Scholarlink

<p>Osteosarcoma is an aggressive malignancy characterized by rapid proliferation and a propensity for metastasis. The endoplasmic reticulum (ER) chaperone GRP78, a critical regulator of osteosarcoma progression, represents a promising therapeutic target. In this study, we identified the natural compound ginkgetin (Gink) as a novel GRP78 inhibitor. Cellular thermal shift assays, surface plasmon resonance, and mutagenesis studies revealed that Gink directly binds to GRP78, with K296 serving as a key interaction site. In vitro, Gink suppressed osteosarcoma cell proliferation, migration, and invasion while inducing apoptosis and autophagy by activating the PERK-eIF2α-ATF4 pathway. Co-immunoprecipitation assays showed that Gink competitively disrupted GRP78-PERK interaction. In orthotopic and patient-derived xenograft models, Gink treatment markedly attenuated tumor growth and metastasis. Gink also reprogrammed the tumor immune microenvironment by reducing M2 macrophage polarization and synergizing with anti-PD1 therapy to enhance CD8<sup>+</sup> T-cell activity. Accordingly, Gink could be developed as a GRP78-targeting agent that triggers ER stress and immune activation, offering a dual-pronged therapeutic strategy against osteosarcoma.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Ginkgetin targets GRP78 to induce dual pathways of ER stress and immune activation in osteosarcoma

  • 期刊论文

  • 发表日期：

    2026年3月3日

查看全文
  • Wenyuan Xu,
  • Tongtong Liu,
  • Xinglong Ma,
  • He Dong,
  • Yinghao Cao,
  • Guanyi Li,
  • Zhuoying Wang,
  • Yingqi Hua,
  • Zhengdong Cai,
  • Mengxiong Sun,
  • Jingjie Li,
  • Tao Zhang

摘要

Osteosarcoma is an aggressive malignancy characterized by rapid proliferation and a propensity for metastasis. The endoplasmic reticulum (ER) chaperone GRP78, a critical regulator of osteosarcoma progression, represents a promising therapeutic target. In this study, we identified the natural compound ginkgetin (Gink) as a novel GRP78 inhibitor. Cellular thermal shift assays, surface plasmon resonance, and mutagenesis studies revealed that Gink directly binds to GRP78, with K296 serving as a key interaction site. In vitro, Gink suppressed osteosarcoma cell proliferation, migration, and invasion while inducing apoptosis and autophagy by activating the PERK-eIF2α-ATF4 pathway. Co-immunoprecipitation assays showed that Gink competitively disrupted GRP78-PERK interaction. In orthotopic and patient-derived xenograft models, Gink treatment markedly attenuated tumor growth and metastasis. Gink also reprogrammed the tumor immune microenvironment by reducing M2 macrophage polarization and synergizing with anti-PD1 therapy to enhance CD8+ T-cell activity. Accordingly, Gink could be developed as a GRP78-targeting agent that triggers ER stress and immune activation, offering a dual-pronged therapeutic strategy against osteosarcoma.