DNA‐PKcs‐Driven YAP1 Phosphorylation and Nuclear Translocation: a Key Regulator of Ferroptosis in Hyperglycemia‐Induced Cardiac Dysfunction in Type 1 Diabetes

Abstract The DNA‐Dependent Protein Kinase catalytic subunit (DNA‐PKcs) acts as a principal executor in the DNA damage response (DDR), mediating the phosphorylation of a broad spectrum of substrates integral to DNA repair and apoptosis. This investigation seeks to discern the possible association and mechanisms linking hyperglycemia‐induced ferroptosis and DNA‐PKcs in DCM. This data exhibits a substantial activation of DNAPKcs‐ dependent DDR in mice with streptozotocin‐induced DCM. However, deletion of DNA‐PKcs in cardiomyocytes notably mitigates DNA damage, enhances heart function and dampens the inflammatory response. Co‐IP/MS analysis and subsequent validation experiments demonstrate that DNA‐PKcs directly interacts with and phosphorylates YAP1 at Thr226. This phosphorylation event facilitates the nuclear retention of YAP1, where it intensifies the transcription of ferroptosis‐associated genes. Knockin mice expressing a nonphosphorylatable T226A YAP1 mutant display decreased ferroptosis, reduced myocardial fibrosis and improved heart function. Taken together, this study unravels that DDR acts as an intracellular stress damage sensor, perceiving hyperglycemic conditions and subsequently transmitting the damage signal to incite ferroptosis through the interplay between DNA‐PKcs and YAP1. This novel insight suggests that the DNA‐PKcs‐mediated YAP1 phosphorylation and the ferroptosis activation could be the promising therapeutic targets for the management of DCM.