Combination of Tanshinone IIA and Matrine Alleviates Lipopolysaccharide‐Induced Acute Lung Injury by Supressing Ferroptosis via Nrf2/ HO ‐1 Pathway Activation

ABSTRACT Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life‐threatening conditions that involve severe lung inflammation leading to respiratory failure. Tanshinone IIA (TIIA) and Matrine (MAT), two herbal medicinal compounds, have been reported to exhibit several similar pharmacological properties including anti‐inflammatory, antioxidant, and anticancer effects. Although previous studies have reported the combined therapeutic efficacy of using two drugs in treating ALI, it remains unknown whether TIIA and MAT have any synergistic effect in alleviating ALI/ARDS. Therefore, this study investigated whether a combined therapy of TIIA and MAT has protective effects against lipopolysaccharide (LPS)‐induced ALI and its mechanism of action using mouse and cell models. The results showed that the TIIA + MAT combination ameliorated ALI by reducing edema, tissue injury, and proinflammatory cytokine secretion. This therapy enhanced antioxidant defences, as indicated by upregulated GPX4 and SLC7A11 levels, decreased 4‐HNE and ROS levels, and ferroptosis inhibition. Furthermore, TIIA + MAT promoted Nrf2 nuclear translocation, leading to increased HO‐1 expression and an anti‐oxidative response. These findings suggest that the combination of TIIA and MAT alleviates LPS‐induced ALI by inhibiting ferroptosis via activation of the Nrf2/HO‐1 pathway. Thus, the co‐administration of TIIA and MAT may be an effective therapeutic strategy for ALI, potentially offering a novel clinical approach to mitigate ferroptosis and inflammation.