Atractylodin targets ASAH3L to regulate galactose metabolism and thereby modulates the HIF-1 signaling pathway for the treatment of acute lung injury

Acute lung injury (ALI) is a lung disease characterized by an excessive inflammatory response and damage to lung epithelial cells. Atractylodin (ATL) is the main active component of Atractylodes lancea (Thunb.) DC., which has good anti-inflammatory activity and protects the integrity of the epithelial cell barrier. However, the efficacy of ATL in the treatment of ALI and its mechanism are unclear. We investigated the efficacy of ATL in treating ALI in vivo and in vitro, and explored its targets and mechanisms of action from metabolic and signaling pathways. The results showed that, in vivo, ATL significantly reduced the wet-dry ratio of lungs of rats with ALI, improved the pathological changes, reduced the aggregation and activation of neutrophils and macrophages in the lungs, and lowered the expression of the inflammatory factors, MCP-1, and MPO. The transcriptomics results suggested that ATL exerts its therapeutic effects by modulating the HIF-1 signaling pathway and metabolic processes. Metabolomics results showed that ATL mainly affected the processes of lactose degradation and galactose metabolism. Combined metabolomic and transcriptomic analyses showed that ASAH3L, a gene related to galactose metabolism, was regulated by ATL, and further experiments demonstrated that ATL reduced the expression of ASAH3L and ROS thereby inhibiting the activation of the HIF-1 signaling pathway. Overexpression of ASAH3L reversed the therapeutic effect of ATL in rats with ALI. In conclusion, ATL can reduce inflammation by inhibiting activating the HIF-1 signaling pathway and targeting ASAH3L to regulate galactose metabolism, thereby alleviating ALI.