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image of SSR2 Promotes Sorafenib Resistance Via Interacting with GPX4 to Inhibit Ferroptosis

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 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.

© 2026 Bentham Science Publishers
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2026-01-09
2026-01-30

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/content/journals/cmm/10.2174/0115665240405981251201125139
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SSR2 Promotes Sorafenib Resistance Via Interacting with GPX4 to Inhibit Ferroptosis
Bentham Science Publishers ; https://doi.org/10.2174/0115665240405981251201125139
/content/journals/cmm/10.2174/0115665240405981251201125139
/content/journals/cmm/10.2174/0115665240405981251201125139
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  • Article Type:     Research Article
Keywords: hepatocellular carcinoma ; sorafenib resistance ; ferroptosis ; HCC therapy ; GPX4 ; SSR2

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