• SPP1 is significantly elevated in sorafenib-resistant HCC and correlates with poor prognosis.
• SPP1 promotes sorafenib resistance by upregulating aerobic glycolysis in endothelial cells, leading to lactate production.
• Lactate derived from HUVECs activates BRAF/ERK and HIF-1α signaling in HepG2 cells, conferring resistance.
• Silencing SPP1 inhibits proliferation and invasion of sorafenib-resistant HCC cells, suggesting a potential therapeutic target.