YAP1 lactylation drives cisplatin resistance in bladder cancer by suppressing ferroptosis via FOSL1

Effective systemic treatment for advanced bladder cancer is severely hampered by cisplatin-based chemotherapy resistance, necessitating novel predictive biomarkers and therapeutic targets. Current approaches often fail due to complex resistance mechanisms, leaving patients with limited options. Understanding post-translational modifications that drive chemoresistance, such as lactylation, could unlock new strategies to overcome this critical therapeutic gap and improve patient outcomes.

Researchers identified YAP1-K90la as a functional post-translational modification causally linked to cisplatin resistance. They analyzed multi-center clinical cohorts to correlate YAP1-K90la levels with therapeutic outcomes and cisplatin responsiveness. Mechanistic studies investigated how YAP1-K90la influences YAP1 nuclear localization and transcriptional activity, focusing on its impact on ferroptosis and cell survival under cisplatin stress. They also identified AARS1 as the 'writer' and SIRT1 as the 'eraser' of YAP1-K90la, with SMURF2-mediated ubiquitination of SIRT1 stabilizing the modification. Finally, a cell-penetrating peptide was used to target YAP1-K90la in bladder cancer cells.

Elevated YAP1-K90la levels were consistently associated with poor therapeutic outcomes in multi-center clinical cohorts, outperforming total YAP1 expression in predicting cisplatin responsiveness. Mechanistically, YAP1-K90la significantly enhanced YAP1 nuclear localization and transcriptional activity. This activation induced a FOSL1-dependent gene program that actively suppressed ferroptosis, thereby promoting bladder cancer cell survival under cisplatin-induced stress. The study further elucidated the regulatory enzymes: AARS1 functions as the 'writer' of YAP1-K90la, while SIRT1 acts as its 'eraser'. Crucially, SMURF2-mediated ubiquitination of SIRT1 was found to stabilize YAP1-K90la, directly driving cisplatin resistance.

Targeting YAP1-K90la using a cell-penetrating peptide successfully restored ferroptotic vulnerability and sensitized bladder cancer cells to cisplatin.