European journal of pharmacologyNov 13, 2025

How a cellular cleanup process controlled by NF-κB, TOM6, and PINK1 reduces blood vessel hardening: Luteolin as a potential treatment

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

Luteolin (LU) may attenuate vascular calcification (VC) by restoring mitophagy through the NF-κB/TOM6/PINK1 pathway.

LU dose-dependently inhibited calcification in vascular smooth muscle cells and arterial rings, reducing osteogenic marker expression.
In vivo studies showed LU improved VC in mice and rats with chronic kidney disease and Vitamin D overload.
RNA sequencing indicated TOM6 is upregulated during calcification and is suppressed by LU.
Silencing TOM6 reduced VC, while its overexpression worsened VC and negated LU's anti-calcific effects.
LU enhanced mitophagy by promoting PINK1/Parkin activity through downregulation of TOM6, improving mitochondrial function.
LU directly interacts with IKKα/IKKβ, inhibiting NF-κB nuclear translocation and TOM6 transcription.

Simplified

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 D(VitD)-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. 3 3

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Declaration of competing interest All authors have declared no conflicts of interest.

PubMed

How a cellular cleanup process controlled by NF-κB, TOM6, and PINK1 reduces blood vessel hardening: Luteolin as a potential treatment

Abstract

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