Research on serine hydroxymethyltransferase 2 mechanisms in malignant tumor development and progression

Sep 22, 2026

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SHMT2 (serine hydroxymethyltransferase 2) is a key enzyme in cellular one-carbon metabolism and is strongly linked to malignant tumor initiation and progression. Aberrant SHMT2 expression is reported across multiple cancers, correlating with aggressive phenotypes and patient outcomes. Mechanistically, SHMT2 provides methyl donors and biosynthetic precursors for tumor proliferation, supports redox homeostasis for survival, and modulates growth, invasion, and metastasis through pathways such as JAK2/STAT3 and Akt/mTOR. Clarifying these molecular mechanisms can inform precision diagnosis, targeted therapy, and prognostic evaluation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages17

Reading Time43 min

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Abstract

Introduction

Warburg effect and metabolic reprogramming

One-carbon metabolism and cancer

Serine catabolism as a source of one-carbon units

SHMT2 in one-carbon metabolism

Structure and function of SHMT2

Genomic location and localization

Oligomerization and cofactor regulation

Relationship with SHMT1 and SHMT family

Submitted 6 August 2025 Accepted 10 June 2026 Published 18 August 2026 Corresponding authors Xiulan Su, [xlsu2024@163.com](xlsu2024@163.com)[ ](xlsu2024@163.com)Jianxun Wen, [448445433@qq.com](448445433@qq.com) Academic editor Sonia Oliveira Additional Information and Declarations can be found on page 9 DOI 10.7717/peerj.21570 Copyright 2026 Li et al. Distributed under Creative Commons CC-BY 4.0 OPEN ACCESS Research on serine hydroxymethyltransferase 2 mechanisms in malignant tumor development and progression Mei Li1 ,2 ,* , Ya Nan Xu1 ,* , Xiulan Su1 and Jianxun Wen2 1 Center for Clinical Epidemiology Research, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China 2 Public Service Center for Medical Research, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China * These authors contributed equally to this work. ABSTRACT SHMT2 (serine hydroxymethyltransferase 2) is a pivotal enzyme in cellular metabolism and is closely associated with the initiation and progression of malignant tumors, garnering significant attention in cancer research and therapy. Aberrant expression of SHMT2 has been observed in various cancers, correlating with tumor aggressiveness and patient prognosis. Functionally, SHMT2 participates in one-carbon metabolism, supplying methyl donors and biosynthetic precursors to support tumor cell proliferation. Additionally, it modulates redox homeostasis, promoting cancer cell survival and progression. SHMT2 also interacts with key signaling pathways, including JAK2/STAT3 and Akt/mTOR, thereby influencing tumor cell growth, invasion, and metastasis. Further elucidation of the molecular mechanisms by which SHMT2 contributes to tumorigenesis may provide critical insights for precision diagnosis, targeted therapy, and prognostic evaluationin oncology. Subjects Cell Biology, Molecular Biology, Oncology Keywords SHMT2, Tumor growth, Regulatory mechanism, Therapeutic target INTRODUCTION In the 1920s, Otto Warburg and colleagues observed that malignant tumor cells exhibit enhanced glycolytic activity for energy production even under aerobic conditions, a phenomenon now known as the ``Warburg effect'' (Warburg, 1956; Koppenol, Bounds & Dang, 2011; Dang & Semenza, 1999 ; Warburg, Wind & Negelein, 1927) . This metabolic reprogramming is critical for sustaining rapid cancer cell proliferation, tumorigenesis, and evasion of cell death (Hanahan & Weinberg, 2011; Coelho, Fortunato & Carvalho, 2018; Hanahan, 2022; Vander Heiden & De Berardinis, 2017) . One-carbon metabolism is a complex biochemical network mediated by folate-dependent reactions, comprising the folate and the methionine cycles. It supplies essential methyl donors and contributes to the synthesis and modification of macromolecules, including nucleic acids, proteins, and lipids, thereby playing a pivotal role in cellular proliferation, differentiation, and survival (Morscher et al., 2018; Tong et al., 2020) . In cancer cells, one-carbon metabolism How to cite this article Li M, Xu YN, Su X, Wen J. 2026. Research on serine hydroxymethyltransferase 2 mechanisms in malignant tumor development and progression. PeerJ 14:e21570 [http://doi.org/10.7717/peerj.21570](http://doi.org/10.7717/peerj.21570) emerges as a key metabolic hub and a therapeutic target to support their accelerated growth. This metabolic adaptation not only provides energy and biosynthetic precursors for anabolic demands (Meiser & Vazquez, 2016; Appling, 1991) but also modulates signal transduction and epigenetic regulation, thereby driving tumor cell proliferation, invasion, and metastasis (Locasale, 2013; Ducker & Rabinowitz, 2017; Newman & Maddocks, 2017) . The primary source of one-carbon units in cancer cells is derived from serine catabolism (Li & Ye, 2020) . Recent studies have identified SHMT2 as a pivotal enzyme in one-carbon metabolism, garnering significant attention in cancer research (gastric cance

FAQs

What role does SHMT2 play in malignant tumor development?

SHMT2 is central to one-carbon metabolism and supports tumor initiation and progression. It contributes methyl donors and biosynthetic precursors required for proliferation and survival.

How does SHMT2 influence tumor cell survival and progression?

SHMT2 modulates redox homeostasis, enhancing cancer cell survival. It also affects signaling networks, including JAK2/STAT3 and Akt/mTOR, which regulate growth, invasion, and metastasis.

Why is SHMT2 considered a potential therapeutic target?

SHMT2 connects serine/glycine biosynthesis with one-carbon metabolism, positioning it as a metabolic hub for cancer cells. Targeting SHMT2 may enable precision diagnosis, targeted therapy, and improved prognostic assessment.

Sep 22, 2026

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