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) 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 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.

Focus of Latest Publications

Recent publications have extensively characterized CASP1 as a central regulator of pyroptosis and PANoptosis (integrated programmed cell death), positioning it at the intersection of inflammatory and cell-death pathways across diverse disease contexts. In inflammatory and degenerative disorders—including inflammatory bowel disease, diabetic nephropathy, rheumatoid arthritis, cerebral ischemia-reperfusion injury, gouty arthritis, and Parkinson's disease—therapeutic strategies converge on suppressing CASP1 activation as part of blocking the NLRP3 inflammasome signaling axis. Multiple studies demonstrated that compounds and interventions including kaempferol, electroacupuncture, amygdalin, emodin, herniarin, and the traditional Chinese medicine formulation "Tianyu" all achieve therapeutic benefit by downregulating CASP1 expression or activity in both cellular and animal models.

The NLRP3-CASP1-GSDMD pyroptotic pathway emerged as a recurrent target across these studies. Eca-miR-148a delivered via donkey milk exosomes directly targeted the NLRP3 pathway to suppress caspase-1-driven inflammatory responses in colitis. Similarly, in diabetic kidney disease models, irbesartan attenuated high-glucose-induced upregulation of CASP1 by inhibiting NLRP3 inflammasome activation. hydrogen sulfide donors restored the CBS-H₂S axis and suppressed CASP1-mediated pyroptosis in Parkinson's disease, while in cerebral ischemia-reperfusion injury, hydromorphone preconditioning and amygdalin each reduced caspase-1 activity to alleviate neuroinflammation. These therapeutic modalities shared the mechanistic principle of interrupting inflammatory cascades upstream or downstream of CASP1 activation.

By contrast, activating CASP1 emerged as a therapeutic strategy in cancer contexts where pyroptosis could overcome apoptotic resistance. In esophageal carcinoma, dexmedetomidine enhanced cisplatin chemosensitivity by suppressing the SREBF1/miR-185-5p regulatory axis, thereby upregulating CASP1 and promoting pyroptosis. An mRNA-based immunotherapy delivering pro-IL-18 and Caspase-1 in lipid nanoparticles targeted the peritoneal tumor microenvironment in ovarian cancer to reprogram immunosuppression. In lung adenocarcinoma, ginsenosides induced PANoptosis through upregulation of the ZBP1/AIM2/RIPK3/CASP1 death complex, while nanotherapeutics employing ARDAP-loaded iron oxide nanoparticles activated PANoptosis-related genes including Casp1 by remodeling chromatin accessibility through the transcription factor ZFP148. These dual approaches—suppression for inflammatory/degenerative disease and activation for cancer—underscore CASP1's fundamental role in cellular fate decisions and its therapeutic tractability across multiple disease classes.