TAOK1-mediated regulation of the YAP/TEAD pathway as a potential therapeutic target in heart failure

Background: This study aimed to explore the roles of interleukin-17 (IL-17), TAO kinase 1 (TAOK1), and NOD-like receptor protein 3 (NLRP3) in cardiomyocyte pyroptosis and proliferation.

Methods: IL-17-treated H9C2 cells were used as an *in vitro* model of heart failure (HF). These cells underwent TAOK1 overexpression or knockdown and were treated with various modulators: BMS-986299 (an NLRP3 inflammasome agonist), MCC950 (an NLRP3 inflammasome inhibitor), and verteporfin (a Yes-associated protein [YAP] inhibitor). Pyroptosis, proliferative capacity, and gene and protein expression were assessed. Additionally, doxorubicin-induced HF rats were used as *in vivo* models, with TAOK1 overexpression applied to evaluate myocardial pathology, NLRP3-mediated pyroptosis, and YAP/TEAD pathway function.

Results: IL-17 treatment enhanced pyroptosis and suppressed the proliferation of H9C2 cells. It also activated NLRP3 inflammasomes and inhibited the YAP/TEAD pathway. The effects of IL-17 were attenuated by TAOK1 overexpression and exacerbated by TAOK1 knockdown. Moreover, BMS-986299 or verteporfin altered pyroptosis, proliferation, and NLRP3 inflammasome activity independently of TAOK1 expression. In the doxorubicin-induced HF rat model, TAOK1 YAP-TEAD Inhibitor 1 overexpression reduced myocardial damage, inhibited NLRP3 inflammasome activation, and restored YAP/TEAD pathway activity.

Conclusion: TAOK1 plays a key regulatory role in IL-17-mediated pyroptosis and impaired cardiomyocyte proliferation by modulating NLRP3 inflammasome activation and YAP/TEAD pathway activity.