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PreprintCC BY-NC-NDbioRxiv

A tRNA-derived small RNA orchestrates cardioprotection through distinct cell-type-specific mechanisms

  • T. Hao
  • J. Li1
  • K. V. Amancherla
  • L. Sun
  • P. Gokulnath
  • A. Patino-Guerrero
  • R. Sharma
  • K. Garcia-Mansfield
  • C. Xiao
  • A. C. Manning
  • E. Chartterjee
  • X. Yu
15 more authors
  • R. Xu
  • Y. Zhang
  • Z. Yang
  • P. Ivanov
  • J. J. Rossi
  • W. A. Goddard
  • H. Zhu
  • O. Akeju
  • E. R. Gamazon
  • W. Zhu
  • P. Pirrotte
  • R. Shah
  • J. Xiao
  • S. Das
  • G. Li1
  1. 1Massachusetts General Hospital
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Abstract

Pathological cardiac fibrosis and hypertrophy, key contributors to adverse remodeling that drives heart failure (HF), are not adequately targeted by current therapies. We identified tRNA-Asp-GTC-3'tDR, an ischemia-induced tRNA-derived small RNA (tDR), as an endogenous regulator of both remodeling processes across cardiac fibroblasts and cardiomyocytes. In murine models of myocardial ischemia- and pressure overload-induced HF, cardiac delivery of tRNA-Asp-GTC-3'tDR reduced fibrosis and hypertrophy, preserved cardiac function, and improved survival, with limited three doses conferring durable protection after ischemia, whereas silencing it worsened both. Strikingly, tRNA-Asp-GTC-3'tDR acts through distinct mechanisms in different cell types: in fibroblasts, it assembles stress granules that sequester ribosome-loaded profibrotic transcripts, whereas in cardiomyocytes it engages pseudouridine synthase PUS7 to activate RNA autophagy. Its regulation and functions were confirmed in human cardiac cells and tissues. These findings demonstrate that a single tDR coordinates cell-type-specific protective programs in the heart, suggesting a new therapeutic axis to mitigate HF progression.

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Cite

BibTeXRIS
BibTeX
@misc{hao2026trnaderived,
  title = {{A tRNA-derived small RNA orchestrates cardioprotection through distinct cell-type-specific mechanisms}},
  author = {T. Hao and J. Li and K. V. Amancherla and L. Sun and P. Gokulnath and A. Patino-Guerrero and R. Sharma and K. Garcia-Mansfield and C. Xiao and A. C. Manning and E. Chartterjee and X. Yu and R. Xu and Y. Zhang and Z. Yang and P. Ivanov and J. J. Rossi and W. A. Goddard and H. Zhu and O. Akeju and E. R. Gamazon and W. Zhu and P. Pirrotte and R. Shah and J. Xiao and S. Das and G. Li},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.28.755177},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.28.755177v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - A tRNA-derived small RNA orchestrates cardioprotection through distinct cell-type-specific mechanisms
AU  - T. Hao
AU  - J. Li
AU  - K. V. Amancherla
AU  - L. Sun
AU  - P. Gokulnath
AU  - A. Patino-Guerrero
AU  - R. Sharma
AU  - K. Garcia-Mansfield
AU  - C. Xiao
AU  - A. C. Manning
AU  - E. Chartterjee
AU  - X. Yu
AU  - R. Xu
AU  - Y. Zhang
AU  - Z. Yang
AU  - P. Ivanov
AU  - J. J. Rossi
AU  - W. A. Goddard
AU  - H. Zhu
AU  - O. Akeju
AU  - E. R. Gamazon
AU  - W. Zhu
AU  - P. Pirrotte
AU  - R. Shah
AU  - J. Xiao
AU  - S. Das
AU  - G. Li
PY  - 2026
DA  - 2026/09/28
PB  - bioRxiv
DO  - 10.64898/2026.09.28.755177
UR  - https://www.biorxiv.org/content/10.64898/2026.09.28.755177v1
AB  - Pathological cardiac fibrosis and hypertrophy, key contributors to adverse remodeling that drives heart failure (HF), are not adequately targeted by current therapies. We identified tRNA-Asp-GTC-3'tDR, an ischemia-induced tRNA-derived small RNA (tDR), as an endogenous regulator of both remodeling processes across cardiac fibroblasts and cardiomyocytes. In murine models of myocardial ischemia- and pressure overload-induced HF, cardiac delivery of tRNA-Asp-GTC-3'tDR reduced fibrosis and hypertrophy, preserved cardiac function, and improved survival, with limited three doses conferring durable protection after ischemia, whereas silencing it worsened both. Strikingly, tRNA-Asp-GTC-3'tDR acts through distinct mechanisms in different cell types: in fibroblasts, it assembles stress granules that sequester ribosome-loaded profibrotic transcripts, whereas in cardiomyocytes it engages pseudouridine synthase PUS7 to activate RNA autophagy. Its regulation and functions were confirmed in human cardiac cells and tissues. These findings demonstrate that a single tDR coordinates cell-type-specific protective programs in the heart, suggesting a new therapeutic axis to mitigate HF progression.
ER  -