Delactylation of the tumor suppressor ARHGDIB drives metastasis and chemoresistance in bladder cancer.

Emerging evidence has highlighted lactylation as a critical link between metabolism and tumor progression. Through integrative lactylome and proteome profiling, we delineate the global landscape of protein lysine lactylation in bladder cancer, identifying lysine (K)47 and K50 of Rho guanosine diphosphate dissociation inhibitor β (ARHGDIB) as lactylation sites. Histone deacetylase (HDAC)2-mediated delactylation abrogates the tumor-suppressive function of ARHGDIB, promoting metastasis and cisplatin resistance of bladder cancer. Mechanistically, delactylation of ARHGDIB attenuates its binding affinity for Rac1, facilitating Rac1 membrane translocation and activation. This enhances DNA damage repair through the Rac1-MRN-ATM-CHK2 axis. Clinically, reduced ARHGDIB-K50 lactylation levels correlate with cisplatin resistance and poor prognosis. Entinostat, an inhibitor of class I HDAC, synergizes with cisplatin by preventing ARHGDIB delactylation. Collectively, our findings unveil a unique paradigm in which delactylation of tumor suppressors drives metastasis and chemoresistance. Targeting lactylation dynamics with HDAC inhibitors presents an avenue for intervention of bladder cancer.