Therapeutic Potential of STE20-Type Kinase STK25 Inhibition for the Prevention and Treatment of Metabolically Induced Hepatocellular Carcinoma

IF 7.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2025-01-01 DOI:10.1016/j.jcmgh.2025.101485

Ying Xia , Mara Caputo , Emma Andersson , Bernice Asiedu , Jingjing Zhang , Wei Hou , Manoj Amrutkar , Emmelie Cansby , Nadia Gul , Anne Gemmink , Caitlyn Myers , Mariam Aghajan , Sheri Booten , Andrew J. Hoy , Anetta Härtlova , Per Lindahl , Anders Ståhlberg , Gert Schaart , Matthijs K.C. Hesselink , Andreas Peter , Margit Mahlapuu

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Abstract

Background & Aims

Hepatocellular carcinoma (HCC) is a rapidly growing malignancy with high mortality. Recently, metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a major HCC catalyst; however, signals driving transition of MASH to HCC remain elusive and treatment options are limited. Herein, we investigated the role of STE20-type kinase STK25, a critical regulator of hepatocellular lipotoxic milieu and MASH susceptibility, in the initiation and progression of MASH-related HCC.

Methods

The clinical relevance of STK25 in HCC was assessed in publicly available datasets and by RT-qPCR and proximity ligation assay in a validation cohort. The functional significance of STK25 silencing in human hepatoma cells was evaluated in vitro and in a subcutaneous xenograft mouse model. The therapeutic potential of STK25 antagonism was examined in a mouse model of MASH-driven HCC, induced by a single diethylnitrosamine injection combined with a high-fat diet.

Results

Analysis of public databases and in-house cohorts revealed that STK25 expression in human liver biopsies positively correlated with HCC incidence and severity. The in vitro silencing of STK25 in human hepatoma cells suppressed proliferation, migration, and invasion with efficacy comparable to that achieved by anti-HCC drugs sorafenib or regorafenib. STK25 knockout in human hepatoma cells also blocked tumor formation and growth in a subcutaneous xenograft mouse model. Furthermore, pharmacologic inhibition of STK25 with antisense oligonucleotides—administered systemically or hepatocyte-specifically—efficiently mitigated the development and exacerbation of hepatocarcinogenesis in a mouse model of MASH-driven HCC.

Conclusion

This study underscores STK25 antagonism as a promising therapeutic strategy for the prevention and treatment of HCC in the context of MASH.

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抑制ste20型激酶STK25预防和治疗代谢性肝细胞癌的治疗潜力

背景与目的：肝细胞癌（HCC）是一种生长迅速、死亡率高的恶性肿瘤。最近，代谢功能障碍相关脂肪性肝炎（MASH）已成为HCC的主要催化剂；然而，推动MASH向HCC转变的信号仍然难以捉摸，治疗选择也有限。本文中，我们研究了ste20型激酶STK25（肝细胞脂毒性环境和MASH敏感性的关键调节因子）在MASH相关HCC的发生和进展中的作用。方法：通过公开可用的数据集以及在验证队列中通过RT-qPCR和邻近结扎试验评估STK25在HCC中的临床相关性。在体外和皮下异种移植小鼠模型中评估了STK25沉默在人肝癌细胞中的功能意义。通过单次二乙基亚硝胺注射联合高脂肪饮食诱导的小鼠肝细胞癌模型，研究了STK25拮抗剂的治疗潜力。结果：对公共数据库和内部队列的分析显示，人肝活检中STK25的表达与HCC的发病率和严重程度呈正相关。体外沉默STK25在人肝癌细胞中抑制增殖、迁移和侵袭，其疗效与抗hcc药物索拉非尼或瑞非尼相当。在皮下异种移植小鼠模型中，敲除人肝癌细胞中的STK25也能阻断肿瘤的形成和生长。此外，用反义寡核苷酸系统或肝细胞特异性给药抑制STK25有效地减轻了mash驱动型HCC小鼠模型中肝癌发生的发展和恶化。结论：本研究强调STK25拮抗剂是一种很有前景的治疗策略，可以预防和治疗MASH背景下的HCC。

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来源期刊

Cellular and Molecular Gastroenterology and Hepatology Medicine-Gastroenterology

CiteScore

13.00

自引率

2.80%

发文量

246

审稿时长

42 days

期刊介绍： "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.