Xiangqi Meng

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.

Supplementary Table S3. Summary of other trial results for recurrent glioblastoma.

Axial, sagittal and coronal gadolinium-enhanced and FLAIR MRI at pre-baseline (A-D). Three months later, MRI demonstrated progressive disease after anlotinib plus temozolomide (E-H).

A. An MR image revealed a hyperintense signal in the DWI sequence, indicating an acute ischemic stroke in the right ACA region (white arrows). B. CT angiography showed poor visualization of the distal ACA.

Supplementary figure 6. Wound dehiscence.

Axial, sagittal and coronal gadolinium-enhanced MRI at pre-baseline (A-C; yellow arrows), 6 months later demonstrating complete response after anlotinib plus temozolomide (E-G). Axial Fluid-Attenuated Inversion Recovery (FLAIR, D) image at pre-baseline, and no progression was observed during anlotinib plus temozolomide treatment after 6 months (H).

A-B. Kaplan-Meier plots of progression-free survival and overall survival (Full analysis set). The x-axes indicated times since enrollment.

Supplementary Table S2. Representativeness of Study Participants

A-B. Kaplan-Meier plots of progression-free survival and overall survival (Full analysis set). The x-axes indicated times since enrollment.

Supplementary Table S1. Patient Characteristics.