# RNA-mediated inhibition of mitochondrial SHMT2 impairs cancer cell proliferation

## TL;DR

This study shows that RNA can be used to inhibit a key cancer-related enzyme in mitochondria, reducing cancer cell growth in lab and animal models.

## Contribution

The paper introduces an RNA-based method to selectively inhibit SHMT2, a mitochondrial enzyme with no existing selective inhibitor.

## Key findings

- RNA inhibited SHMT2's activity in vitro with an IC50 of 4.4 ± 0.2 nM.
- Mitochondrial delivery of the RNA reduced lung cancer cell viability and tumor growth in mice.
- RNA-based strategies may target other RNA-binding metabolic enzymes where traditional inhibitors fail.

## 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.