@article{HUANG2026, 
author = {Yingying HUANG and Wei WU and Xiaoying HONG and Xiandong JIANG and Yan XUE and Donghong LIN},
title = {Sphingomyelin phosphodiesterase 1 knockdown promotes exogenous dihomo-γ-linolenic acid-induced ferroptosis in acute myeloid leukemia cells},
year = {2026},
journal = {Journal of Southern Medical University},
volume = {46},
number = {10},
pages = {2424-2433},
keywords = {dihomo-γ-linolenic acid, ferroptosis, polyunsaturated fatty acid, sphingomyelin phosphodiesterase 1, acute myeloid leukemia},
url = {https://www.sciopen.com/article/10.12122/j.issn.1673-4254.2026.10.12},
doi = {10.12122/j.issn.1673-4254.2026.10.12},
abstract = {ObjectiveTo identify the potential target genes involved in the regulation of dihomo-γ-linolenic acid (DGLA)-induced ferroptosis in acute myeloid leukemia (AML) cells and to investigate their functional role in this process.MethodsBALB/c nude mouse models bearing subcutaneous THP-1 cell xenografts were treated with DGLA or an equal volume of vehicle by gavage (n=6). Tumor growth was monitored, and ferroptosis-related markers in the xenografts were detected. RNA-seq combined with FerrDb analysis was used to identify a target gene involved in DGLA-induced ferroptosis in AML cells, followed by qRT-PCR validation. A target gene-knockdown AML cell line was established to evaluate the effects of knockdown combined with DGLA treatment on AML cell phenotypes and ferroptosis in vitro and in vivo.ResultsIn the tumor-bearing mice, DGLA treatment markedly reduced the tumor volume and weight, and the tumor cells showed typical ultrastructural changes of ferroptosis with upregulated levels of ROS, MDA, and Fe2+ and increased mRNA and protein expression levels of TfR1 and PTGS2. RNA-seq combined with the FerrDb database analysis revealed significant upregulation of SMPD1 in AML cells with DGLA-induced ferroptosis. In THP-1 cells with SMPD1 knockdown, DGLA treatment significantly reduced the cell viability, aggravated mitochondrial ferroptotic injury, and increased intracellular ROS, MDA and Fe2+ levels, causing also significant reductions of protein levels of GPX4 and SLC7A11. In the mouse models bearing xenografts derived from THP-1 cells with SMPD1 knockdown, DGLA treatment significantly decreased tumor volume and weight and increased the expressions of the lipid peroxidation markers (MDA, ROS, and Fe2+) and the protein levels of TfR1 and PTGS2.ConclusionSMPD1 knockdown enhances DGLA-induced ferroptosis and represses cell viability in AML cells both in vitro and in vivo.}
}