Chrysin mitigates therapy-induced senescence in breast cancer via cGAS–STING pathway inhibition

Aug 25, 2025Medical oncology (Northwood, London, England)

Chrysin may reduce treatment-related aging in breast cancer by blocking the cell’s immune response pathway

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Abstract

Chrysin significantly reduces levels of H3K9me3 and H3K27me3 in senescent breast cancer cells.

Cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway activation is associated with increased chronic inflammation in senescent cells.
Treatment with Chrysin led to decreased expression of inflammatory cytokines IL-6 and IL-8 in MDA-MB-231 and MCF-7 breast cancer cells.
Chrysin treatment resulted in significantly reduced phosphorylation of STING and lower levels of cytoplasmic chromatin fragments marked by H3K9me3 and H3K27me3.
The expression of senescence markers p16 and p21 remained unchanged after Chrysin treatment.
Chrysin inhibited SASP-driven invasion and colony formation of breast cancer cells, suggesting its potential as an anti-inflammatory and senomorphic agent.

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Breast cancer continues to be a leading cause of cancer-related deaths among women globally, with cellular senescence having a complex role in its progression. Senescence is linked to chronic inflammation via the senescence-associated secretory phenotype (SASP). The cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway, activated by cytoplasmic chromatin fragments (CCFs) marked by histone modifications (H3K27me3 and H3K9me3), is crucial for SASP production. This study investigates the potential of a natural flavonoid, Chrysin, as a senomorphic agent that targets these CCF markers to reduce inflammation in senescent breast cancer cells. We induced senescence in MDA-MB-231 and MCF-7 cells using doxorubicin and analyzed the expression levels of inflammatory cytokines IL-6 and IL-8 after treatment with various concentrations of Chrysin through qRT-PCR. Western blotting and immunofluorescence revealed significantly reduced CCF markers H3K9me3 and H3K27me3, along with decreased STING phosphorylation. Notably, Chrysin did not change the expression of senescent markers p16 or p21. Additionally, Chrysin effectively inhibited SASP-driven breast cancer cell invasion and colony formation, highlighting its potential as both an anti-inflammatory agent and a senomorphic drug. Chrysin notably decreases H3K9me3 and H3K27me3-marked CCF levels, suppressing cGAS-STING pathway activation and reducing IL-6 and IL-8 levels. Our findings indicate that Chrysin represents a promising therapeutic strategy, targeting the epigenetic landscape of CCFs and modulating the SASP to mitigate the harmful effects of senescent cells in the tumor microenvironment.

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Chrysin mitigates therapy-induced senescence in breast cancer via cGAS–STING pathway inhibition

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