Inhibiting SSBP1 enhances ferroptosis and improves the effectiveness of sorafenib treatment for liver cancer

Sep 23, 2026

Liver cancer is a major cause of cancer-related death worldwide, and sorafenib—an effective first-line multi-kinase inhibitor—has limited benefit due to poor responsiveness, resistance, and adverse effects. Progression and metastasis correlate with altered mitochondrial metabolism, mitochondrial stress signaling, oxidative phosphorylation defects, and reactive oxygen species accumulation. Bioinformatics indicated that SSBP1 expression is markedly increased in liver cancer. Experimental assays showed that SSBP1 promoted proliferation and metastasis, while knockout impaired mitochondrial function, increased sorafenib sensitivity, and reduced tumor progression. Higher SSBP1 also predicted worse patient prognosis, supporting SSBP1 as a therapeutic target and biomarker.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

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Abstract

Introduction

INTERNATIONAL JOURNAL OF ONCOLOGY 67: 72, 2025 Inhibiting SSBP1 enhances ferroptosis and improves the effectiveness of sorafenib treatment for liver cancer SAI LI 1 , XINYU YANG 1 , HAOXUAN GAO 1 , XIUYA HU 1 , DANNI WANG 1 , QIQI ZHANG 1 , JUAN XU 1 , JIAQI ZHANG2 , LU ZHU 1,3 and ZIHAN WANG 1 1Department of Pharmacology, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co‑Sponsored Collaborative Innovation Center for Medical Epigenetics, National Health Commission Key Laboratory of Hormones and Development, Chu Hsien‑I Memorial Hospital and Tianjin Institute of Endocrinology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, P.R. China; 2Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, P.R. China; 3Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin 300070, P.R. China Received March 27, 2025; Accepted July 3, 2025 DOI: 10.3892/ijo.2025.5778 Abstract. Liver cancer is the third leading cause of cancer‑related mortality globally, with increasing morbidity and mortality rates. Sorafenib, a multi‑kinase inhibitor, is an effective first‑line therapy for late‑stage liver cancer. However, its effectiveness is hindered by low responsiveness, high drug resistance and significant side effects. The progression and metastasis of liver cancer are associated with alterations in mitochondrial metabolism, including mitochondrial stress responses and defects in oxidative phosphorylation, which are involved in the increased production of reactive oxygen species. Targeting mitochondrial biogenesis and bioenergetics presentsa promising therapeutic strategy. Bioinformatics analysis (inte‑ grated analysis of The Cancer Genome Atlas, mitochondrial genomes, liver cancer mouse models, and bioinformatics tools) revealed that the expression of single‑stranded DNA‑binding protein 1 (SSBP1) was significantly elevated in liver cancer. In addition, MTT and colony formation assays showed that increased SSBP1 expression notably enhanced cell prolifera‑ tion, while wound healing and Transwell assays demonstrated enhanced metastasis. Furthermore, flow cytometry, qPCR, Correspondence to: Dr Zihan Wang or Professor Lu Zhu, Department of Pharmacology, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co‑Sponsored Collaborative Innovation Center for Medical Epigenetics, National Health Commission Key Laboratory of Hormones and Development, Chu Hsien‑I Memorial Hospital and Tianjin Institute of Endocrinology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Heping, Tianjin 300070, P.R. China E‑mail: [zihanwang@tmu.edu.cn](zihanwang@tmu.edu.cn) E‑mail: [zhulu@tmu.edu.cn](zhulu@tmu.edu.cn) Key words: SSBP1, liver cancer, ferroptosis, sorafenib and western blotting indicated that SSBP1 knockout impaired mitochondrial function and increased sensitivity to sorafenib, effectively attenuating cancer progression. Clinical correla‑ tion analysis demonstrated that higher SSBP1 expression was associated with poorer prognosis in patients with liver cancer. In summary, the present study identified SSBP1 as a potential driver of tumor growth and a promising prognostic biomarker and therapeutic target in liver cancer, thus providing novel insight for improving patient outcomes. Introduction Liver cancer, the third leading cause of cancer‑associated death worldwide (1), with an estimated 865,269 new liver cancer cases and 757,948 related deaths occurring worldwide in 2022, poses a significant public health challenge, especially in China, where the 5‑year survival rate was 12.1% from 1990 to 2021 (2) . By 2040, liver cancer may result in ~1.3 million fatalities worldwide (3,4) . The pathogenesis of liver cancer is associated with chron

FAQs

Why is sorafenib treatment for liver cancer limited in effectiveness?

Sorafenib’s benefit is reduced by low responsiveness, high drug resistance, and significant side effects.

What does the study identify about SSBP1 in liver cancer?

Bioinformatics and experiments show that SSBP1 expression is significantly elevated and promotes tumor cell proliferation and metastasis.

How does SSBP1 knockout affect mitochondrial function and sorafenib sensitivity?

SSBP1 knockout impairs mitochondrial function and increases sensitivity to sorafenib, attenuating cancer progression.

Sep 23, 2026

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