2. Academic Validation
  3. Silencing CCL5 suppresses ferroptosis to alleviate calcific aortic valve disease through chemokine pathway inhibition

Silencing CCL5 suppresses ferroptosis to alleviate calcific aortic valve disease through chemokine pathway inhibition

  • Atherosclerosis. 2026 Jan 16:414:120640. doi: 10.1016/j.atherosclerosis.2026.120640.
Hongjin Zhang 1,  Wencheng Yan 1,  Jiayuan Ling 1,  Xing Shi 2,  Ping Lai 3,  Bei Wang 1,  Yongling Liao 1,  Hongzhou Zhang 4
Affiliations

Affiliations

  • 1 Department of Cardiovascular Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
  • 2 Blood Transfusion Department, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
  • 3 Department of Cardiovascular Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China.
  • 4 Department of Cardiovascular Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China. Electronic address: [email protected].
PMID: 41621141 DOI: 10.1016/j.atherosclerosis.2026.120640
Abstract

Background: Calcific aortic valve disease (CAVD) involves pathological mineralization, but the roles of chemokine signaling and Ferroptosis remain unclear. This study investigated the regulatory function of C-C motif chemokine ligand 5 (CCL5) in CAVD progression via the chemokine pathway and Ferroptosis.

Methods: Bioinformatics analysis and single-cell RNA Sequencing analysis were performed to identify hub genes and potential cell types. Human aortic valve interstitial cells (VICs) were treated with osteogenic medium (OM) to induce calcification. apoE-/- mice were induced by a high-fat diet in vivo. Calcification, oxidative stress, and Ferroptosis markers were assessed by pathological staining, enzyme-linked immunosorbent assay, and Western blot, respectively. Ferroptosis was modulated using Ferrostatin-1 (inhibitor) or Erastin (inducer), and chemokine signaling was activated with the CXC motif Chemokine Receptor 4 (CXCR4) agonist ATI-2341 TFA.

Results: CCL5 was identified as a key hub gene in CAVD. Knockdown of CCL5 significantly attenuated OM-induced VICs calcification, osteogenic differentiation, oxidative stress, and Ferroptosis. Similar protective effects were observed in vivo, with reduced valve thickening and calcification in apoE-/- mice. Ferroptosis inhibition mirrored these effects, while its induction reversed CCL5-knockdown benefits. Furthermore, chemokine signaling pathway was screened as the downstream pathway of CCL5. Mechanistically, CCL5 knockdown suppressed CXCR4/CXCL12 expression. Activating chemokine signaling with TFA abolished the protective effects of CCL5 silencing on calcification, Ferroptosis, and oxidative stress in vitro and in vivo.

Conclusion: CCL5 promoted CAVD progression by activating the chemokine signaling pathway to induce Ferroptosis. Targeting CCL5 may offer a novel therapeutic strategy for CAVD.

Keywords

CCL5; Calcific aortic valve disease; Ferroptosis; The chemokine signaling pathway.

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