NF-κB/TOM6/PINK1-mediated mitophagy attenuates vascular calcification: Luteolin as a therapeutic modulator

  • Eur J Pharmacol. 2025 Dec 5:1008:178355. doi: 10.1016/j.ejphar.2025.178355.
Jinhe Li  1 ,  Qingchun Liang  2 ,  Yining Li  3 ,  Bing Liang  4 ,  Jinshu Liang  1 ,  Jianyun Yan  5 ,  Jun Zhou  6
Affiliations
  • 1. Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, China.
  • 2. Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, China; Department of Anesthesiology, Linzhi People's Hospital, Linzhi, 850400, Tibet, China. Electronic address: [email protected].
  • 3. Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangzhou, 510282, China.
  • 4. Department of Anesthesiology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, China.
  • 5. Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangzhou, 510282, China. Electronic address: [email protected].
  • 6. Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, China. Electronic address: [email protected].
PMID: 41232657 DOI: 10.1016/j.ejphar.2025.178355
Abstract

Vascular calcification (VC), a significant contributor to cardiovascular risk, lacks effective therapies. The natural flavonoid luteolin (LU) shows therapeutic potential, but its mechanism against VC is not fully elucidated. This study identifies a novel pathway wherein LU attenuates VC by restoring Mitophagy via the Nuclear Factor Kappa B (NF-κB)/Translocase of Outer Mitochondrial Membrane 6 (TOM6)/PTEN-induced kinase 1 (PINK1) pathway. In vitro, LU dose-dependently inhibited calcification in vascular smooth muscle cells (VSMCs) and arterial rings, suppressing expression of osteogenic markers such as Bone Morphogenetic Protein 2 (BMP2), Runt-related transcription factor 2 (RUNX2), and restoring expression of contractile proteins such as alpha-smooth muscle actin (α-SMA), smooth muscle protein 22-alpha (SM22). In vivo, LU ameliorated VC in Vitamin D3 (VitD3)-overloaded mice and rats with chronic kidney disease (CKD). RNA Sequencing identified TOM6 as a key gene upregulated during calcification and suppressed by LU. Functionally, TOM6 knockdown attenuated VC, whereas its overexpression exacerbated VC and reversed the anti-calcific effect of LU. Mechanistically, LU enhanced PINK1/Parkin-mediated Mitophagy by downregulating TOM6, thereby improving mitochondrial bioenergetics. Furthermore, LU directly binds the inhibitor of nuclear factor kappa-B kinase subunits alpha and beta (IKKα/IKKβ), thereby inhibiting NF-κB nuclear translocation and TOM6 transcription. Collectively, our results identify the NF-κB/TOM6/PINK1 Mitophagy axis as a key mechanistic pathway required for LU to mitigate VC, suggesting a novel therapeutic target.

Keywords
Luteolin; Mitophagy; PINK1; TOM6; Vascular calcification; Vascular smooth muscle cells.
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