Targeting UCP2 rewires metabolism to suppress leukemia progression

Acute myeloid leukemia (AML) is a multifaceted and devastating blood cancer characterized by frequent genetic mutations, mitochondrial dysregulation, and a high relapse rate following standard chemotherapy. While the mitochondrial uncoupling protein 2 (UCP2) is known to facilitate tumor cell growth and promote metastasis in various solid cancers, its precise role in the development of hematological malignancies has remained elusive.

This new research, published in the Genes & Diseases journal by a team from Shanghai Jiao Tong University School of Medicine, Fudan University and Xinjiang Medical University, investigated the pathogenetic role of UCP2 and its modulation of branched-chain amino acids (BCAAs) in AML progression.

Bioinformatics analyses and primary clinical cohort data revealed that UCP2 is significantly overexpressed in AML patients, with elevated levels closely correlated with poor overall survival and therapeutic resistance. Through rigorous in vitro and in vivo experiments, researchers demonstrated that genetically silencing UCP2 profoundly impairs leukemic cell proliferation, triggers apoptosis, and disrupts mitochondrial homeostasis by increasing mitochondrial mass and reactive oxygen species (ROS).

Extensive RNA-sequencing and metabolic mass spectrometry analyses deciphered the underlying mechanism, revealing that suppressing UCP2 leads to a massive intracellular accumulation of BCAAs, specifically leucine, isoleucine, and valine. This high concentration of BCAAs aggressively induces cellular oxidative stress. Mechanistically, this BCAA-driven oxidative stress activates the PI3K/AKT/mTOR signaling pathway, which fundamentally halts leukemogenesis. Validating this metabolic dependency, removing BCAAs from the cellular environment successfully restored leukemic cell survival and counteracted the anti-tumor effects of UCP2 inhibition.

Remarkably, in vivo mouse xenograft models confirmed that pharmacological inhibition of UCP2 using the selective inhibitor genipin significantly eradicated AML blasts and improved overall survival. More importantly, providing dietary supplementation of BCAAs dramatically amplified genipin's anti-tumor efficacy, leading to magnified oxidative stress and sharply reduced AML engraftment in both the bone marrow and peripheral blood.

While these collective data robustly highlight the critical influence of BCAA-induced oxidative stress on leukemia progression, additional studies are necessary to fully integrate these targeted interventions into clinical therapies.

In conclusion, targeting the UCP2-BCAA-PI3K/AKT/mTOR signaling axis offers a powerful new strategy to exploit the metabolic vulnerabilities of leukemic cells. This profound finding positions specific UCP2 inhibitors, potentially combined with targeted amino acid modulation, as compelling therapeutic candidates for next-generation acute myeloid leukemia treatments.

Reference

Title of Original Paper: Suppression of UCP2 alleviates leukemogenesis by enhancing branched-chain amino acids-induced oxidative stress via activating the PI3K/AKT/mTOR signaling pathway

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101794

Funding Information:
The Natural Science Foundation of Shanghai, China (No. 23ZR1436100)
The National Key R&D Program of China (No. 2020TFA0803603)
The National Natural Science Foundation of China (No. 82370186, No. 82030075, No. 82230049)

Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus Cite Score: 8.4 | Impact Factor: 9.4

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Fichiers joints

(A) TGCA database analysis of UCP2 mRNA level in healthy donors identified in the gray box (n = 70) versus AML patients identified with the red box (n = 173). (B) Kaplan–Meier plot of UCP2 overall survival in the low-risk versus high-risk AML group. (C) Quantitative PCR of UCP2 mRNA level in a panel of AML cell lines versus either peripheral blood (PBL) or bone marrow (BM) normal controls. (D) Time-dependent receiver operating characteristic curve according to the 1-year, 3-year, and 5-year survival of the area under the curve (AUC value). (E) Immunoblotting of UCP2 protein level in a panel of AML primary cells (n = 10) versus healthy donors (n = 2). Band intensity was measured using the Image J software and normalized to GAPDH control. (F) Quantitative PCR of UCP2 mRNA level in de novo AML primary cells (n = 18) versus paired relapsed AML primary cells (n = 18). All experiments were repeated three times. Data represent mean ± standard deviation from technical triplicates (∗p < 0.01, ∗∗p < 0.05, and ∗∗∗p < 0.001; Two-way ANOVA for BM or PBL controls versus cell lines, unpaired t-test for the normal versus AML and the de novo versus the relapse). UCP2, uncoupling protein 2; AML, acute myeloid leukemia.
THP-1 or KG-1 cells overexpressing either a scramble control, shUCP2#2, or shUCP2#3 stable transfectants were subjected to RNA-sequencing analysis. (A) KEGG pathway analysis of the top signaling pathways that were aberrantly regulated in the above stable transfectants (∗common signaling pathways in both cell lines). THP-1 or KG-1 cells overexpressing either a scramble control, shUCP2#2, or shUCP2#3 stable transfectants were subjected to metabolic mass spectrometry. (B) Heatmap of the expression profile of amino acid metabolism-related gene expression. (C–E) The peak area for the fold chain of amino acid gene expression (data were normalized to scramble control). (F, G) The BCAA content of THP-1 or KG-1 cells overexpressing either a scramble control, shUCP2#2, or shUCP2#3 stable transfectants (data were normalized to the scramble control). All experiments were repeated three times. Data represent mean ± standard deviation from technical triplicates (∗p < 0.01, ∗∗p < 0.05, ∗∗∗p < 0.001, and ∗∗∗∗p < 0.005; two-way ANOVA for scramble control versus shUCP2s). BCAA, branched-chain amino acid; UCP2, uncoupling protein 2.
Supplementation of BCAA enhanced the anti-tumor activity of genipin.

27/05/2026 Compuscript Ltd

Regions: Europe, Ireland, United Kingdom, Asia, China

Keywords: Science, Life Sciences

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