• SPP1 is significantly elevated in sorafenib-resistant HCC and correlates with poor prognosis, vascular invasion, and advanced disease stage.
• SPP1 promotes sorafenib resistance by upregulating aerobic glycolysis in endothelial cells, leading to lactate production that activates BRAF/ERK and HIF-1α signaling in HCC cells.
• Silencing SPP1 inhibits proliferation and invasion of sorafenib-resistant HCC cells in vitro and in vivo, highlighting its potential as a therapeutic target.
• Lactate derived from endothelial cells plays a more dominant role than SPP1 itself in driving sorafenib resistance, suggesting the SPP1-aerobic glycolysis axis as a prognostic biomarker and therapeutic target.