The primary objectives of this research were to investigate the protective effects of
liriodendrin against
IgG immune complex (
IgG-IC)-induced
acute lung injury (ALI) and to elucidate the underlying mechanisms. This study employed a mouse and cell model of
IgG-IC-induced
acute lung injury. Lung tissue was stained with
hematoxylin-
eosin to observe pathological alterations and arterial blood gas analysis was tested. Inflammatory
cytokines, including
interleukin-6 (IL-6), interleukin-1β (IL-1β), and
tumor necrosis factor-alpha (TNF-α), were measured using ELISA. The
mRNA expression of inflammatory
cytokines was assessed via RT-qPCR. Molecular docking and enrichment analysis were combined to identify the most potential signaling pathways modulated by
liriodendrin, which were then verified using western blot analysis in
IgG-IC-induced ALI models. We identified 253 shared targets between
liriodendrin and
IgG-IC-induced
acute lung injury from the database. Through network pharmacology, enrichment analysis, and molecular docking, SRC was determined to be the most closely associated target of
liriodendrin in
IgG-IC-induced ALI. Pretreatment with
liriodendrin notably reduced the increased
cytokine secretion of IL-1β,
IL-6, and TNF-α. Histopathological analysis of lung tissue demonstrated a protective effect of
liriodendrin on
IgG-IC-induced
acute lung injury in mice. Arterial blood gas analysis showed
liriodendrin ameliorated
acidosis and
hypoxemia efficiently. Further studies revealed that
liriodendrin pretreatment substantially attenuated the elevated phosphorylation levels of SRC's downstream components (JNK, P38, and STAT3), suggesting that
liriodendrin may protect against
IgG-IC-induced ALI via the SRC/STAT3/MAPK pathway. Our findings indicate that
liriodendrin protects against
IgG-IC-induced
acute lung injury by inhibiting the SRC/STAT3/MAPK signaling pathway, suggesting that
liriodendrin may serve as a potential treatment for
acute lung injury caused by
IgG-IC.