Intestinal ischemia-reperfusion (I/R) injury is a critical condition associated with high mortality and morbidities. It commonly arises as a complication during cardiovascular and abdominal surgeries and also occurs following trauma, hemorrhagic shock and intestinal transplantation (Mallick et al., 2004, Grootjans et al., 2010). The pathogenesis of intestinal I/R injury begins with the interruption of blood flow to the intestines, which is paradoxically worsened upon reperfusion. During this phase a burst of proinflammatory cytokines and reactive oxygen species (ROS) damages local intestinal tissue and triggers distant inflammation, causing multiple organ failure (Harward et al., 1993).
Recent studies have identified ferroptosis as a lethal process trigger by intestinal I/R (Wang et al., 2024, Xu et al., 2021). Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation and the impairment of glutathione (GSH) antioxidant defense system (Yan et al., 2021). During intestinal I/R, ferrous iron overload due to transferrin dysfunction and cellular breakdown directly promote the production of reactive oxygen species (ROS) and induce lipid peroxidation (Huo et al., 2022). The accumulation of lipid peroxides damages cellular membrane, leading to cell death and intestinal injury (Gaschler and Stockwell, 2017). At the meantime, GSH loss and deactivation of GSH dependent antioxidant enzyme GPX4 amplify oxidative stress and ferroptosis (Wang et al., 2023). Notably, ferroptosis occurs earlier than the other forms of cell death, such as apoptosis, indicating its potential as an early intervention target (Li et al., 2019).
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor regulating cellular antioxidant response. Under normal condition, Nrf2 is retained in cytoplasm and constitutively degraded through ubiquitin-proteasome pathway. Upon stress stimuli, such as oxidative stress, Nrf2 is stabilized and translocates to nucleus to trigger the transcription of numerous antioxidant genes (Tonelli et al., 2018). Additionally, Nrf2 has been increasingly recognized for its role in preventing ferroptosis. Nrf2 promotes the transcription of ferritin subunits (e.g., FTH and FTL) to sequester excess free iron (He et al., 2020). It also regulates genes involved in GSH biosynthesis, such as SLC7A11, GCLC, GCLM and GSS, to increase GSH production and protect against iron-induced oxidative stress during ferroptosis (He et al., 2020). Recent study has revealed that, sevoflurane, a volatile anesthetic widely used in clinical practice, can activate Nrf2 and mitigate I/R-induced oxidative stress, inflammation and apoptosis in renal tissue (Wang et al., 2022). However, the specific anti-ferroptotic effect of Nrf2 in response to sevoflurane remains largely unexplored, especially in the context of intestinal I/R injury. In present study, we aim to elucidate the interplay between sevoflurane, Nrf2 and ferroptotic cell death during intestinal I/R. We believe that understanding these mechanisms will advance our knowledge of intestinal I/R injury pathogenesis and inform clinical treatment strategies and decision-making.
