PCBP2 Regulates p16INK4a ‐Dependent Cellular Senescence in Response to Iron

Recently, we have identified rs1333046 as one of the candidate functional single nucleotide polymorphisms (fSNPs) on the atherosclerosis‐associated CDKN2A/B locus. However, how rs1333046 influences the pathogenesis of and susceptibility to atherosclerosis is unknown. In this work, we demonstrate that rs1333046 is part of a cis‐regulatory element (cis‐RE) that regulates p16INK4a and p16INK4a‐dependent cellular senescence in human endothelial cells (ECs). This is achieved by recruiting poly(rC)‐binding protein 2 (PCBP2), a member of the poly‐cytosine binding protein family. We also reveal that PCBP2 is an upstream regulator of CD40, which regulates the expression of senescence‐associated secretory phenotype (SASP) genes through NF‐κB signaling. Moreover, consistent with PCBP2 being an iron chaperone, we discover that iron can induce cellular senescence by regulating both p16INK4a and CD40‐mediated SASP gene expression through PCBP2. Notably, iron dynamically regulates p16INK4a expression by altering the binding of PCBP2 to rs1333046. In addition, reducing intracellular labile iron by overexpressing both iron storage protein ferritin light chain (FTL) and iron exporter ferroportin 1 (FPN1) in ECs suppresses cellular senescence, and overexpression of PCBP2 in both FTL‐ and FPN1‐overexpressing cells restores cellular senescence. Thus, our studies suggest that iron could be a potential environmental factor regulating atherosclerosis‐associated cellular senescence, and this is achieved by modulating PCBP2‐dependent p16INK4a and CD40 expression. This study shows the mechanism by which iron affects the pathology of atherosclerosis.

• Publication year

  2025

• Venue

  Aging Cell

• Publication date

  2025-11-11

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1111/acel.70283PMID 41216990PMCID 12686567
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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