Licochalcone A Attenuates Acute Lung Injury through Modulation of STING Signaling and Mitochondrial Quality Control

Acute lung injury (ALI) is characterized by excessive inflammatory responses and mitochondrial dysfunction, yet effective pharmacological interventions remain limited. Aberrant activation of the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway has emerged as an important contributor to inflammatory tissue injury. Licochalcone A (LCA), a bioactive chalcone derived from licorice, possesses broad anti-inflammatory activity, but its molecular basis in ALI remains incompletely understood. In this study, we investigated whether LCA protects against ALI by modulating STING-associated inflammatory signaling and mitochondrial homeostasis. Target-prediction, computational, and cellular target-engagement analyses supported STING as a molecular target of LCA. LCA attenuated STING activation and downstream TBK1–IRF3/NF-κB signaling, accompanied by reduced inflammatory responses in macrophages and improved pulmonary injury in an LPS-induced mouse model. Further analyses showed that LCA alleviated mitochondrial dysfunction and restored cellular quality-control processes associated with lysosomal function and mitophagy. Collectively, these findings identify LCA as a natural small-molecule modulator of STING signaling and suggest that coordinated regulation of inflammatory signaling and mitochondrial homeostasis contributes to its protective effects against ALI. LCA may therefore provide a promising natural-product scaffold for the development of STING-targeted therapeutics.