Molecular cellApr 17, 2026

FOXF1 and FOXF2 create specific DNA regions that turn on inflammation signals during cell aging

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 18, 2026

Abstract

FOXF1/2 depletion in senescent cells significantly suppresses the pro-inflammatory SASP.

The senescence-associated secretory phenotype (SASP) is characterized by pro-inflammatory factors that contribute to age-related diseases.
FOXF1/2 play a crucial role in defining the enhancer landscape specific to senescent cells by influencing chromatin accessibility.
FOXF1/2 interact with proteins that promote acetylation and chromatin opening at new enhancers of SASP genes.
Depleting FOXF1/2 reduces the secretion of pro-inflammatory factors without affecting the cells' growth arrest.
Loss of FOXF1/2 alters the distribution of AP-1 c-JUN to regulatory elements of genes that are downregulated in senescence.

Simplified

The pro-inflammatory, senescence-associated secretory phenotype (SASP) is a hallmark of senescent cells (SnCs) that exacerbates age-related pathophysiology and chronic diseases. Although unique gene regulation is essential for fulfilling the pro-inflammatory SASP, the epigenomic basis in SnCs remains largely unknown. Here, we show that FOXF1/2 define the senescence-specific enhancer landscape by shaping chromatin accessibility. FOXF1/2 interact with p300/CREB-binding protein (CBP) and stimulate H3K27 acetylation and chromatin opening at de novo enhancers of pro-inflammatory SASP genes, together with the recruitment of AP-1 c-JUN to these regions. FOXF1/2 depletion in SnCs significantly suppresses pro-inflammatory SASP, independent of persistent growth arrest, and diminishes the paracrine effect on surrounding cells. Notably, loss of FOXF1/2 leads to the redistribution of AP-1 c-JUN to regulatory elements of senescence-associated downregulated genes. Our results uncover that FOXF1/2 coordinate the pro-inflammatory SASP program, suggesting that FOXF1/2-mediated enhancer remodeling is a key target for modulating SnCs to promote healthy aging.

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Competing interests

Declaration of interests The authors declare no competing interests.

PubMed

FOXF1 and FOXF2 create specific DNA regions that turn on inflammation signals during cell aging

Abstract

Full Text

Funding

Competing interests

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