Activation of aryl hydrocarbon receptor alleviates sepsis by promoting Nuclear Factor Erythroid 2-related Factor 2 expression to inhibit ferroptosis.

Background: Sepsis-induced acute kidney injury (AKI) is a major global public health challenge. Key pathogenic mechanisms include inflammatory responses and renal tubular epithelial cell damage. The aryl hydrocarbon receptor (AhR), a widely expressed protein receptor, has been reported to alleviate AKI upon activation; however, its precise mechanisms remain unclear.

Methods: Lipopolysaccharide (LPS) was used to establish sepsis-induced AKI models in vivo and in vitro. Protein expression was analyzed by western blotting, and histological staining was performed to assess tissue injury.

Results: AhR activation significantly attenuated LPS-induced AKI and reduced cell death following treatment with the AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ). Mechanistically, FICZ decreased renal accumulation of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and Fe²⁺, while upregulating glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression. Furthermore, FICZ promoted AhR nuclear translocation, which subsequently enhanced nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation and expression, ultimately mitigating LPS-induced cellular ferroptosis.

Conclusions: This study demonstrates that AhR activation enhances NRF2 nuclear translocation and expression, thereby upregulating GPX4 and SLC7A11. This mechanism reduces intracellular lipid peroxide accumulation and suppresses ferroptosis, providing potential therapeutic targets for AKI treatment and translational research.