STK39 interacts with MAPK14 to facilitate cardiomyocyte pyroptosis in septic cardiomyopathy by inducing NLRP3 inflammasome.

Background

Septic cardiomyopathy (SCM) is a severe manifestation of sepsis characterized by myocardial dysfunction and systemic inflammation. The NLRP3 inflammasome-driven pyroptosis plays a pivotal role in SCM pathogenesis. This study aimed to elucidate the upstream molecular regulators of pyroptosis in SCM and investigate the functional role of serine/threonine kinase 39 (STK39) in modulating NLRP3 inflammasome activation.

Methods

Peripheral blood samples were collected from 44 patients with sepsis (19 with SCM) and 30 healthy controls. A murine cecal ligation and puncture (CLP) model and LPS-stimulated human cardiomyocytes (HCMs) were employed to simulate SCM. Cardiac function was assessed via echocardiography, and pyroptosis markers were quantified using ELISA, qRT-PCR, and western blot. Protein interactions and transcriptional regulation were evaluated by co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), immunofluorescence, and dual-luciferase reporter assays.

Results

STK39 expression was upregulated in SCM patients and septic mice. STK39 knockdown significantly attenuated cardiac pyroptosis in LPS-treated HCMs, and improved myocardial function in CLP-induced mice. Mechanistically, STK39 interacted with MAPK14 to activate p38 MAPK signaling, promoting ELK1-mediated transcriptional upregulation of NLRP3 and subsequent pyroptotic cell death. Rescue assay demonstrated that activation of p38 MAPK signaling greatly diminished the protective roles of STK39 silence on cardiomyocyte pyroptosis.

Conclusion

This study identifies STK39 as a novel upstream regulator of NLRP3 inflammasome-mediated pyroptosis in SCM through the MAPK14/ELK1 signaling axis. These findings suggest that STK39 may serve as a potential molecular target for SCM.