YAP1 lactylation confers cisplatin resistance and prognostic value by suppressing ferroptosis via FOSL1 in bladder cancer.

Resistance to cisplatin-based chemotherapy remains a major barrier to effective systemic treatment of bladder cancer, underscoring the need for predictive biomarkers and therapeutic targets. Here, we identify YAP1-K90la as a functional post-translational modification that causally drives cisplatin resistance. Across multi-center clinical cohorts, elevated YAP1-K90la levels were associated with poor therapeutic outcomes and outperformed total YAP1 expression in predicting cisplatin responsiveness. Mechanistically, YAP1-K90la enhances YAP1 nuclear localization and transcriptional activity to induce a FOSL1-dependent program that suppresses ferroptosis and promotes cell survival under cisplatin stress. Notably, AARS1 and SIRT1 function as the "writer" and "eraser" of YAP1-K90la, respectively, with SMURF2-mediated ubiquitination of SIRT1 stabilizing YAP1-K90la and driving resistance. Targeting YAP1-K90la using a cell-penetrating peptide restored ferroptotic vulnerability and sensitized bladder cancer cells to cisplatin. Collectively, these findings reveal the YAP1-K90la/FOSL1 pathway that drives cisplatin resistance and position YAP1-K90la as a clinically actionable biomarker and therapeutic target in bladder cancer.