法托他汀通过靶向SCAP/SREBP通路促进铁死亡及抑制ARID1A缺失型非小细胞肺癌

doi:10.3969/j.issn.1674-8115.2026.10.005

上海交通大学学报（医学版） ›› 2026, Vol. 46 ›› Issue (10): 1355-1365.doi: 10.3969/j.issn.1674-8115.2026.10.005

• 论著 · 基础研究 • 上一篇

法托他汀通过靶向SCAP/SREBP通路促进铁死亡及抑制ARID1A缺失型非小细胞肺癌

陈鑫鸿¹, 张雪², 刘婷², 张淑敏³, 马雨鹏¹, 来佳辉¹, 章子晗¹, 池永斌²()

^1.上海理工大学附属公利医院医学技术学院，上海 200093
^2.上海市浦东新区公利医院中心实验室，上海市卫生健康委员会炎症与慢性病人工智能管理重点实验室，上海 200135
^3.宁夏医科大学基础医学院，银川 750004

收稿日期:2026-01-29 接受日期:2026-04-28 出版日期:2026-10-28 发布日期:2026-10-28
通讯作者: 池永斌，主任技师，博士；电子信箱:chiyb1@hotmail.com。
基金资助:
上海市浦东新区科技创新项目(PKJ2025Y-17);上海市浦东新区卫生健康委员会卫生科技研究基金(PW2023A-19)

Fatostatin targets SCAP/SREBP pathway to inhibit ARID1A-deficient non-small cell lung cancer by promoting ferroptosis

Chen Xinhong¹, Zhang Xue², Liu Ting², Zhang Shumin³, Ma Yupeng¹, Lai Jiahui¹, Zhang Zihan¹, Chi Yongbin²()

^1.School of Gongli Hospital Medical Technology, University of Shanghai for Science and Technology, Shanghai 200093, China
^2.Shanghai 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
^3.Ningxia Medical University School of Basic Medical Sciences, Yinchuan, 750004, China

Received:2026-01-29 Accepted:2026-04-28 Online:2026-10-28 Published:2026-10-28
Contact: Chi Yongbin, E-mail: chiyb1@hotmail.com.
Supported by:
Shanghai Pudong New District Science and Technology Innovation Project(PKJ2025Y-17);Research Grant for Health Science and Technology of the Pudong Health Bureau of Shanghai(PW2023A-19)

摘要/Abstract

摘要：

目的·分析富含AT相互作用域1A（AT-rich interaction domain 1A，ARID1A）缺失调控非小细胞肺癌（non-small cell lung cancer，NSCLC）脂质代谢重编程的分子机制，探讨甾醇调节元件结合蛋白激活蛋白（SCAP）/甾醇调节元件结合蛋白（SREBP）通路抑制剂法托他汀的靶向治疗潜力及作用模式。方法·采用CRISPR-Cas9技术构建ARID1A野生型（WT组）、敲除型（KO组）A549细胞系。结合转录组学与蛋白质组学联合分析筛选差异表达基因及核心通路，蛋白质印迹法验证热休克蛋白90B1（HSP90B1）、SREBP1/2等关键蛋白的表达水平，油红O染色观察细胞内脂质滴积累，胆固醇及甘油三酯定量试剂盒检测脂质合成能力，CCK-8法、划痕愈合实验及Transwell侵袭实验评估不同浓度法托他汀对2组细胞增殖、迁移及侵袭能力的影响，JC-1荧光探针检测线粒体膜电位变化，蛋白质印迹法检测铁死亡标志物ACSL4、GPX4及SLC7A11的表达。结果·蛋白质印迹法实验结果显示，与WT组比较，KO组细胞HSP90B1及SREBP1、SREBP2蛋白表达上调，INSIG1蛋白表达无明显变化。油红O染色及脂质定量分析结果显示，KO组细胞脂质滴积累、总胆固醇及甘油三酯含量均高于WT组（均P<0.05）。CCK-8实验结果显示，法托他汀呈浓度依赖性抑制2组细胞增殖，KO组细胞半数抑制浓度（IC₅₀）低于WT组，差异有统计学意义（P<0.001）。划痕愈合及Transwell实验结果显示，经相同浓度法托他汀处理后，KO组细胞划痕闭合率及迁移、侵袭细胞数的下降幅度均大于WT组（均P<0.05）。JC-1染色结果显示，法托他汀处理后KO组细胞线粒体膜电位显著降低，而WT组无明显变化。蛋白质印迹法实验结果显示，KO组细胞ACSL4表达上调，GPX4及SLC7A11表达下调。结论·ARID1A/HSP90B1/SREBP轴是调控ARID1A缺失型NSCLC脂质代谢重编程的关键通路；法托他汀通过靶向该通路抑制脂质合成，并特异性诱导肿瘤细胞铁死亡，发挥选择性抗肿瘤效应。

关键词: 富含AT相互作用域1A（ARID1A）, 甾醇调节元件结合蛋白（SREBP）, 热休克蛋白90B1（HSP90B1）, 法托他汀, 铁死亡, 非小细胞肺癌

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.

