Abstract

Objective Macrophage ferroptosis plays a pivotal role in sepsis-induced acute lung injury (ALI). Tangeretin (TAN), derived from the traditional Chinese medicine Chen pi ( Citrus reticulata ), exhibits antiproliferative, anti-invasive, anti-metastatic, and antioxidant properties. This study investigated the protective effects of TAN against sepsis-induced macrophage ferroptosis in ALI and its underlying mechanism, while also exploring whether co-delivery via extracellular vesicle (EVs) could enhance its therapeutic efficacy. Materials and methods TAN's effects were evaluated in vivo using a cecal ligation and puncture (CLP)-induced sepsis mouse model and in vitro using lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Mechanistic insights were obtained through HE staining, MASSON staining, TUNEL staining, immunofluorescence, network pharmacology, molecular docking, transmission electron microscopy, qRT-PCR, and Western blotting. Results TAN and T-EV significantly ameliorated lung histopathology in CLP-mice, suppressed inflammatory cytokines, and attenuated interstitial fibrosis. T-EV demonstrated superior efficacy compared to TAN alone. Furthermore, TAN inhibited ferroptosis in both models. Bioinformatics and molecular docking identified Lipoxygenase-5 (ALOX5) as a potential target; TAN significantly inhibited ALOX5 expression and downregulated acyl coenzyme A synthase long-chain family member 4 (ACSL4) protein levels in CLP-induced ferroptosis. Conclusions TAN mitigates sepsis-induced ALI by inhibiting macrophage ferroptosis through the ALOX5/ACSL4 signaling pathway, and notably, co-delivery via EVs significantly potentiates its therapeutic efficacy.