Garcinol Protects Against Allergic Asthma by Suppressing Ferroptosis via the SIRT1/PPARα Signaling Pathway

Background: Allergic asthma is a chronic inflammatory disorder of the airways, marked by airway hyperresponsiveness, overproduction of mucus, and structural alterations within the airway wall. Garcinol is a natural compound extracted from plants of the Garcinia genus and exhibits antitumor effects. This study aims to investigate the protective effects and underlying mechanisms of garcinol against asthma-induced lung injury in both in vivo and in vitro models, focusing on the role of ferroptosis. Methods: An asthma mouse model was established by ovalbumin (OVA) sensitization, followed by treatment with garcinol or budesonide. Airway hyperresponsiveness was assessed, and bronchoalveolar lavage fluid (BALF) was collected for cell counts and inflammatory cytokine measurements. Lung tissues were harvested for histopathological staining. E-cadherin and Claudin-1 were examined using Western blot analysis to evaluate pathological alterations. Solute carrier family 7 member 11 (SLC7A11), ferroptosis suppressor protein 1 (FSP1), glutathione peroxidase 4 (GPX4), transferrin receptor 1 (TFR1), glutathione (GSH), malondialdehyde (MDA), iron content, and reactive oxygen species (ROS) levels were determined. Sirtuin 1 (SIRT1) and peroxisome proliferator–activated receptor alpha (PPARα) expression in lung tissues was analyzed. In vitro, human bronchial epithelial cells (BEAS-2B) were stimulated with interleukin-13 (IL-13) to establish a cellular asthma model and treated with garcinol, a ferroptosis inhibitor, or a SIRT1 inhibitor. Results: Garcinol significantly alleviated airway hyperresponsiveness, attenuated the recruitment of inflammatory cells, and decreased cytokine concentrations in BALF. It attenuated lung tissue injury in the asthma mouse model. Garcinol markedly downregulated TFR1 expression while upregulating SLC7A11, GPX4, and FSP1. Garcinol decreased ROS and MDA levels and increased GSH content, thereby inhibiting ferroptosis. Garcinol also activated the SIRT1/PPARα signaling in lung tissues. In vitro experiments further confirmed that garcinol activated the SIRT1/PPARα pathway to regulate ferroptosis. Conclusion: Garcinol exerts protective effects against allergic asthma–induced lung injury by activating the SIRT1/PPARα signaling pathway and suppressing ferroptosis.