disease models, sulforaphane inhibited NLRP3 inflammasome activation and caspase-1 while promoting mitophagy and restoring the CBS-H2S axis 41797134Mar.

Overall, these publications portray Caspase-1 as a recurring effector of inflammasome activation and pyroptosis, with therapeutic strategies ranging from small molecules and electroacupuncture to nucleic acid-based delivery systems and mRNA formulations. Across cancer, inflammatory disease, kidney injury, neurological injury, and dental tissue damage, modulation of Caspase-1 was consistently linked to changes in IL-1β/IL-18 signaling, GSDMD-associated pyroptosis, and broader inflammatory outcomes 42318962Jun42318970Jun42013993Apr41967209Apr41966778Apr41850405Mar41797134Mar42116169May41935997Apr.

What Changes, What Holds

1. CASP1 is being repurposed as a payload and marker in cancer immunotherapy, but its core inflammatory role remains intact
REINFORCES These studies do not revise what CASP1 does; they extend its use into tumor settings where inflammasome-linked signaling and cell-death programs are being harnessed or mapped. The ovarian cancer delivery strategy treats caspase-1 as part of a cytokine-producing therapeutic cassette, while the lung adenocarcinoma analysis places CASP1 among PANoptosis-related genes tied to the tumor microenvironment 42116169May41935997Apr. That broadens application, but it does not displace the established inflammasome/pyroptosis account.

2. Caspase-1 remains a readout and mediator of NLRP3-driven injury across metabolic, ischemic, and inflammatory models
REINFORCES The new work sharpens the same axis already in the Overview: NLRP3 activation, caspase-1 induction, and downstream inflammatory injury. Across kidney, brain, gout, and arthritis models, the studies consistently place caspase-1 downstream of NLRP3 and upstream of IL-1β/GSDMD-associated damage, which strengthens the baseline rather than changing it 42318962Jun42318970Jun. The only nuance is therapeutic diversity, not mechanistic revision.

3. Caspase-1 is increasingly a therapeutic handle for forcing or blocking pyroptosis in cancer and tissue injury
REINFORCES These reports extend the established idea that CASP1 is druggable in inflammatory disease into more explicit intervention strategies, including sensitizing tumors to chemotherapy and suppressing destructive pyroptosis in periodontal injury. That still fits the Overview’s view of CASP1 as a central effector of inflammasome-linked cell death; it does not introduce a new biological role 41966778Apr41850405Mar. The cancer and dental applications are new examples, not a new class of function.

4. The recent literature mostly confirms CASP1 as a recurring inflammasome effector, but it also widens the therapeutic toolbox around it
REINFORCES Across the cited studies, the common thread is unchanged: modulation of caspase-1 tracks with IL-1β/IL-18 signaling, GSDMD-mediated pyroptosis, and inflammatory outcomes. What is new is the breadth of modalities now aimed at that axis, from small molecules and electroacupuncture to siRNA nanoparticles and mRNA delivery systems 42318962Jun41966778Apr. That broadens translational interest, but the underlying account in the Overview stands.

Overview update candidates: none.