The dual role of FSP1 in programmed cell death: resisting ferroptosis in the cell membrane and promoting necroptosis in the nucleus of THP-1 cells

Xiaoqian Tan; Yinling He; Panpan Yu; Yunong Deng; Zhongcheng Xie; Jiami Guo; Qin Hou; Pin Li; Xiaoyan Lin; Siyu Ouyang; Wentao Ma; Yushu Xie; Zilong Guo; Dandan Chen; Zhixia Zhang; Yunyu Zhu; Fei Huang; Ziye Zhao; Cen Zhang; Zhirong Guo; Xi Chen; Tianhong Peng; Liang Li; Wei Xie

doi:10.1186/s10020-024-00861-4

Molecular Medicine (Jul 2024)

The dual role of FSP1 in programmed cell death: resisting ferroptosis in the cell membrane and promoting necroptosis in the nucleus of THP-1 cells

Xiaoqian Tan,
Yinling He,
Panpan Yu,
Yunong Deng,
Zhongcheng Xie,
Jiami Guo,
Qin Hou,
Pin Li,
Xiaoyan Lin,
Siyu Ouyang,
Wentao Ma,
Yushu Xie,
Zilong Guo,
Dandan Chen,
Zhixia Zhang,
Yunyu Zhu,
Fei Huang,
Ziye Zhao,
Cen Zhang,
Zhirong Guo,
Xi Chen,
Tianhong Peng,
Liang Li,
Wei Xie

Affiliations

Xiaoqian Tan: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Yinling He: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Panpan Yu: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Yunong Deng: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Zhongcheng Xie: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Jiami Guo: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Qin Hou: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Pin Li: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Xiaoyan Lin: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Siyu Ouyang: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Wentao Ma: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Yushu Xie: Class of Clinical Medicine, University of South China
Zilong Guo: Class of Clinical Medicine, University of South China
Dandan Chen: Class of Clinical Medicine, University of South China
Zhixia Zhang: Class of Clinical Medicine, University of South China
Yunyu Zhu: Class of Clinical Medicine, University of South China
Fei Huang: Class of Clinical Medicine, University of South China
Ziye Zhao: Class of Clinical Medicine, University of South China
Cen Zhang: Class of Clinical Medicine, University of South China
Zhirong Guo: Class of Clinical Medicine, University of South China
Xi Chen: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Tianhong Peng: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Liang Li: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China
Wei Xie: Department of Physiology, Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China

DOI: https://doi.org/10.1186/s10020-024-00861-4
Journal volume & issue: Vol. 30, no. 1
pp. 1 – 27

Abstract

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Abstract Background Acute monocytic leukemia-M5 (AML-M5) remains a challenging disease due to its high morbidity and poor prognosis. In addition to the evidence mentioned earlier, several studies have shown that programmed cell death (PCD) serves a critical function in treatment of AML-M5. However, the role and relationship between ferroptosis and necroptosis in AML-M5 remains unclear. Methods THP-1 cells were mainly treated with Erastin and IMP-366. The changes of ferroptosis and necroptosis levels were detected by CCK-8, western blot, quantitative real-time PCR, and electron microscopy. Flow cytometry was applied to detect the ROS and lipid ROS levels. MDA, 4-HNE, GSH and GSSG were assessed by ELISA kits. Intracellular distribution of FSP1 was studied by immunofluorescent staining and western blot. Results The addition of the myristoylation inhibitor IMP-366 to erastin-treated acute monocytic leukemia cell line THP-1 cell not only resulted in greater susceptibility to ferroptosis characterized by lipid peroxidation, glutathione (GSH) depletion and mitochondrial shrinkage, as the FSP1 position on membrane was inhibited, but also increased p-RIPK1 and p-MLKL protein expression, as well as a decrease in caspase-8 expression, and triggered the characteristic necroptosis phenomena, including cytoplasmic translucency, mitochondrial swelling, membranous fractures by FSP1 migration into the nucleus via binding importin α2. It is interesting to note that ferroptosis inhibitor fer-1 reversed necroptosis. Conclusion We demonstrated that inhibition of myristoylation by IMP-366 is capable of switching ferroptosis and ferroptosis-dependent necroptosis in THP-1 cells. In these findings, FSP1-mediated ferroptosis and necroptosis are described as alternative mechanisms of PCD of THP-1 cells, providing potential therapeutic strategies and targets for AML-M5.

Published in Molecular Medicine

ISSN: 1076-1551 (Print); 1528-3658 (Online)
Publisher: BMC
Country of publisher: United Kingdom
LCC subjects: Medicine: Therapeutics. Pharmacology; Science: Chemistry: Organic chemistry: Biochemistry
Website: https://molmed.biomedcentral.com

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