SSR2 Promotes Sorafenib Resistance Via Interacting with GPX4 to Inhibit Ferroptosis.

IF 2.8 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Current molecular medicine Pub Date : 2026-01-09 DOI:10.2174/0115665240405981251201125139

Zebing Song, Mengdan Zhou, Xiaodong Song, Hongyun Jia, Xuewei Yang

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引用次数: 0

Abstract

Aim & objectives: Sorafenib is a first-line drug for hepatocellular carcinoma (HCC). Understanding the regulatory mechanisms of sorafenib resistance is critical to inhibit sorafenib resistance and develop novel therapeutic strategies. Here, we aimed to study the role of SSR2 (signal sequence receptor subunit 2) in sorafenib resistance of HCC.

Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and cell viability assay were used to determine the role of SSR2 in sorafenib resistance of HCC. Co-immunoprecipitation (CoIP) was used to determine the interacting protein of SSR2.

Results: We found SSR2 was upregulated in sorafenib-resistant HCC tissues. In addition, in HCC patients, SSR2 was associated with both poor response to sorafenib and poor clinical outcomes. Functional assay showed that SSR2 promoted sorafenib resistance in HCC cells. Mechanistically, SSR2 suppressed ferroptosis. Further analysis showed that SSR2 interacted with ferroptosis master regulator glutathione peroxidase 4 (GPX4) and increased the catalytic activity of GPX4, leading to inhibition of ferroptosis. Induction of ferroptosis could reverse the promotion effect of SSR2 overexpression on sorafenib resistance.

Discussion: SRR2 plays a critical role in sorafenib resistance generation. However, the detailed mechanism of SRR2 increasing the catalytic activity of GPX4 will be further studied.

Conclusions: In summary, we reveal that SSR2 enhances sorafenib resistance of HCC via interacting with GPX4 and inhibiting ferroptosis, providing a potential target for HCC treatment. The molecular mechanism of GPX4-SSR2 interaction in ferroptosis will be further studied.

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SSR2通过与GPX4相互作用抑制铁下沉促进索拉非尼耐药性。

目的：索拉非尼是治疗肝细胞癌（HCC）的一线药物。了解索拉非尼耐药的调控机制对于抑制索拉非尼耐药和开发新的治疗策略至关重要。在这里，我们旨在研究SSR2（信号序列受体亚基2）在HCC索拉非尼耐药中的作用。方法：采用3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑（MTT）法、菌落形成法和细胞活力法检测SSR2在HCC索拉非尼耐药中的作用。采用共免疫沉淀法（CoIP）测定SSR2的相互作用蛋白。结果：我们发现SSR2在索拉非尼耐药的HCC组织中上调。此外，在HCC患者中，SSR2与索拉非尼不良反应和不良临床结果相关。功能分析显示，SSR2促进肝癌细胞索拉非尼耐药。机制上，SSR2抑制铁下垂。进一步分析表明，SSR2与铁下垂主调控因子谷胱甘肽过氧化物酶4 （glutathione peroxidase 4, GPX4）相互作用，提高GPX4的催化活性，从而抑制铁下垂。诱导铁下垂可逆转SSR2过表达对索拉非尼耐药的促进作用。讨论：SRR2在索拉非尼耐药产生中起关键作用。但SRR2提高GPX4催化活性的具体机理有待进一步研究。结论：综上所述，我们发现SSR2通过与GPX4相互作用和抑制铁上沉来增强HCC对索拉非尼的耐药性，为HCC治疗提供了一个潜在的靶点。GPX4-SSR2相互作用在铁下垂中的分子机制有待进一步研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current molecular medicine 医学-医学：研究与实验

CiteScore

5.00

自引率

4.00%

发文量

141

审稿时长

4-8 weeks

期刊介绍： Current Molecular Medicine is an interdisciplinary journal focused on providing the readership with current and comprehensive reviews/ mini-reviews, original research articles, short communications/letters and drug clinical trial studies on fundamental molecular mechanisms of disease pathogenesis, the development of molecular-diagnosis and/or novel approaches to rational treatment. The reviews should be of significant interest to basic researchers and clinical investigators in molecular medicine. Periodically the journal invites guest editors to devote an issue on a basic research area that shows promise to advance our understanding of the molecular mechanism(s) of a disease or has potential for clinical applications.