Work

Enoyl-CoA hydratase domain-containing protein 3 (ECHDC3) regulates mitochondrial metabolism and chemotherapy resistance in acute myeloid leukemia (AML)

Year: 2025

Type: article

Abstract: Background Acute myeloid leukemia (AML) is characterized by high relapse and mortality rates. Our previous investigation identified enoyl-CoA hydratase domain-containing protein 3 ( ECHDC3 ) as being of prognostic significance in AML; however, the underlying pathways remain elusive. The intricate crosstalk among genetic abnormalities, metabolic pathways, and protein dysfunctions underpins the complexity contributing to its poor prognosis. Methods ECHDC3 was knocked down by siRNA and subjected to RNA sequencing, chromatin immunoprecipitation (ChIP), and metabolomic assessments. Cell culture media were subjected to metabolomic assessments to evaluate changes in the bone marrow microenvironment. Mass spectrometry was conducted on bone marrow leukemia stem cells (CD34+) from chemotherapy-sensitive (S) and chemotherapy-resistant (R) patients. Additionally, untargeted metabolomic sequencing was performed on bone marrow supernatants from this patient cohort, and a combined proteomic-metabolomic analysis was conducted on the sequencing results from paired samples. Results Knockdown of ECHDC3 significantly reduced the mitochondrial membrane potential ( p < 0.0001), increased the mitochondrial DNA copy number MT-CO1 ( p = 0.0367) and MT-CO2 ( p = 0.0081), and enhanced manganese superoxide dismutase (MnSOD) activity ( p = 0.0003). Significant differences were observed in choline metabolism in cancer ( p = 0.0063), linoleic acid ( p = 0.0160), and alpha-linolenic acid metabolism ( p = 0.0250) between the R and S groups. Furthermore, correlation analysis of proteomic and metabolomic data suggested that choline and glycerophospholipid metabolism may play pivotal roles in the development of chemotherapy resistance in AML. Conclusions ECHDC3 contributes to chemotherapy resistance in AML by regulating mitochondrial function, autophagy, and metabolic pathways. This study highlights ECHDC3 as a potential therapeutic target and offers insights into the development of AML treatments to overcome drug resistance.

Source: Cancer Pathogenesis and Therapy

DOI: 10.1016/j.cpt.2025.08.002

Authors: Yijing Zhao, Hanfei Guo, Liting Niu, Jinfang Zhao

Institutions: Peking University People's Hospital, VA Palo Alto Health Care System, First Hospital of Jilin University, Stanford University

Language: English

Topic: Acute Myeloid Leukemia Research

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $1,100