ZDHHC18-YTHDF2 axis suppresses USP13 to drive cardiac hypertrophy

Cardiac hypertrophy, a significant pathological response to various stressors, often culminates in heart failure and necessitates the identification of novel regulatory targets for developing effective therapeutic strategies. In our study, an integrated transcriptomic and proteomic analysis revealed that deubiquitinating enzyme 13 (USP13) was significantly downregulated during cardiac hypertrophy. Subsequent functional experiments confirmed that USP13 overexpression markedly ameliorated transverse aortic constriction-induced cardiac dysfunction and attenuated cardiomyocyte hypertrophy, indicating that USP13 functions as a potential suppressor of this pathological condition. Mechanistic studies demonstrated that USP13 bound to and deubiquitinated sorting nexin 13 (SNX13), thereby stabilizing the SNX13 protein. SNX13 promoted nuclear accumulation of Nrf2, upregulating key ferroptosis-related genes including SLC7A11 and GPX4, thereby attenuating ferroptosis and ameliorating cardiac hypertrophy. Additionally, the m6A reader YTHDF2 was found to bind m6A-modified USP13 mRNA, facilitating its degradation and subsequent reduction in USP13 expression. We also established that the palmitoyltransferase ZDHHC18 enhanced YTHDF2 stability by mediating YTHDF2 S-palmitoylation, specifically at Cys468. This study identifies a functional ZDHHC18/YTHDF2/USP13/SNX13/Nrf2/ferroptosis signaling axis in cardiac hypertrophy, highlighting its potential as a therapeutic target.