SV2B Promotes the Progression of TFE3‐Rearranged Renal Cell Carcinoma by Interacting with HERC2 to Impede the Degradation of NF‐κB Subunits

TFE3-rearranged renal cell carcinoma (TFE3-RCC) represents an aggressive subtype of renal cancer characterized by a poor prognosis, yet lacking clearly defined diagnostic and therapeutic targets. Here, the study demonstrates that synaptic vesicle protein 2B (SV2B) is a potential diagnostic marker and therapeutic target for TFE3-RCC. SV2B, identified as a TFE3 target gene, is significantly upregulated in TFE3-RCC and displays high diagnostic accuracy for this subtype. Functionally, SV2B enhances the proliferation, migration, and invasion of TFE3-RCC cells. Mechanistically, SV2B competes with RELA/NFKB1 for binding to the E3 ligase HERC2, preventing their degradation and activating the NF-κB pathway. The drug padsevonil, targeting SV2B, selectively inhibits the growth of TFE3-RCC cells and organoids, similar to the NF-κB inhibitor Withaferin A. Clinically, RELA/NFKB1 expression positively correlates with SV2B levels but negatively with HERC2 expression, confirming the activation of TFE3-SV2B-NF-κB axis in TFE3-RCC. These findings establish SV2B as a novel diagnostic biomarker for TFE3-RCC and validate SV2B-NF-κB signaling as a therapeutic target, providing potential strategies for managing TFE3-RCC.