Succinate drives breast cancer bone metastasis by activating the HIF1α/YTHDF1/YAP signaling axis to upregulate chemokine CXCL5 and disrupt the bone microenvironment.

This study aimed to clarify how the metabolite succinate contributes to breast cancer (BC) bone metastasis by upregulating the chemokine CXCL5, mediated through the HIF1α/YTHDF1/YAP signaling pathway, ultimately altering the bone microenvironment. A murine bone metastasis model was established using 4T1 BC cells. Tumor progression and osteolysis were monitored via in vivo imaging (IVIS) and micro-computed tomography (micro-CT). Integrated metabolomics and RNA-seq analyses identified key alterations. The proposed signaling axis was validated using Western blot, RT-qPCR, Chromatin Immunoprecipitation (ChIP-qPCR), m6A RNA immunoprecipitation (MeRIP-qPCR), and luciferase reporter assays. Macrophage polarization was analyzed by flow cytometry. Functional impacts on bone cells were assessed using osteoblast mineralization and osteoclast tartrate-resistant acid phosphatase (TRAP) staining assays. Metabolomic profiling revealed significant succinate enrichment. Succinate activated HIF1α via its receptor SUCNR1. HIF1α transcriptionally upregulated YTHDF1, which subsequently stabilized YAP mRNA via an m6A-dependent mechanism. YAP directly bound to the CXCL5 promoter, enhancing its expression. In vitro, succinate-induced CXCL5 promoted tumor-associated macrophage (TAM) polarization, inhibited osteoblast function, and activated osteoclasts. In vivo, succinate-treated mice exhibited enhanced bone metastasis, severe osteolysis, elevated serum CTX-I, and reduced OCN levels. Succinate drives BC bone metastasis by activating the HIF1α/YTHDF1/YAP/CXCL5 axis, which reprograms the bone microenvironment. This study reveals a novel metabolic-inflammatory-bone niche interplay, identifying CXCL5 as a potential therapeutic target.