TGFβ3-SMAD2/ETV4/CARM1 axis drives metastatic progression in Muscle-invasive Bladder Cancer via succinate metabolic rewiring

The mechanistic connection between intramuscular invasion and distant metastasis in muscle-invasive bladder cancer (MIBC) remains unclear. In this study, a TGFβ3 signaling pathway that drives metastatic progression by altering succinate metabolism was identified. Mechanistically, a SMAD3/4-independent TGFβ3 signaling cascade that promotes the formation of a SMAD2/ETV4/CARM1 transcriptional complex was discovered. This complex epigenetically activates sulfide quinone oxidoreductase (SQOR), leading to mitochondrial metabolic reprogramming and succinate accumulation. The accumulated succinate then acts as a powerful paracrine signal, activating succinate receptor (SUCNR1) on smooth muscle cells (SMCs) to coordinate stromal remodeling and vascular niche formation that supports metastasis. Additionally, structure-based virtual screening reveals L-chicoric acid as a specific inhibitor that disrupts the critical SMAD2-ETV4 interaction, thereby blocking the metabolic loop and inhibiting metastasis. These findings establish TGFβ3 as an essential mediator of metabolic flexibility, and highlight the TGFβ3/SMAD2/ETV4/succinate axis as a promising therapeutic target.