Clinical and translational study of YBX1 as a biomarker and therapeutic target in bone metastasis of non–small cell lung cancer.

Abstract

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.