Endothelial Filamin C Alleviates Atherosclerosis via PINK1/Parkin-Dependent Mitophagy and mtDNA-cGAS-STING Inflammation Suppression

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Abstract
Endothelial dysfunction and impaired mitophagy represent core pathological drivers of atherosclerosis progression, yet upstream molecular regulators governing this process in vascular endothelium remain largely uncharacterized. This study delineated the functional role and mechanistic basis of filamin C (FLNC) in atherosclerosis-related endothelial injury. We profiled FLNC expression in 20 paired human carotid plaque and adjacent normal vascular tissues collected from patients undergoing carotid endarterectomy. In vitro, CRISPRa/CRISPRi-stable HUVEC lines were challenged with ox-LDL, with pharmacological (Mdivi-1) and genetic (si-PINK1/si-Parkin) rescue assays used to verify causal signaling. In vivo, Tie2-driven endothelial-specific FLNC-overexpressing ApoE−/− mice were fed a high-fat diet to induce atherosclerotic lesions. FLNC was significantly downregulated in human plaques, ox-LDL-treated HUVECs, and atherosclerotic mouse aortas. FLNC overexpression attenuated endothelial apoptosis and oxidative stress, while its knockdown exacerbated these injuries. Mechanistically, FLNC activated PINK1/Parkin-mediated mitophagy to restrict cytosolic mtDNA leakage and suppress subsequent activation of the cGAS-STING inflammatory cascade. Mitophagy inhibition or PINK1/Parkin silencing fully abrogated FLNC’s cytoprotection, and endothelial FLNC overexpression retarded plaque progression in vivo. Collectively, our findings identify FLNC as a novel endogenous endothelial mitophagy regulator, revealing an unreported regulatory mechanism and supporting FLNC as a promising therapeutic target for atherosclerotic disease.
Funding Information
  • National Natural Science Foundation of China (82272988)
  • Beijing Kanghua Foundation for the Development of Traditional Chinese and Western Medicine (070500020557(2023))
  • Central-Guided Local Science and Technology Development Fund Project (246Z7775G)
  • National Engineering Research Center of Science and Technology Information STI Digital Health Laboratory (2026STI343)

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