Molecular Targeting of the Isocitrate Dehydrogenase Pathway and the Implications for Cancer Therapy - review

Sep 22, 2026

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Comprehensive genomic profiling enabled by next-generation sequencing has revealed numerous potentially actionable cancer mutations, reshaping understanding of tumor biology. Isocitrate dehydrogenase (IDH) exists in cytosol (IDH1) and mitochondria (IDH2, IDH3), driving oxidative decarboxylation of isocitrate and regulating α-ketoglutarate and NADPH generation. IDH-mediated rate-limiting steps influence gene regulation, differentiation, and tissue homeostasis. Mutations in IDH1/IDH2, and less often IDH3, occur across glioma, AML, chondrosarcoma, and intrahepatic cholangiocarcinoma, motivating review of IDH isomer pathophysiology and emerging inhibitor data.

LanguageEnglish

CategoryHealthcare

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Pages11

Reading Time28 min

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Introduction

Biology of Isocitrate Dehydrogenase

Review Molecular Targeting of the Isocitrate Dehydrogenase Pathway and the Implications for Cancer Therapy Stanislav Ivanov *, Olger Nano, Caroline Hana , Amalia Bonano-Rios and Atif Hussein Citation: Ivanov, S.; Nano, O.; Hana, C.; Bonano-Rios, A.; Hussein, A. Molecular Targeting of the Isocitrate Dehydrogenase Pathway and the Implications for Cancer Therapy. Int. J. Mol. Sci. 2024, 25, 7337. [https://](https://)[ ](https://)[doi.org/10.3390/ijms25137337](doi.org/10.3390/ijms25137337) Academic Editor: Erik A.C. Wiemer Received: 15 April 2024 Revised: 31 May 2024 Accepted: 25 June 2024 Published: 4 July 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . Memorial Cancer Institute, Memorial Healthcare System, Pembroke Pines, FL 33028, USA; [onano@mhs.net](onano@mhs.net) (O.N.); [abonanorios@mhs.net](abonanorios@mhs.net) (A.B.-R.); [ahussein@mhs.net](ahussein@mhs.net) (A.H.) * Correspondence: [sivanov@mhs.net](sivanov@mhs.net); Tel.: +1-(954)-265-4325 Abstract: The advent of comprehensive genomic profiling using next-generation sequencing (NGS) has unveiled an abundance of potentially actionable genetic aberrations that have shaped our understanding of the cancer biology landscape. Isocitrate dehydrogenase (IDH) is an enzyme present in the cytosol (IDH1) and mitochondria (IDH2 and IDH3) . In the mitochondrion, it catalyzes the irreversible oxidative decarboxylation of isocitrate, yielding the production of α-ketoglutarate and nicotinamide adenine dinucleotide phosphate (NADPH) as well as carbon dioxide (CO 2) . In the cytosol, IDH catalyzes the decarboxylation of isocitrate to α-ketoglutarate as well as the reverse reductive carboxylation of α-ketoglutarate to isocitrate. These rate-limiting steps in the tricarboxylic acid cycle, as well as the cytoplasmic response to oxidative stress, play key roles in gene regulation, cell differentiation, and tissue homeostasis. Mutations in the genes encoding IDH1 and IDH2 and, less commonly, IDH3 have been found in a variety of cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. In this paper, we intend to elucidate the theorized pathophysiology behind IDH isomer mutation, its implication in cancer manifestation, and discuss some of the available clinical data regarding the use of novel IDH inhibitors and their role in therapy. Keywords: IDH; isocitrate dehydrogenase; AML; MDS; glioma; cholangiocarcinoma; ivosidenib; enasidenib; vorasidenib; olutasidenib; oncometabolite 1. Introduction The fundamental abnormality resulting in the development of cancer is the continuous unregulated proliferation of clonal cells. This unregulated proliferation is a result of the net accumulation of anomalies in multiple cell regulatory systems. Such regulatory systems include checkpoint inhibition and triggered cell death, DNA repair mechanisms, and resilience to epigenetic stressors and oncometabolites. Cells that have acquired the ability to bypass these and other regulatory systems result in malignant proliferation that is able to disrupt normal tissue and spread to distant parts of the body, contributing to end-organ damage. Recent developments in genomic profiling via next-generation sequencing (NGS) have identified a multitude of targetable mutations that are presently being researched as potential avenues for therapy. One such target is the isocitrate dehydrogenase (IDH) enzyme system. This protein product, found both in the cytosol and mitochondria of cells, plays a key role in cellular metabolism, growth, and differentiation. Mutations in the catalytic domain of IDH can result in fundamental impairments

FAQs

What roles do IDH1, IDH2, and IDH3 play in cellular metabolism?

IDH1 works in the cytosol and catalyzes isocitrate to α-ketoglutarate, while IDH2 operates in mitochondria with similar chemistry. IDH3 is a heterotetrameric form that primarily drives the irreversible conversion of isocitrate to α-ketoglutarate as part of the tricarboxylic acid cycle.

How can IDH mutations contribute to cancer development?

Mutations in IDH1 and IDH2 impair normal cellular regulation, including effects on the cell cycle, and can promote production of oncometabolites that support aberrant growth. These changes are linked to tumor manifestation across multiple cancer types.

Which IDH inhibitor strategies and targetable outcomes are discussed?

The paper focuses on the theoretical pathophysiology of IDH isomer mutations and their implications for cancer, and it reviews available clinical data on novel IDH inhibitors and their therapeutic role.

Sep 22, 2026

Upload by Liam