SH3GL1-activated FTH1 inhibits ferroptosis and confers doxorubicin resistance in diffuse large B-cell lymphoma

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-03-04 DOI:10.1002/ctm2.70246

Zi-Wen Duan, Wei-Ting Wang, Yan Wang, Rong Wang, Wei Hua, Chun-Yu Shang, Rui Gao, Hao-Rui Shen, Yue Li, Jia-Zhu Wu, Hua Yin, Li Wang, Jian-Yong Li, Wei Xu, Jin-Hua Liang

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引用次数: 0

Abstract

Background

Diffuse large B-cell lymphoma (DLBCL) is predominant subtype of non-Hodgkin lymphoma and can be effectively treated. Nevertheless, a subset of patients experiences refractory or relapsed disease, highlighting the need for new therapeutic strategies.

Methods

Depmap database based on CRISPR/Cas9 knock out analysis was employed to identify the essential gene SH3GL1, which encodes endophilin A2, as crucial for the proliferation and survival of DLBCL cells. Immunohistochemistry (IHC) staining was performed on the 126 paraffin-embedded clinical DLBCL samples to investigate the association between SH3GL1 expression levels and the prognosis. To investigate the specific mechanism modulated by SH3GL1 in the progression of DLBCL, an integrative approach was employed. This approach combined high-throughput sequencing technologies, such as Deep-DIA and LC-MS, with functional validation techniques, including CRISPR/Cas9 gene editing, xenograft models, and molecular pathway analyses.

Results

Our study found that high expression levels of SH3GL1 correlate with poor prognosis in a cohort of 126 newly diagnosed DLBCL patients, underscoring its significance in disease progression. Mechanistically, we found that SH3GL1 deficiency triggers ferritin heavy chain 1 (FTH1)-mediated ferroptosis, specifically ferritinophagy-induced ferroptosis, in DLBCL cells. Additionally, high expression of SH3GL1 suppresses doxorubicin-induced ferroptosis. Cancer cells' resistance to conventional therapies is associated with increased sensitivity to ferroptosis.

Conclusions

These findings emphasise SH3GL1 as a promising prognostic biomarker and a potential therapeutic target in DLBCL, offering new avenues for treatment strategies aimed at overcoming drug resistance and improving patients' outcomes.

Key points

Elevated SH3GL1 expression in DLBCL patients was associated with a negative prognosis.
SH3GL1 plays a crucial role in promoting DLBCL cell survival through the regulation of FTH1-mediated ferroptosis and doxorubicin resistance.

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.