Ethanol extract of Rosa rugosa improves cisplatin-induced nephrotoxicity by promoting Hint1-mediated upregulation of Nrf2 and subsequent suppression of intrarenal ferroptosis

Roses (flowers of Rosa rugosa ) constitute a food with a wide range of biological activities. Nephrotoxicity limits the clinical application of cisplatin (CDDP). This study was designed to understand protective effects and mechanisms of ethanol extract of flower buds of Rosa rugosa (ERS) against cisplatin-induced nephrotoxicity. We found that ERS alleviated CDDP-induced kidney injury and fibrosis in both Kunming (KM) and C57 mice. Transcriptomic analysis revealed that ERS modulated renal ferroptosis and Nrf2 pathways and elevated Hint1. Consistently, in kidneys of KM and C57 mice, ERS elevated Hint1 and Nrf2 and inhibited CDDP-induced oxidative stress and ferroptosis. Moreover, ERS ameliorated CDDP-induced ferroptosis in HK2 kidney cells in vitro. In these cells, ERS increased Hint1 and potentiated Nrf2 signaling. Inhibition of Nrf2 abrogated renoprotective effects of ERS without affecting ERS-mediated upregulation of Hint1. Knockdown of Hint1 blocked ERS-mediated Nrf2 activation. Overexpression of Hint1 suppressed CDDP-induced ferroptosis in HK2 cells. Hint1 bound to the 500-base-pair region upstream of the transcription start site of Nrf2 encoding gene and promoted its expression. Finally, we unveiled that knockdown of Hint1 in mice abolished ERS-mediated renoprotection against CDDP. Our findings identified Hint1 as a new positive regulator of the expression of Nrf2 and revealed that ERS reduces intracellular oxidative stress and suppresses CDDP-provoked ferroptosis of nephrocytes via potentiating the Hint1/Nrf2 axis.