High throughput screening identifies sanguinarine chloride as a multi-faceted therapeutic agent for PRCC-TFE3 rRCC by targeting lactylation-driven VEGFB-VEGFR2 signaling and PMN-MDSC infiltration

INTRODUCTION: PRCC-TFE3 rearranged renal cell carcinoma (PRCC-TFE3 rRCC) is a highly malignant renal malignancy with limited therapeutic options, underscoring the urgent need for novel treatment strategies. OBJECTIVES: This study aimed to identify potential therapeutic compounds for PRCC-TFE3 rRCC through high-throughput screening and to elucidate the underlying oncogenic mechanisms that could be targeted. METHODS: A high-throughput screening of a 1,823-compound library was conducted using UOK120. Promising candidates were further evaluated in a C57BL/6J mouse model. Mechanistic insights were gained through integrated bioinformatic and functional analyses. RESULTS: Our investigation revealed a novel oncogenic pathway driven by the PRCC-TFE3 fusion, which directly enhances the transcription of key glycolytic enzymes to promote lactate accumulation and upregulates the lactyltransferase KAT6A, leading to increased histone H3 lysine 9 lactylation (H3K9la). This epigenetic modification enhanced VEGFB transcription, thereby activating the VEGF-VEGFR2 signaling axis. From the initial screening, sanguinarine chloride (SGC) was identified as a potent inhibitor of this pathway. SGC exerts a dual mechanism of action: it directly antagonizes VEGFR2 on the cell membrane to block VEGFB autocrine signaling, and it suppresses VEGFB transcription via ROS/p-STAT3 axis. Furthermore, SGC treatment effectively inhibited the infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) by reducing tumor-derived chemokine secretion, thereby reversing their pro-tumorigenic effects within the tumor microenvironment. CONCLUSION: This study uncovers a novel, lactylation-driven oncogenic pathway in PRCC-TFE3 rRCC through epigenetic activation of VEGFB-VEGFR2 signaling, and characterizes SGC as a promising therapeutic candidate that dually targets this pathway and modulates the tumor immune microenvironment.