Hyperoside attenuates sepsis-induced acute lung injury by Nrf2 activation and ferroptosis inhibition

Sepsis-induced acute lung injury (ALI) is a life-threatening condition associated with high morbidity and mortality rates in intensive care units (ICUs). Emerging evidence from clinical studies suggests that compounds derived from traditional Chinese medicine (TCM) have shown promising therapeutic effects in treating sepsis-induced ALI. Hyperoside is a bioactive compound extracted from TCM. Prior studies reported that hyperoside exhibits potent anti-inflammatory, antioxidant, and organ-protective properties, however, the underlying mechanisms of its effects on ALI remain unclear. Hyperoside pretreatment significantly reduced inflammation, iron accumulation, and lipid peroxidation in the pulmonary tissues of ALI mice induced by CLP and in LPS-stimulated MLE-12 cells. In particular, hyperoside preferentially binds with Keap1 at Arg380 and Arg415, thereby inhibiting the ubiquitin-mediated degradation of nuclear Nrf2, promoting its translocation to the nucleus, and leading to upregulation of anti-ferroptosis gene expression. Moreover, the protective effects of hyperoside were significantly abrogated after Nrf2 expression was silenced or its activity was inhibited by chemical inhibitors, highlighting that Nrf2 is critically involved in the impact of hyperoside. This study confirms that hyperoside exhibits a therapeutically protective effect against sepsis-induced ALI by inhibiting ferroptosis through Nrf2-mediated signaling pathway. Hyperoside acts as an Nrf2 activator by preferentially binding to Arg380 and Arg415 of Keap1 and disrupting the Keap1/Nrf2 interaction.