m6A reader YTHDF3 elicits hypertensive effects by degrading XRCC1 mRNA in the rostral ventrolateral medulla.

N6-methyladenosine (m6A) modification, mediated by its associated regulatory proteins, has been increasingly recognized for its involvement in diverse pathological conditions. The rostral ventrolateral medulla (RVLM), a key vasomotor center, plays a crucial role in regulating hypertension. However, alterations in m6A and associated regulators including YTHDF3 within the RVLM, along with their functional contributions to hypertension development, remain to be fully elucidated. Here, we identified that YTHDF3 levels were significantly higher in the RVLM of SHRs than in WKY rats. YTHDF3 knockdown in the RVLM of SHRs reduced neuronal excitability, sympathetic tone, and blood pressure (BP). Mechanistically, YTHDF3 promoted the degradation of XRCC1 mRNA in an m6A-dependent manner. YTHDF3 silencing increased XRCC1 expression, facilitating the repair of neuronal DNA oxidative damage and suppressing neuronal apoptosis in vitro and in vivo. These beneficial effects were abrogated by XRCC1 inhibition. Notably, XRCC1 downregulation significantly reversed the suppressive effects on RVLM neuronal excitability, sympathetic tone, and BP in SHRs caused by YTHDF3 repression. The study established, for the first time, the significance of YTHDF3 as a key regulatory factor in the neural regulation of hypertension. Targeting the YTHDF3-XRCC1 axis in the RVLM represents a promising therapeutic strategy for hypertension.