Biochemical pharmacologyJan 16, 2026

Reducing DNMT1 helps prevent heart problems in sepsis by stopping mitochondrial DNA release and controlling immune cell response

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 10, 2026

Abstract

Inhibition of DNA methyltransferase 1 (DNMT1) improved survival and cardiac function in a mouse model of sepsis-induced myocardial dysfunction (SIMD).

Pretreatment with the DNMT1 inhibitor decitabine reduced cardiomyocyte apoptosis in SIMD mice.
DNMT1 knockdown in macrophages promoted M2 polarization and suppressed M1 polarization.
Depletion of DNMT1 increased mitochondrial transcription factor A (TFAM), which alleviated mitochondrial dysfunction.
Reduced DNA methylation from DNMT1 depletion limited mitochondrial DNA release into the cytosol.
Activation of the cGAS-STING pathway was associated with DNMT1's regulation of mitochondrial dysfunction and cytosolic mtDNA release.

Simplified

Sepsis-induced myocardial dysfunction (SIMD) is a prevalent complication of sepsis and correlates with high mortality. The study investigated the effect of inhibiting DNA methyltransferase 1 (DNMT1) on SIMD and its potential mechanism. In this study, an SIMD mouse model was established using lipopolysaccharide (LPS). Two weeks before modeling, mice were intraperitoneally injected with the DNMT1 inhibitor decitabine or Vehicle. Pretreatment with the DNMT1 inhibitor decitabine in SIMD mice improved survival, cardiac function, and reduced cardiomyocyte apoptosis. In LPS-stimulated RAW264.7 macrophages, DNMT1 knockdown promoted M2 polarization while suppressing M1 polarization, and reduced apoptosis in cardiomyocytes cultured with conditioned media. Mechanistically, DNMT1 depletion upregulated mitochondrial transcription factor A (TFAM) by reducing DNA methylation modification, which alleviated mitochondrial dysfunction and limited mitochondrial DNA (mtDNA) release into the cytosol. This subsequently inactivated the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. TFAM downregulation reversed the improvement in mitochondrial function achieved by DNMT1 knockdown, while cGAS upregulation averted DNMT1 knockdown-inhibited mtDNA cytosolic escape-mediated cGAS-STING. In vivo validation confirmed this mechanism. Collectively, DNMT1 regulates mitochondrial dysfunction and cytosolic mtDNA release by modulating TFAM promoter DNA methylation, thereby activating the cGAS-STING pathway, further influencing macrophage polarization and cardiomyocyte apoptosis, and ultimately exacerbating SIMD.

Full Text

Full text is available at the source.

View Full Text ↗

Reducing DNMT1 helps prevent heart problems in sepsis by stopping mitochondrial DNA release and controlling immune cell response

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief