Chrysin-loaded PLGA nanoparticle attenuates ferroptosis in lipopolysaccharide-induced indirect acute lung injury by upregulating Nrf2-dependent antioxidant responses

Chrysin (CHR) is the principal active compound in honey, propolis and plants. Its pharmacological effects include anti-inflammatory, antiallergic, and antioxidant capabilities. However, its poor solubility and bioavailability constitute a limitation. In this study, Poly-lactic-co-glycolic acid (PLGA) was used as a nanocarrier to enhance the stability, bioavailability, and effectiveness of CHR to protect mice from indirect acute lung injury (ALI) caused by lipopolysaccharide (LPS). CHR-loaded PLGA nanoparticle (CHR-NP) was prepared and characterized using techniques such as FTIR, zeta potential analysis, DLS, in vitro drug release assessment, encapsulation efficiency measurement, and TEM. Prior to the intraperitoneal injection of LPS (10 mg/kg), C57BL/6 mice were orally administered CHR (50 mg/kg), PLGA (50 mg/kg), CHR-NP (50 mg/kg), and dexamethasone (Dexa) (5 mg/kg) for a duration of six days. Following 24 h of LPS or normal saline (control) injection, the mice were anesthetized. CHR-NP increased catalase, glutathione, and glutathione peroxidase while decreasing malondialdehyde, myeloperoxidase, nitric oxide, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-12, and interferon (IFN)-γ. Moreover, treatment with CHR-NP augmented the gene and protein expression of the Keap1/Nrf2/ARE signaling pathway utilizing quantitative real-time PCR (RT-PCR), western blotting, and immunohistochemistry. Additionally, CHR-NP reduced histological alterations, pulmonary edema, damage, and iron deposition. Our findings indicate that CHR-NP significantly mitigated indirect ALI, possibly through the suppression of inflammation, oxidative stress, and ferroptosis via the activation of the Keap1/Nrf2/ARE signaling pathways.