نبذة مختصرة : Renal cell carcinoma is characterized by a poor prognosis. Recently, renal cell carcinoma has been recognized as a metabolic disease associated with fatty acid metabolic reprogramming, although in-depth studies on this topic are still lacking. We found that fatty acid metabolism reprogramming in renal cell carcinoma is primarily characterized by high expression of FABP1. FABP1 + tumors significantly impact survival and display distinct differentiation trajectories compared to other tumor subclusters. They show elevated expression of angiogenesis and cell migration signals, with PLG-PLAT-mediated interactions with endothelial cells notably enhanced. Spatial transcriptomics show a prominent co-localization of FABP1 + tumors with endothelial cells, and their spatial distribution closely aligns with that of PLAT + endothelial cells. FABP1 + tumors exhibit a unique pattern in spatial transcriptomics, enriched in Extracellular Matrix and angiogenesis-related pathways. Through receptor-ligand interaction analysis, a novel PLG-PLAT functional axis was found between tumor epithelial cells and endothelial cells. Based on results of experiments, we infer that FABP1 + tumors can promote plasmin-related tumor angiogenesis by triggering the PLG-PLAT signaling axis. Finally, utilizing preclinical models, we suggest that targeting the FABP1-PLG-PLAT axis may serve as promising strategy enhancing the sensitivity of Tyrosine Kinase Inhibitor therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-025-02377-9.
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