RNA-mediated inhibition of mitochondrial SHMT2 impairs cancer cell proliferation

  • Cell Death Discov. 2025 Aug 6;11(1):369. doi: 10.1038/s41420-025-02646-y.
Francesca Romana Liberati  #  1 ,  Sharon Spizzichino  #  1 ,  Sara Di Russo  #  1 ,  Giulia Elizabeth Borsatti  1 ,  Agnese Riva  1 ,  Maria Chiara Magnifico  1 ,  Amani Bouzidi  1  2 ,  Giorgio Giardina  1 ,  Marzia Arese  1 ,  Chiara Scribani Rossi  1 ,  Dalila Boi  3 ,  Giovanna Boumis  1 ,  Federica Di Fonzo  1 ,  Giulia Guarguaglini  3 ,  Roberto Contestabile  1 ,  Angela Tramonti  3 ,  Alberto Macone  1 ,  Alessandro Paiardini  1 ,  Serena Rinaldo  1 ,  Alessio Paone  4  5 ,  Francesca Cutruzzolà  6  7
Affiliations
  • 1. Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy.
  • 2. Translational Oncology Research Unit IRCCS Regina Elena National Cancer Institute, Rome, Italy.
  • 3. Istituto di Biologia e Patologia Molecolari, Consiglio Nazionale delle Ricerche, c/o Sapienza University of Rome, Rome, Italy.
  • 4. Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy. [email protected].
  • 5. Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy. [email protected].
  • 6. Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy. [email protected].
  • 7. Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy. [email protected].
  • # Contributed equally.
PMID: 40770176 DOI: 10.1038/s41420-025-02646-y
Abstract

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.