Glycyrrhiza Uralensis Fisch. Alleviates Paraquat‐Induced Lung Injury by Repairing Mitochondrial Respiratory Chain Dysfunction

ABSTRACT Paraquat (PQ) causes acute lung injury in part via mitochondrial respiratory dysfunction. We evaluated whether Glycyrrhiza uralensis . extract (LE) confers holistic protection and whether liquiritin (LQ) is a key mitochondria‐targeting constituent. A PQ lung‐injury model was established in KM mice by a single oral dose of PQ (20 mg/kg). LE was gavaged after PQ exposure for in vivo assessment; LQ was used as pretreatment in A549 and HPAEpic cells. Outcomes included lung function, pulmonary microcirculation, histopathology, and oxidative‐stress markers (MDA, SOD). UPLC‐Q/TOF‐MS profiled LE composition. Differential genes and pathway enrichment were derived from integrated transcriptomics (GSE171625 plus our RNA‐seq). Mitochondrial superoxide, membrane potential (Δψm), mtDNA leakage, and respiratory‐chain proteins were measured. Rotenone and antimycin A were used as pharmacological probes, and molecular docking was employed to assess target engagement. Eighteen major LE constituents were identified; enrichment linked them to oxidative stress, inflammation, fibrosis, and metabolism pathways. Transcriptomics converged on mitochondrial pathways. LE treatment improved clinical appearance and lung function, enhanced microcirculation, reduced alveolar wall thickening, inflammation, and early fibrosis, lowered MDA levels, and restored SOD levels in PQ‐exposed mice. In vitro, LQ restored mitochondrial function, increasing Δψm and respiratory activity while limiting PQ‐induced damage. Perturbation with rotenone/antimycin A supported Complex I as a core target, consistent with docking. This work establishes a prediction‐to‐validation chain from LE's multi‐component holistic efficacy to LQ's mitochondria‐targeted mechanism, validating Complex I as a mechanistic node and supporting LE/LQ as candidates against PQ‐induced lung injury.