While KRAS mutation is the leading cause of low survival rates in lung cancer bone metastasis patients, effective treatments are still lacking. Here, we identified homeobox C10 (HOXC10) as a lynchpin in pan-KRAS-mutant lung cancer bone metastasis. Through RNA-seq approach and patient tissue studies, we demonstrated that HOXC10 expression was dramatically increased. Genetic depletion of HOXC10 preferentially impeded cell proliferation and migration in vitro. The bioluminescence imaging and micro-CT results demonstrated that inhibition of HOXC10 significantly reduced bone metastasis of KRAS-mutant lung cancer in vivo. Mechanistically, the transcription factor HOXC10 activated NOD1/ERK signaling pathway to reprogram epithelial-mesenchymal transition (EMT) and bone microenvironment by activating the NOD1 promoter. Strikingly, inhibition of HOXC10 in combination with STAT3 inhibitor was effective against KRAS-mutant lung cancer bone metastasis by triggering ferroptosis. Taken together, these findings reveal that HOXC10 effectively alleviates pan-KRAS-mutant lung cancer with bone metastasis in the NOD1/ERK axis-dependent manner, and support further development of an effective combinatorial strategy for this kind of disease.

虽然 KRAS 突变是肺癌骨转移患者生存率低的主要原因，但仍然缺乏有效的治疗方法。在这里，我们确定同源框 C10 （HOXC10） 是泛 KRAS 突变肺癌骨转移的关键。通过 RNA-seq 方法和患者组织研究，我们证明 HOXC10 表达显着增加。HOXC10 的基因耗竭优先阻碍了体外细胞的增殖和迁移。生物发光成像和显微 CT 结果表明，抑制 HOXC10 可显着减少体内 KRAS 突变肺癌的骨转移。从机制上讲，转录因子 HOXC10 通过激活 NOD1 启动子激活 NOD1/ERK 信号通路，以重编程上皮-间充质转化 （EMT） 和骨微环境。引人注目的是，抑制 HOXC10 联合 STAT3 抑制剂通过触发铁死亡对 KRAS 突变肺癌骨转移有效。综上所述，这些发现揭示了 HOXC10 以 NOD1/ERK 轴依赖性方式有效缓解骨转移的泛 KRAS 突变肺癌，并支持进一步开发针对此类疾病的有效组合策略。