CDK5RAP3 Deficiency Exacerbates Hepatic Inflammation via NLRP3 Inflammasome-Mediated Pyroptosis and Apoptotic Crosstalk

Background/Objectives: CDK5RAP3 (CDK5 regulatory subunit associated protein 3), is a ubiquitously expressed protein in mammalian tissues, with emerging evidence indicating its critical involvement in hepatic inflammation. Although its precise mechanistic roles remain elusive. Methods: To delineate the pathological link between CDK5RAP3 deficiency and liver inflammation, we established liver-specific CDK5RAP3 knockout murine models and mouse embryonic fibroblasts (MEFs) from conditional knockout mice. Results: CDK5RAP3 deficiency induces hepatic injury and inflammatory responses in mice accompanied by NLRP3 inflammasome activation. This activation was mechanistically characterized by ASC oligomerization, Caspase-1 recruitment, and subsequent Gasdermin D (GSDMD) cleavage, which collectively triggered pyroptosis. Notably, CDK5RAP3-deficient MEFs exhibit compromised proliferative capacity and elevated apoptotic rates. Conclusions: Our findings demonstrate that CDK5RAP3 is indispensable for maintaining hepatic homeostasis. Its deficiency can induce liver damage and inflammatory cell death in mice. Therefore, CDK5RAP3 can be a potential therapeutic target for treating inflammatory liver pathologies.