Role of MTH1 in oxidative stress and therapeutic targeting of cancer - Review

Sep 21, 2026

Upload by Skyler

Cancer cells sustain high reactive oxygen species (ROS) to support growth, yet ROS can also trigger oxidative stress, DNA damage, and cell death. To tolerate elevated ROS, tumors activate antioxidant and nucleotide-protection defenses, including the MTH1 enzyme. MTH1 prevents oxidized nucleotide incorporation into DNA, enabling proliferation. Because MTH1 is often upregulated across cancers, selective MTH1 inhibition is presented as a strategy to induce DNA damage and suppress tumor growth and metastasis, while sparing normal cells with lower ROS dependence.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages24

Reading Time1 h 0 min

AccessFree to download

Introduction

Redox homeostasis and disease link

ROS generation and dual role

Oxidative stress, DNA damage, and cancer development

Antioxidant systems and immune implications

Redox Biology 77 (2024) 103394 Contents lists available at ScienceDirect Redox Biology journal [homepage:](homepage: www.elsevier.com/locate/redox)[ www.elsevier.com/locate/redox](homepage: www.elsevier.com/locate/redox) | Role of MTH1 in oxidative stress and therapeutic targeting of cancer
Aaliya Taiyaba, Anam Ashrafa, Md Nayab Sulaimania, Aanchal Rathib, Anas Shamsic,**, Md Imtaiyaz Hassan a,*
a Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India b Department of Biotechnology, Faculty of Life Sciences, Jamia Millia Islamia, New Delhi, 110025, India
c Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, P.O. Box 346, United Arab Emirates | | | | --- | --- | --- | | A R T I C L E I N F O | | A B S T R A C T | | Keywords:
MTH1 enzyme Therapeutic target Oxidative stress Reactive oxygen species MTH1 inhibitors Cancer therapy | | Cancer cells maintain high levels of reactive oxygen species (ROS) to drive their growth, but ROS can trigger cell death through oxidative stress and DNA damage. To survive enhanced ROS levels, cancer cells activate their antioxidant defenses. One such defense is MTH1, an enzyme that prevents the incorporation of oxidized nucleotides into DNA, thus preventing DNA damage and allowing cancer to proliferate. MTH1 levels are often elevated in many cancers, and thus, inhibiting MTH1 is an attractive strategy for suppressing tumor growth and metastasis. Targeted MTH1 inhibition can induce DNA damage in cancer cells, exploiting their vulnerability to oxidative stress and selectively targeting them for destruction. Targeting MTH1 is promising for cancer treatment because normal cells have lower ROS levels and are less dependent on these pathways, making the approach both effective and specific to cancer. This review aims to investigate the potential of MTH1 as a therapeutic target, especially in cancer treatment, offering detailed insights into its structure, function, and role in disease progression. We also discussed various MTH1 inhibitors that have been developed to selectively induce oxidative damage in cancer cells, though their effectiveness varies. In addition, this review provide deeper mechanistic insights into the role of MTH1 in cancer prevention and oxidative stress management in various diseases. | 1. Introduction The human body requires redox homeostasis for vital physiological functioning, and its imbalance is a key contributor to several frequently occurring diseases, including type 2 diabetes, atherosclerosis, chronic obstructive pulmonary disease, Alzheimer’s disease (AD), and cancer [1]. A hallmark in the pathogenesis of cancer is oxidative stress, which is favored by redox imbalance. It gives rise to numerous malignant behaviors in cancer cells [2,3]. Reactive oxygen species (ROS) are the main mediators in redox reactions, often considered as by-products of cellular respiration. The reactions involving cyclooxygenase, NADPH oxidase, xanthine oxidase, lipogenesis, and the Fenton reaction, generating hydroxyl radicals, superoxide radicals, and hydrogen peroxide, give rise to ROS [4,5]. Physiologically, ROS in low to moderate concentrations aid in maintaining intracellular activities and signaling pathways. However, elevated levels promote malignant transformation, cellular damage, and even cell death. Excessive accumulation of ROS creates a highly reactive cellular environment, which leads to DNA damage via alkylation, deamination, oxo-group modification, methylation, or halogenation of bases, thereby altering the morphology of bases. This further leads to the improper incorporation of bases into DNA and subsequent DNA damage, thus promoting disease pathology [6]. Redox reactions play key roles in cellular respiration, particularly in ATP production within mitochondria. ROS act as signaling molecules, regulating cellular processes like proliferation, differentiation, and apoptosis

FAQs

Why do cancer cells rely on oxidative stress and high ROS levels?

Cancer cells maintain elevated ROS to drive growth and survival. However, ROS can also cause oxidative stress and damage, so tumors must counterbalance it to avoid cell death.

What role does MTH1 play in protecting cancer cells from ROS-induced damage?

MTH1 prevents oxidized nucleotides from being incorporated into DNA, reducing DNA damage. This enables cancer cells to proliferate despite enhanced ROS.

How does inhibiting MTH1 help treat cancer?

Targeted MTH1 inhibition promotes DNA damage by undermining the nucleotide protection pathway. This strategy exploits cancer cells’ vulnerability while normal cells are less dependent due to lower ROS levels.

Sep 21, 2026

Upload by Skyler