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. Here, NFKB1 is linked to renal cell carcinoma.