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.

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