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April 26, 2026Journal of Translational MedicineOpen Access

Fibroblast-specific PGC-1α overexpression or METTL3/YTHDF2 knockdown reduces cardiac fibrosis and restores mitochondrial dynamics in mice.

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Why the study?

Upstream regulatory mechanisms of dysregulated mitochondrial fission in cardiac fibrosis, particularly the role of N6-methyladenosine epitranscriptomic regulation, remain poorly understood.

Population

TGF-β1-stimulated cardiac fibroblasts, isoproterenol-treated mice, and human atrial fibrillation tissues

Comparison

Fibroblast-targeted METTL3 or YTHDF2 inhibition vs controls

Design

Preclinical in vitro and in vivo translational study

Key result

Fibroblast-specific overexpression of PGC-1α or knockdown of METTL3 and YTHDF2 ameliorated isoproterenol-induced cardiac fibrosis and restored mitochondrial dynamics in mice.

Authors

XCXiao-Ying CaoBTBin TuZCZhen-Rui Cao

Discussion

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Overview

Should not yet change practice in cardiac fibrosis or AF; leaves open m6A epitranscriptomic control of mitochondrial fission for mechanistic and translational study.**[[1]](https://link.springer.com/article/10.

Key Points

  • This study investigates how m6A-mediated epitranscriptomic changes influence cardiac fibrosis by targeting PGC-1α.
  • Used in vitro TGF-β1-stimulated cardiac fibroblasts and in vivo mouse models of cardiac fibrosis.
  • Conducted molecular profiling, m6A-specific assays, and gene manipulation in fibroblasts.
  • Analyzed human atrial fibrillation tissues to correlate findings with disease severity.
  • METTL3 and YTHDF2 upregulated in fibrotic hearts, influencing PGC-1α mRNA degradation.
  • Inhibition of METTL3 or YTHDF2 restored PGC-1α levels and improved mitochondrial function.
  • In vivo knockdown of METTL3 or YTHDF2 alleviated fibrosis and enhanced cardiac function.

Structured PICO

P
Population
In vitro TGF-β1-stimulated primary neonatal mouse cardiac fibroblasts, in vivo C57BL/6J mice (n=68, aged 8-10 weeks) with isoproterenol-induced cardiac fibrosis, and human atrial fibrillation tissues.
I
Intervention
Fibroblast-targeted AAV9-mediated gene manipulation (AAV9-POSTN-oePGC-1α, AAV9-shYTHDF2, AAV9-shMETTL3) and in vitro siRNA/plasmid transfections.
C
Comparator
Control groups (AAV9-POSTN-NC, no ISO/no virus, ISO only, NC siRNA).
O
Outcome
Cardiac fibrosis, mitochondrial fission, PGC-1α expression, and cardiac function.surrogate

Targeting the METTL3/YTHDF2 epitranscriptomic axis presents a promising strategy for therapeutic intervention in cardiac fibrosis by restoring PGC-1α and normalizing mitochondrial dynamics.

Cite This Study

Cao et al. (2026) studied Cardiac fibrosis (n=68). AAV9-mediated gene manipulation (AAV9-POSTN-OE-PGC1α, AAV9-shYTHDF2, AAV9-shMETTL3) vs. AAV9-POSTN-NC (control virus) or no virus control was evaluated on Cardiac fibrosis and mitochondrial fragmentation. Fibroblast-specific overexpression of PGC-1α or knockdown of METTL3 and YTHDF2 ameliorated isoproterenol-induced cardiac fibrosis and restored mitochondrial dynamics in mice.

synapsesocial.com/papers/69edadd94a46254e215b575fhttps://doi.org/10.1186/s12967-026-08163-5
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