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.

Key Publications

• NEWJul Donkey Milk Exosomes Protect Against Dextran Sulfate Sodium-Induced Colitis by Delivering Anti-Inflammatory miRNAs and Reshaping Gut Microbiota. (Journal of food science, 2026, PMID 42378030): "Mechanistically, eca‐let‐7g directly targeted TLR4 3'UTR to inhibit NF‐κB, while eca‐miR‐148a targeted NLRP3 3'UTR to suppress the NLRP3‐Caspase‐1‐IL‐18 axis."
• NEWJun Irbesartan ameliorates high‑glucose‑induced epithelial‑mesenchymal transition by downregulating the expression of NLRP3 in HK‑2 cells. (Molecular medicine reports, 2026, PMID 42318962): "The present study detected the mRNA and protein expression of NLRP3, caspase‐1, NF‐κB p65, α-SMA, vimentin and N-cadherin using reverse transcription‐quantitative PCR and western blotting."
• NEWJun Molecular mechanism of hydromorphone preconditioning in cerebral ischemia/reperfusion‑induced inflammatory injury. (International journal of molecular medicine, 2026, PMID 42318970): "NLRP3-positive expression and caspase-1 activity were assessed by immunostaining and caspase-1 activity assays, respectively."
• NEWJun Identification of potential targets of kaempferol for the treatment of intervertebral disc degeneration based on network pharmacology and multi-omics analysis. (Naunyn-Schmiedeberg's archives of pharmacology, 2026, PMID 42283840): "Topological analysis identified three core hub genes-STAT1, CASP1, and NOX4-all significantly upregulated in IVDD tissues."
• May Superparamagnetic iron oxide nanoparticle-driven 3-aroyl-1,4-diarylpyrrole nanocomposites (ARDAP@SPION-PEI) mediate renal cancer cell PANoptosis by regulating chromatin accessibility. (Molecular biomedicine, 2026, PMID 42138776): "Luciferase reporter assays demonstrated that ZFP148 directly bound to and activated promoters of key PANoptosis-related genes, including receptor-interacting serine/threonine kinase 3 (Ripk3), gasdermin D (Gsdmd), IL-1β (Il1b), and caspase-1 (Casp1)."
• May A novel mRNA-based multi-cytokine strategy to reprogram the peritoneal tumor microenvironment in ovarian cancer. (Journal of nanobiotechnology, 2026, PMID 42116169): "An intraperitoneal mRNA-based immunotherapy delivering a combination of single-chain interleukins (IL), including IL-12, IL-15, pro-IL-18, and Caspase-1, encapsulated in lipid nanoparticles, is administered to reprogram the immunosuppressive tumor microenvironment (TME) in a syngeneic ID8-Fluc ovarian cancer mouse model."
• May An Integrated Approach Combining Chemical Profiling, Network Pharmacology, and In Vitro Validation to Uncover the Multitarget Mechanisms of Naokang II Decoction against Vascular Dementia. (Journal of natural products, 2026, PMID 42099108): "Network analysis identified 10 core targets, including NLRP3, CASP1, and TLR2."
• May The "Tianyu" Formulation Alleviates Rheumatoid Arthritis by Modulating the NLRP3/Caspase-1/GSDMD-Mediated Pyroptosis Pathway. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42033182): "...molecular docking showed that all five major compounds (Apigenin, Isorhamnetin, Kaempferol, Quercetin, and Salidroside) bound well to NLRP3, Caspase-1, and GSDMD, with all binding energies below -5 kcal/mol."
• May Amygdalin attenuates post-ischemic neuroinflammation by targeting TLR4/NF-κB signaling and NLRP3 inflammasome in cerebral ischemia-reperfusion injury. (European journal of pharmacology, 2026, PMID 42013993): "...and identified Tlr4, Myd88, Nlrp3, and Caspase-1 as key candidate molecules;"
• Jun Dexmedetomidine potentiates cisplatin chemosensitivity in esophageal carcinoma cells via the SREBF1/miR-185-5p/Caspase-1 axis through pyroptosis. (International immunopharmacology, 2026, PMID 41966778): "miR-185-5p directly targeted the Caspase-1 3'UTR."