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<p>Targeting metabolic reprogramming is crucial for cancer treatment. Recent advances highlight RNA’s ability to directly regulate enzyme activity through riboregulation. In this study, we used an RNA-based approach to inhibit the mitochondrial enzyme Serine hydroxymethyltransferase 2 (SHMT2), which lacks a selective in vivo inhibitor. SHMT2, often overexpressed in various cancers, is pivotal in one-carbon metabolism, a pathway vital for cell proliferation. Our results show that RNA effectively inhibits SHMT2’s serine-to-glycine conversion in vitro (IC<sub>50</sub> = 4.4 ± 0.2 nM). By using a mitochondrial import signal, we successfully delivered the inhibitory RNA into the mitochondria of lung cancer cells, reducing cell viability in vitro and tumor growth in vivo in a xenograft mouse model. These findings suggest that RNA-based strategies could be extended to selectively target other RNA-binding metabolic enzymes, offering potential solutions where small molecule inhibitors fall short or to counteract drug resistance.</p>

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RNA-mediated inhibition of mitochondrial SHMT2 impairs cancer cell proliferation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月6日

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  • Francesca Romana Liberati,
  • Sharon Spizzichino,
  • Sara Di Russo,
  • Giulia Elizabeth Borsatti,
  • Agnese Riva,
  • Maria Chiara Magnifico,
  • Amani Bouzidi,
  • Giorgio Giardina,
  • Marzia Arese,
  • Chiara Scribani Rossi,
  • Dalila Boi,
  • Giovanna Boumis,
  • Federica Di Fonzo,
  • Giulia Guarguaglini,
  • Roberto Contestabile,
  • Angela Tramonti,
  • Alberto Macone,
  • Alessandro Paiardini,
  • Serena Rinaldo,
  • Alessio Paone,
  • Francesca Cutruzzolà

摘要

Targeting metabolic reprogramming is crucial for cancer treatment. Recent advances highlight RNA’s ability to directly regulate enzyme activity through riboregulation. In this study, we used an RNA-based approach to inhibit the mitochondrial enzyme Serine hydroxymethyltransferase 2 (SHMT2), which lacks a selective in vivo inhibitor. SHMT2, often overexpressed in various cancers, is pivotal in one-carbon metabolism, a pathway vital for cell proliferation. Our results show that RNA effectively inhibits SHMT2’s serine-to-glycine conversion in vitro (IC50 = 4.4 ± 0.2 nM). By using a mitochondrial import signal, we successfully delivered the inhibitory RNA into the mitochondria of lung cancer cells, reducing cell viability in vitro and tumor growth in vivo in a xenograft mouse model. These findings suggest that RNA-based strategies could be extended to selectively target other RNA-binding metabolic enzymes, offering potential solutions where small molecule inhibitors fall short or to counteract drug resistance.