PAX5 alleviates atherosclerosis by transcriptionally regulating GSDMD and inhibiting STAT3-mediated pyroptosis.

Authors

Xiangkui Wang, Peipei Wu, Yadi Shen, Shiwei Xu, Qi Wan, Qilun Zhang, Ran Lu

Published in

Biology direct. Jul 18, 2026. Epub Jul 18, 2026.

Abstract

This study aims to elucidate the role of PAX5 in the pathogenesis of atherosclerosis (AS) and its underlying mechanisms, with a particular focus on the transcriptional regulation of GSDMD and STAT3-mediated pyroptosis.
Serum PAX5 and GSDMD levels were detected in AS patients and healthy controls. In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with oxidized low-density lipoprotein (ox-LDL) and transfected with PAX5 overexpression vectors, followed by assays for cell viability, tube formation, lipid accumulation, LDH release, and pro-inflammatory cytokine (IL-1β, IL-18) secretion. Immunofluorescence and dual-luciferase reporter assays were performed to verify the co-localization of PAX5 and GSDMD, and the transcriptional interaction between PAX5 and the GSDMD promoter. Co-immunoprecipitation (Co-IP) ubiquitination assays were conducted to determine whether PAX5 promotes GSDMD poly-ubiquitination. In vivo, ApoE⁻/⁻ AS mouse models were treated with AAV-mediated PAX5 overexpression, followed by histopathological assessment of atherosclerotic lesions, lipid metabolism detection, and Western blot analysis of pyroptosis and STAT3 signaling-related proteins.
Serum PAX5 was significantly downregulated in AS patients, while GSDMD was upregulated. In vitro, PAX5 overexpression reversed ox-LDL-induced viability reduction, lipid accumulation, LDH release, and IL-1β/IL-18 hypersecretion in HUVECs. Dual-luciferase assay confirmed that PAX5 directly binds to and activates the GSDMD promoter. Ubiquitination assays demonstrated that PAX5 promotes both K48-linked and K63-linked poly-ubiquitination of GSDMD, with the degradation pathway predominating over transcriptional activation, resulting in a net decrease in GSDMD protein abundance. In vivo, PAX5 overexpression reduced atherosclerotic lesion size, lipid deposition, and systemic inflammatory levels, improved serum lipid profiles, and inhibited STAT3 phosphorylation, GSDMD-N generation, and pyroptosis-related protein expression.
PAX5 alleviates AS progression through a dual regulatory mechanism involving transcriptional activation and ubiquitin-proteasome-mediated degradation of GSDMD, thereby inhibiting STAT3-associated pyroptosis. PAX5 represents a promising therapeutic target for AS intervention.

PMID:
42471738
Bibliographic data and abstract were imported from PubMed on 19 Jul 2026.

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