Key words: AT-rich interaction domain 1A (ARID1A), sterol regulatory element-binding protein (SREBP), heat shock protein 90 beta family member 1 (HSP90B1), fatostatin, ferroptosis, non-small cell lung cancer

中图分类号:

R734.2

陈鑫鸿, 张雪, 刘婷, 张淑敏, 马雨鹏, 来佳辉, 章子晗, 池永斌. 法托他汀通过靶向SCAP/SREBP通路促进铁死亡及抑制ARID1A缺失型非小细胞肺癌[J]. 上海交通大学学报（医学版）, 2026, 46(10): 1355-1365.

Chen Xinhong, Zhang Xue, Liu Ting, Zhang Shumin, Ma Yupeng, Lai Jiahui, Zhang Zihan, Chi Yongbin. Fatostatin targets SCAP/SREBP pathway to inhibit ARID1A-deficient non-small cell lung cancer by promoting ferroptosis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026,(10): 1355-1365.

图/表 4

图1 ARID1A缺失对NSCLC 细胞脂质和胆固醇合成的影响Note： A. Efficient knockout of ARID1A protein in A549 cells confirmed by Western blotting. B.Quantification of ARID1A protein expression in the KO group and WT group. C. GO enrichment analysis for the joint functional annotation of transcriptomic and proteomic data. D. KEGG pathway enrichment analysis of DEGs identified in the transcriptomic dataset. E.Volcano plot depicting differential gene expression between the WT group and KO group. F. KEGG pathway enrichment analysis of differentially expressed proteins identified in the proteomic dataset. G. Volcano plot depicting differential protein expression between the WT group and KO group.

Fig 1 Effect of ARID1A loss on lipid and cholesterol synthesis in NSCLC cells

图2 ARID1A缺失对NSCLC细胞脂质、胆固醇合成及HSP90B1表达的影响Note： A. GSEA of the cholesterol homeostasis and fatty acid metabolism pathways. B/C. Neutral lipid droplet accumulation by Oil Red O staining (B) and quantification (C) in the WT and KO groups. D. Comparison of TCHO levels between the WT and KO groups. E. Comparison of TG levels between the WT and KO groups. F. Box plots of the HSP90B1 and INSIG1 mRNA levels from transcriptome sequencing data. G. Western blotting analysis of SREBP1, SREBP2, HSP90B1, and INSIG1 expression in the WT and KO groups. H. Densitometric quantification of SREBP1, SREBP2, and HSP90B1 protein levels. I/J. Lipid droplet accumulation in ARID1A-KO cells after 17-AAG treatment by Oil Red O staining (I) and quantification (J). K/L. TCHO (K) and TG (L) levels in ARID1A-KO cells after 17-AAG treatment. M/N. Western blotting analysis of SREBP1/2 expression in ARID1A-KO cells after 17-AAG treatment (M) and densitometric quantification (N).

Fig 2 Effects of ARID1Aloss on lipid and cholesterol synthesis and HSP90B1 expression in NSCLC cells

图3 ARID1A缺失的NSCLC细胞对法托他汀敏感性的变化Note： A. Dose-response curves of fatostatin in WT and ARID1A-KO A549 cells. B/C. Neutral lipid droplets in the WT and KO groups after fatostatin treatment (5 or 10 μmol·L-1, 24 h) by Oil Red O staining (B) and quantification of Oil Red O-positive area (C). D. TCHO levels after 24 h of fatostatin treatment.E. TG levels after 24 h of fatostatin treatment.F. Scratch wound healing assay of WT and ARID1A-KO cells treated with DMSO or fatostatin (5 or 10 μmol·L-1) for 24 h. G.Quantification of wound closure rate. H. Transwell migration and invasion assays after 24 h of fatostatin treatment. I. Quantification of migrated and invaded cells.

Fig 3 Changes in the sensitivity of ARID1A-deficient NSCLC cells to fatostatin

图4 法托他汀对 ARID1A 敲除NSCLC细胞铁死亡的诱导作用Note： A. KEGG enrichment map of cell growth- and death-related pathways between ARID1A-KO and WT A549 cells. B. Viability of ARID1A-KO cells treated with fatostatin (10 μmol·L-1, 24 h) with or without deferoxamine (DFO, 100 μmol·L-1, 2 h) pretreatment. C/D. Western blotting analysis of ferroptosis markers after fatostatin treatment (10 μmol·L-1, 24 h) (C) and densitometric quantification (D). E/F. Representative JC-1 staining images (E) and red/green fluorescence intensity ratios (F) of mitochondrial membrane potential in A549 WT cells after fatostatin treatment. G/H. Representative JC-1 staining images (G) and red/green fluorescence intensity ratios (H) in ARID1A-KO A549 cells after fatostatin treatment. CCCP—carbonyl cyanide m-chlorophenylhydrazone.

Fig 4 Fatostatin-induced ferroptosis in ARID1A-knockout NSCLC cells

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法托他汀通过靶向SCAP/SREBP通路促进铁死亡及抑制ARID1A缺失型非小细胞肺癌

Fatostatin targets SCAP/SREBP pathway to inhibit ARID1A-deficient non-small cell lung cancer by promoting ferroptosis

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