HMGB1 orchestrates tumor-osteoclast crosstalk to drive bone metastasis in hepatocellular carcinoma.

IF 9.6 1区生物学 Q1 CELL BIOLOGY

Cell Death & Disease Pub Date : 2025-10-07 DOI:10.1038/s41419-025-08037-6

Yan-Zhu Chen, Di Xu, Ya-Xun Jia, Jie Ma, Zuo-Lin Xiang

{"title":"HMGB1 orchestrates tumor-osteoclast crosstalk to drive bone metastasis in hepatocellular carcinoma.","authors":"Yan-Zhu Chen, Di Xu, Ya-Xun Jia, Jie Ma, Zuo-Lin Xiang","doi":"10.1038/s41419-025-08037-6","DOIUrl":null,"url":null,"abstract":"<p><p>Bone metastasis in hepatocellular carcinoma (HCC) poses a significant clinical challenge, characterized by poor prognosis and severe skeletal complications. This study identifies the HMGB1/LCN2/JAK1/STAT3 axis as the central mechanism driving HCC bone metastasis through tumor-osteoclast crosstalk. High-mobility group box 1 (HMGB1) induces osteoclast activation and differentiation, promoting lipocalin-2 (LCN2) secretion by osteoclasts, which activates the JAK1/STAT3 pathway in HCC cells, forming a feedback loop that enhances osteolytic bone resorption and tumor dissemination. Integrated single-cell and bulk RNA sequencing reveal enriched osteoclast-related and pro-metastatic pathways in the tumor-bone microenvironment, while functional assays involving knockdown and overexpression demonstrate that modulating the HMGB1/LCN2/JAK1/STAT3 axis regulates osteoclast activity, tumor growth, and bone destruction in vitro and in vivo. These results suggest the HMGB1/LCN2/JAK1/STAT3 axis as a potential therapeutic target, offering a strategy to reduce skeletal damage and systemic tumor progression, thereby contributing to improved management of advanced HCC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"712"},"PeriodicalIF":9.6000,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504543/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death & Disease","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41419-025-08037-6","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Bone metastasis in hepatocellular carcinoma (HCC) poses a significant clinical challenge, characterized by poor prognosis and severe skeletal complications. This study identifies the HMGB1/LCN2/JAK1/STAT3 axis as the central mechanism driving HCC bone metastasis through tumor-osteoclast crosstalk. High-mobility group box 1 (HMGB1) induces osteoclast activation and differentiation, promoting lipocalin-2 (LCN2) secretion by osteoclasts, which activates the JAK1/STAT3 pathway in HCC cells, forming a feedback loop that enhances osteolytic bone resorption and tumor dissemination. Integrated single-cell and bulk RNA sequencing reveal enriched osteoclast-related and pro-metastatic pathways in the tumor-bone microenvironment, while functional assays involving knockdown and overexpression demonstrate that modulating the HMGB1/LCN2/JAK1/STAT3 axis regulates osteoclast activity, tumor growth, and bone destruction in vitro and in vivo. These results suggest the HMGB1/LCN2/JAK1/STAT3 axis as a potential therapeutic target, offering a strategy to reduce skeletal damage and systemic tumor progression, thereby contributing to improved management of advanced HCC.

查看原文本刊更多论文

HMGB1调控肿瘤-破骨细胞串扰，驱动肝癌骨转移。

肝细胞癌（HCC）骨转移是一项重大的临床挑战，其特点是预后差和严重的骨骼并发症。本研究确定HMGB1/LCN2/JAK1/STAT3轴是通过肿瘤-破骨细胞串扰驱动HCC骨转移的中心机制。高迁移率组框1 （HMGB1）诱导破骨细胞活化和分化，促进破骨细胞分泌脂载素-2 (LCN2)，激活HCC细胞中JAK1/STAT3通路，形成增强溶骨吸收和肿瘤扩散的反馈回路。整合的单细胞和大体积RNA测序揭示了肿瘤-骨微环境中丰富的破骨细胞相关和促转移途径，而涉及敲低和过表达的功能分析表明，调节HMGB1/LCN2/JAK1/STAT3轴在体外和体内调节破骨细胞活性、肿瘤生长和骨破坏。这些结果表明HMGB1/LCN2/JAK1/STAT3轴是一个潜在的治疗靶点，提供了一种减少骨骼损伤和全身肿瘤进展的策略，从而有助于改善晚期HCC的管理。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell Death & Disease CELL BIOLOGY-

CiteScore

15.10

自引率

2.20%

发文量

935

审稿时长

2 months

期刊介绍： Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism