A novel curcumin analog sAc15 alleviates LPS-induced acute lung injury by activating the PI3K/AKT/Nrf2 pathway in pulmonary epithelial cells

Objectives Acute lung injury (ALI) is driven by oxidative stress and disrupted redox homeostasis. While curcumin is a potent natural antioxidant, its clinical application is limited. We evaluated the protective capacity and underlying mechanisms of sAc15, a stable curcumin analog, in ALI models.Methods In vivo, mice were intratracheally instilled with lipopolysaccharide (LPS) to induce ALI. In vitro, Beas-2b cells were exposed to t-BHP for oxidative damage. Target engagement was evaluated via surface Plasmon resonance (SPR). Protective effects and mechanisms were evaluated via histopathology, ROS accumulation, apoptosis assays, network pharmacology, Western blotting, LY294002 and Nrf2-specific siRNA.Results sAc15 exhibited broader safety margins and superior ROS suppression compared to natural curcumin. SPR established direct binding between sAc15 and recombinant Nrf2 (KD = 2.68 μM). In vivo and in vitro, sAc15 mitigated pulmonary inflammation, oxidative stress, mitochondrial dysfunction and apoptosis. Mechanistically, sAc15 promoting PI3K/AKT phosphorylation and upregulating the expression of Nrf2, HO-1 and NQO-1. Crucially, Nrf2 silencing or PI3K inhibition markedly attenuated sAc15-mediated cytoprotective, anti-apoptotic, and antioxidant benefits.Conclusion sAc15 ameliorates ALI by activating the PI3K/AKT/Nrf2 axis to restore oxidative equilibrium, hightlighhting its promise as a therapeutic candidate for ALI/ARDS.