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Updated: Aug 6, 2026

Scanning Electron Microscopy of Macerated Tissue to Visualize the Extracellular Matrix
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A novel tsRNA, 5'tiRNA-GluCTC, mediates cardiomyocyte-fibroblast cross-talk to promote cardiac fibrosis in

Jie Tian1, Xiaohui Xu1, Xiaoli Yan1

  • 1Department of Cardiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Key Cardiovascular Specialty, Chongqing Municipal Health Commission Key Laboratory of Children's Vital Organ Development and Diseases, Chongqing 401122, China.

Clinical Science (London, England : 1979)
|August 5, 2026
PubMed

Insights

Cardiomyopathy fibrosis is driven by cardiomyocyte-released tRNA fragments. A specific fragment, 5'tiRNA-GluCTC, activates fibroblasts via the Foxq1/Smad3 pathway, offering a therapeutic target for restrictive cardiomyopathy.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Exosome Biology

Background:

  • Restrictive cardiomyopathy (RCM) involves cardiac fibrosis and diastolic dysfunction.
  • The precise mechanisms initiating pro-fibrotic signaling in RCM remain unclear.
  • Cardiomyocyte mutations can trigger RCM, but intercellular communication pathways are not fully understood.

Purpose of the Study:

  • To investigate the role of cardiomyocyte-derived exosomes and tRNA-derived small RNAs (tsRNAs) in RCM pathogenesis.
  • To identify specific tsRNAs involved in intercellular communication driving cardiac fibrosis.
  • To elucidate the molecular mechanisms by which these tsRNAs mediate fibrosis.

Main Methods:

  • Utilized a cTnIR193H knock-in mouse model of RCM.
  • Performed small RNA sequencing on cardiomyocyte-derived exosomes.
  • Conducted in vitro functional assays and in vivo studies using AAV-mediated gene silencing.
  • Analyzed fibroblast activation and cardiac fibrosis markers.

Main Results:

  • Cardiac fibrosis precedes heart failure in the RCM model, mediated by paracrine signaling.
  • The tRNA-derived fragment 5'tiRNA-GluCTC was significantly enriched in cardiomyocyte exosomes.
  • Overexpression of 5'tiRNA-GluCTC exacerbated fibrosis; inhibition attenuated it in RCM mice.
  • 5'tiRNA-GluCTC targets Foxq1, repressing its expression and activating the Smad3 pathway.

Conclusions:

  • A novel signaling axis involving 5'tiRNA-GluCTC, Foxq1, and Smad3 drives fibrosis in RCM.
  • Cardiomyocyte-derived exosomes mediate intercellular communication in RCM.
  • This pathway represents a potential therapeutic target for restrictive cardiomyopathy.
Keywords:
5’tiRNA-GluCTCCardiac fibrosisExosomeFoxq1/Smad3Restrictive cardiomyopathy

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