Coordination of SLC39A1 and DRP1 facilitates HCC recurrence by impairing mitochondrial quality control

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-06-03 DOI:10.1002/ctm2.70362

Rui Li, Zhe Wang, Lixin Cheng, Zhiqiang Cheng, Qiong Wu, Fengjuan Chen, Dong Ji, Qingxian Cai, Yijin Wang

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引用次数: 0

Abstract

Background

Despite rapid advances in HCC therapy, surgical resection is still the most effective treatment. However, postoperative relapse develops in a large population and the mechanism remains to be explored.

Methods

HCC resection samples were retrospectively collected from 12 nonrelapsed and 15 relapsed HCC patients for RNA sequencing. Liver-specific solute carrier family 39 member 1 (SLC39A1) knockout mice were generated by crossing Alb-Cre mice and SLC39A1^flox/flox mice. Liver samples were examined for inflammation, fibrosis, proliferation, and apoptosis. Mitochondrial mass, autophagy, ROS, and mitochondrial membrane potential (MMP), were detected. Co-immunoprecipitation and molecular docking were used to identify protein interactions.

Results

SLC39A1 is highly expressed in relapsed HCC patients and negatively correlated with overall survival. Knockdown of SLC39A1 inhibited cell proliferation by arresting the cell cycle and promoted cell apoptosis, accompanied by suppressing autophagic flux. Mechanistically, SLC39A1 interacts with a member of the dynamin superfamily of GTPases dynamin-related protein 1 (DRP1), followed by facilitating mitochondrial fission and MMP reduction. Inhibition of DRP1 abolished SLC39A1-induced mitochondrial division and MMP depolarization, while overexpression of DRP1 reversed mitochondrial fusion and MMP hyperpolarization in SLC39A1 silenced cells, accompanied by recuperative cell proliferative ability. SLC39A1^flox/flox,Alb-Cre mice displayed fewer tumour numbers and less liver damage compared with SLC39A1^flox/flox mice. A specific peptide targeting SLC39A1 to disturb the combination of full-length SLC39A1 and DRP1 efficiently suppressed HCC progression.

Conclusions

Our findings reveal a key role of SLC39A1-DRP1 interaction in HCC progression by disturbing mitochondrial quality control and providing a competitive peptide as a potential anti-tumour therapy.

Key points

SLC39A1 correlates with HCC recurrence and HCC mortality.
Interaction of SLC39A1 and DRP1 facilitates HCC by regulating mitochondrial quality control.
Specific peptide targeting SLC39A1 efficiently prevents HCC progression.

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SLC39A1和DRP1的协同作用通过损害线粒体质量控制促进HCC复发

背景尽管肝癌治疗进展迅速，手术切除仍是最有效的治疗方法。然而，术后复发发生在大量人群中，其机制仍有待探索。方法回顾性收集12例非复发和15例复发HCC患者肝细胞癌切除术标本，进行RNA测序。通过Alb-Cre小鼠与SLC39A1flox/flox小鼠杂交产生肝脏特异性溶质载体家族39成员1 （SLC39A1）敲除小鼠。检测肝脏样本的炎症、纤维化、增殖和凋亡。检测线粒体质量、自噬、活性氧和线粒体膜电位（MMP）。共免疫沉淀和分子对接用于鉴定蛋白质相互作用。结果SLC39A1在复发HCC患者中高表达，与总生存期呈负相关。SLC39A1基因的下调通过阻滞细胞周期和促进细胞凋亡抑制细胞增殖，同时抑制自噬通量。在机制上，SLC39A1与GTPases动力蛋白相关蛋白1 （DRP1）的动力蛋白超家族成员相互作用，随后促进线粒体裂变和MMP还原。抑制DRP1可消除SLC39A1诱导的线粒体分裂和MMP去极化，而过表达DRP1可逆转SLC39A1沉默细胞的线粒体融合和MMP超极化，同时恢复细胞增殖能力。SLC39A1flox/flox与SLC39A1flox/flox相比，Alb-Cre小鼠显示出更少的肿瘤数量和更少的肝损伤。靶向SLC39A1的特异性肽干扰全长SLC39A1和DRP1的结合，有效抑制HCC进展。我们的研究结果揭示了SLC39A1-DRP1相互作用通过干扰线粒体质量控制和提供竞争性肽作为潜在的抗肿瘤治疗在HCC进展中的关键作用。SLC39A1与HCC复发及死亡率相关。SLC39A1和DRP1的相互作用通过调节线粒体质量控制促进HCC。靶向SLC39A1的特异性肽有效阻止HCC进展。

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

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.