Fatostatin targets SCAP/SREBP pathway to inhibit ARID1A-deficient non-small cell lung cancer by promoting ferroptosis
- 1School of Gongli Hospital Medical Technology, University of Shanghai for Science and Technology, Shanghai 200093, China
- 2Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Department of Central Laboratory, Gongli Hospital of Shanghai Pudong New Area, Shanghai 200135, China
- 3Ningxia Medical University School of Basic Medical Sciences, Yinchuan, 750004, China
Abstract
Objective·To analyze the molecular mechanism by which AT-rich interaction domain 1A (ARID1A) deletion regulates lipid metabolism reprogramming in non-small cell lung cancer (NSCLC), and to explore the targeted therapeutic potential and mode of action of the SCAP/SREBP pathway inhibitor fatostatin.Methods·ARID1A wild-type (WT) and knockout (KO) A549 cell lines were constructed using CRISPR-Cas9 technology. Transcriptomic and proteomic analyses were combined to screen for differentially expressed genes and core pathways, and Western blotting was performed to verify the expression of key proteins, including HSP90B1 and SREBP1/2. Oil Red O staining was used to observe intracellular lipid droplet accumulation, and cholesterol and triglyceride quantification kits were used to assess lipid synthesis capacity. CCK-8, scratch wound healing, and Transwell invasion assays were used to evaluate the effects of different concentrations of fatostatin on the proliferation, migration, and invasion of cells in the two groups. JC-1 fluorescent probe was used to detect changes in mitochondrial membrane potential, and Western blotting was used to detect the expression of ferroptosis markers, including ACSL4, GPX4, and SLC7A11.Results·Western blotting showed that, compared with the WT group, the expression of HSP90B1, SREBP1, and SREBP2 proteins was upregulated in KO cells, whereas INSIG1 expression showed no significant change. Oil Red O staining and lipid quantification showed that lipid droplet accumulation and the levels of total cholesterol and triglycerides were higher in KO cells than in WT cells (all P<0.05). The CCK-8 assay showed that fatostatin inhibited the proliferation of cells in both groups in a concentration-dependent manner, and the half-maximal inhibitory concentration (IC50) in the KO group was significantly lower than that in the WT group (P<0.001). Scratch wound healing and Transwell assays showed that, after treatment with the same concentration of fatostatin, the reductions in wound closure rate and in the numbers of migrated and invaded cells were greater in the KO group than in the WT group(all P<0.05). JC-1 staining showed that fatostatin decreased the mitochondrial membrane potential in KO cells but had no significant effect in WT cells. Western blotting showed that ACSL4 expression was upregulated and GPX4 and SLC7A11 expression were downregulated in KO cells.Conclusion·The ARID1A/HSP90B1/SREBP axis is a key pathway regulating lipid metabolism reprogramming in ARID1A-deficient NSCLC. Fatostatin exerts selective anti-tumor effects by targeting this pathway to inhibit lipid synthesis and specifically induce ferroptosis in tumor cells.
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BibTeX
@article{xinhong2026fatostatin,
title = {{Fatostatin targets SCAP/SREBP pathway to inhibit ARID1A-deficient non-small cell lung cancer by promoting ferroptosis}},
author = {Chen Xinhong and Zhang Xue and Liu Ting and Zhang Shumin and Ma Yupeng and Lai Jiahui and Zhang Zihan and Chi Yongbin},
journal = {Shanghai Jiaotong Daxue xuebao. Yixue ban},
year = {2026},
month = oct,
doi = {10.3969/j.issn.1674-8115.2026.10.005},
url = {https://doi.org/10.3969/j.issn.1674-8115.2026.10.005},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Fatostatin targets SCAP/SREBP pathway to inhibit ARID1A-deficient non-small cell lung cancer by promoting ferroptosis
AU - Chen Xinhong
AU - Zhang Xue
AU - Liu Ting
AU - Zhang Shumin
AU - Ma Yupeng
AU - Lai Jiahui
AU - Zhang Zihan
AU - Chi Yongbin
PY - 2026
DA - 2026/10/01
JO - Shanghai Jiaotong Daxue xuebao. Yixue ban
DO - 10.3969/j.issn.1674-8115.2026.10.005
UR - https://doi.org/10.3969/j.issn.1674-8115.2026.10.005
AB - Objective·To analyze the molecular mechanism by which AT-rich interaction domain 1A (ARID1A) deletion regulates lipid metabolism reprogramming in non-small cell lung cancer (NSCLC), and to explore the targeted therapeutic potential and mode of action of the SCAP/SREBP pathway inhibitor fatostatin.Methods·ARID1A wild-type (WT) and knockout (KO) A549 cell lines were constructed using CRISPR-Cas9 technology. Transcriptomic and proteomic analyses were combined to screen for differentially expressed genes and core pathways, and Western blotting was performed to verify the expression of key proteins, including HSP90B1 and SREBP1/2. Oil Red O staining was used to observe intracellular lipid droplet accumulation, and cholesterol and triglyceride quantification kits were used to assess lipid synthesis capacity. CCK-8, scratch wound healing, and Transwell invasion assays were used to evaluate the effects of different concentrations of fatostatin on the proliferation, migration, and invasion of cells in the two groups. JC-1 fluorescent probe was used to detect changes in mitochondrial membrane potential, and Western blotting was used to detect the expression of ferroptosis markers, including ACSL4, GPX4, and SLC7A11.Results·Western blotting showed that, compared with the WT group, the expression of HSP90B1, SREBP1, and SREBP2 proteins was upregulated in KO cells, whereas INSIG1 expression showed no significant change. Oil Red O staining and lipid quantification showed that lipid droplet accumulation and the levels of total cholesterol and triglycerides were higher in KO cells than in WT cells (all P<0.05). The CCK-8 assay showed that fatostatin inhibited the proliferation of cells in both groups in a concentration-dependent manner, and the half-maximal inhibitory concentration (IC50) in the KO group was significantly lower than that in the WT group (P<0.001). Scratch wound healing and Transwell assays showed that, after treatment with the same concentration of fatostatin, the reductions in wound closure rate and in the numbers of migrated and invaded cells were greater in the KO group than in the WT group(all P<0.05). JC-1 staining showed that fatostatin decreased the mitochondrial membrane potential in KO cells but had no significant effect in WT cells. Western blotting showed that ACSL4 expression was upregulated and GPX4 and SLC7A11 expression were downregulated in KO cells.Conclusion·The ARID1A/HSP90B1/SREBP axis is a key pathway regulating lipid metabolism reprogramming in ARID1A-deficient NSCLC. Fatostatin exerts selective anti-tumor effects by targeting this pathway to inhibit lipid synthesis and specifically induce ferroptosis in tumor cells.
SN - 1674-8115
ER -