南方医科大学学报

南方医科大学学报 ›› 2026, Vol. 46 ›› Issue (10): 2424-2433.doi: 10.12122/j.issn.1673-4254.2026.10.12

• • 上一篇    

干扰鞘磷脂磷酸二酯酶1促进外源性二高-γ-亚麻酸诱导的急性髓系白血病细胞铁死亡

黄莹莹1,2(), 吴玮1,2(), 洪小颖1,2, 江贤栋1,2, 薛龑1,2(), 林东红1,2()   

  1. 1.福建医科大学医学技术与工程学院，福建 福州 350122
    2.精准医学临床检验技术福建省高校重点实验室，福建 福州 350122
  • 收稿日期:2026-04-24 出版日期:2026-10-20 发布日期:2026-10-26
  • 通讯作者: 薛龑,林东红 E-mail:xxx810310@163.com;914525752@qq.com;XY0804@139.com;lindh65@163.com
  • 作者简介:黄莹莹，在读博士研究生，E-mail: xxx810310@163.com
    吴 玮，硕士，实验师，E-mail: 914525752@qq.com
    第一联系人：（黄莹莹、吴玮并列第一作者）
  • 基金资助:
    国家自然科学基金(82072355);福建省财政专项(23SCZZX006);福建省自然科学基金(2024J01692)

Sphingomyelin phosphodiesterase 1 knockdown promotes exogenous dihomo-γ-linolenic acid-induced ferroptosis in acute myeloid leukemia cells

Yingying HUANG1,2(), Wei WU1,2(), Xiaoying HONG1,2, Xiandong JIANG1,2, Yan XUE1,2(), Donghong LIN1,2()   

  1. 1.School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China
    2.Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fuzhou 350122, China
  • Received:2026-04-24 Online:2026-10-20 Published:2026-10-26
  • Contact: Yan XUE, Donghong LIN E-mail:xxx810310@163.com;914525752@qq.com;XY0804@139.com;lindh65@163.com
  • Supported by:
    National Natural Science Foundation of China(82072355)

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摘要：

目的 明确参与调控二高-γ-亚麻酸（DGLA）诱导急性髓系白血病（AML）细胞铁死亡的潜在靶基因，探讨其对DGLA诱导的AML细胞铁死亡的影响。 方法 将BALB/c裸鼠分为DGLA组和Vehicle组，6只/组，接种THP-1细胞建立AML皮下荷瘤模型，DGLA组给予DGLA灌胃处理，Vehicle组以等量溶剂作对照。监测肿瘤生长并检测铁死亡指标以鉴定体内铁死亡模型。采用RNA-seq结合FerrDb数据库，筛选调控DGLA诱导AML细胞铁死亡的相关靶基因并进行qRT-PCR验证。构建靶基因下调的AML细胞系，结合体外细胞实验与体内荷瘤模型，评估靶基因下调联合DGLA处理对AML细胞、移植瘤表型及铁死亡相关指标的影响。 结果 成功建立铁死亡AML细胞皮下荷瘤模型，DGLA组小鼠肿瘤体积及质量减小（P<0.01），瘤体组织AML细胞线粒体可见体积缩小、外膜破裂等铁死亡性结构破坏，ROS、MDA和Fe2+水平升高（P<0.01），TfR1和PTGS2的mRNA和蛋白表达水平升高（P<0.05）。FerrDb数据库与脂质代谢通路基因联合分析，发现鞘磷脂磷酸二酯酶1（SMPD1）上调（P<0.001）。SMPD1下调的THP-1细胞经DGLA干预后，细胞活力明显减弱（P<0.01），线粒体铁死亡性破坏加剧，ROS、MDA和Fe2+水平升高（P<0.01），抗氧化防御关键分子GPX4和SLC7A11蛋白水平下调（P<0.05）。体内动物实验表明，shRNA组小鼠经DGLA处理后，肿瘤体积和质量均减小（P<0.01），MDA、ROS和Fe2+升高（P<0.01），TfR1和PTGS2表达水平升高（P<0.05）。 结论 下调SMPD1可促进DGLA诱导的体内外AML细胞铁死亡，抑制AML细胞活力。

关键词: 二高-γ-亚麻酸, 铁死亡, 多不饱和脂肪酸, 鞘磷脂磷酸二酯酶1, 急性髓系白血病

Abstract:

Objective To 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.. Methods BALB/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. Results In 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. Conclusion SMPD1 knockdown enhances DGLA-induced ferroptosis and represses cell viability in AML cells both in vitro and in vivo.

Key words: dihomo?γ?linolenic acid, ferroptosis, polyunsaturated fatty acid, sphingomyelin phosphodiesterase 1, acute myeloid leukemia