DIXDC1 Promotes Lymphatic Metastasis and Resistance to Cuproptosis in Bladder Cancer Through Mediating DLAT.

Lymph node metastasis (LN) represents a major clinical challenge in bladder cancer (BCa) and is associated with dismal prognosis; however, the underlying molecular drivers remain incompletely understood. Here, we demonstrate that DIX domain-containing protein 1 (DIXDC1) is significantly upregulated in LN-metastatic BCa tissues and is associated with unfavorable clinical outcomes. Functionally, DIXDC1 enhances BCa cell migration, invasion, proliferation, and lymph node dissemination in vivo. Mechanistically, DIXDC1 directly binds to dihydrolipoamide S-acetyltransferase (DLAT), a key enzyme in the tricarboxylic acid cycle and a central effector of cuproptosis. This interaction impedes ubiquitin-proteasome-mediated degradation of DLAT, thereby stabilizing DLAT protein levels. Through a DLAT-dependent pathway, DIXDC1 further augments the mRNA stability of the oncogenes NEK7 and CCNE2, fueling tumor progression. Importantly, DIXDC1 shields BCa cells from copper-induced DLAT oligomerization and confers marked resistance to Elesclomol-Cu (ES-Cu)-triggered cuproptosis. Depletion of DIXDC1 profoundly sensitizes tumors to cuproptosis in vivo. Collectively, our study unveils the DIXDC1-DLAT axis as a pivotal regulator that coordinately drives metastatic progression and suppresses copper-induced cell death, offering a promising therapeutic target for advanced BCa.