e20574 Background: Bone metastasis in non-small cell lung cancer (NSCLC) is associated with poor prognosis and immunosuppression, yet reliable biomarkers and therapeutic targets are lacking. YBX1, a transcription factor, may play a key role in bone metastasis progression. Methods: This study included 180 NSCLC patients without initial metastasis (2018–2020) and 80 patients with bone metastasis at diagnosis. YBX1 expression was evaluated by immunohistochemistry. Functional experiments were conducted using high-metastatic NSCLC cell lines and mouse models. A small-molecule library was screened to identify YBX1-targeting compounds. Statistical analysis employed Kaplan–Meier, Cox regression, and t-tests. Results: Among the 180 follow-up patients, 38 developed bone metastasis. YBX1 expression was significantly higher in bone metastasis cases (p<0.001) and independently predicted metastasis risk (HR=2.91, 95% CI 1.45–5.71, p<0.01). High YBX1 correlated with elevated serum IL-6 and CCL5 and poorer survival. Mechanistically, YBX1 promoted osteoclast activation and Treg recruitment via IL-6/CCL5. The compound Icaritin enhanced YBX1 O-GlcNAcylation at T271, promoted its mitochondrial translocation and degradation, and suppressed bone metastasis in mouse models. Combining Icaritin with anti-PD-1 therapy enhanced CD8⁺ T-cell infiltration and reduced Treg accumulation. Conclusions: YBX1 is a promising prognostic biomarker and therapeutic target in NSCLC bone metastasis. Its upregulation drives immunosuppression and osteolytic progression, while targeting YBX1 glycosylation with Icaritin inhibits metastasis and synergizes with immunotherapy.
Wang et al. (2026) studied this question.