Publication Date

8-1-2025

Journal

Leukemia

DOI

10.1038/s41375-025-02673-9

PMID

40588567

PMCID

PMC12310510

PubMedCentral® Posted Date

6-30-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Metabolic reprogramming is a key focus of targeted therapies in acute myeloid leukemia (AML). The mitochondrial sirtuin SIRT5 removes succinyl groups from specific lysines and impacts cell metabolism, but its role in AML tumorigenesis has not been extensively explored. A recent study highlighted that SIRT5 regulates AML cell activity by modulating glutamine metabolism, but its molecular targets in AML remain unclear. This study aims to identify the substrates of SIRT5 in AML. It was found that a total of 83 proteins with 121 lysine (K) residues showed increased succinylation after SIRT5 knockdown, as determined by succinylome analysis of MOLM-13 cells. SIRT5 was validated to interact with HADHA, a key molecule in the fatty acid oxidation pathway. Knockdown of SIRT5 resulted in hypersuccinylation and reduced enzymatic activity of HADHA. Mimetic mutations of lysine indicated that SIRT5 desuccinylates HADHA at K644. Inhibiting SIRT5 or HADHA increased sensitivity to venetoclax (VEN) in both VEN-sensitive and VEN-resistant cell lines. SIRT5 knockdown enhanced VEN-mediated suppression of mitochondrial metabolism and improved the survival of AML-transplanted NSG mice when combined with VEN. This study reveals the role of SIRT5 in AML metabolic regulation and provides valuable insights for developing SIRT5-targeted drugs and combination therapies with metabolic inhibitors.

Keywords

Humans, Animals, Leukemia, Myeloid, Acute, Mice, Sirtuins, Sulfonamides, Mitochondria, Bridged Bicyclo Compounds, Heterocyclic, Xenograft Model Antitumor Assays, Antineoplastic Agents, Mice, Inbred NOD, Apoptosis, Tumor Cells, Cultured, Cell Line, Tumor

Published Open-Access

yes

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