LACC1 attenuates LPS-induced acute lung injury by inhibiting inflammatory response in alveolar macrophage through LPAR3/PI3K/AKT/mTOR signaling pathway

Laccase domain containing 1 (LACC1) is an enzyme abundantly expressed in inflammatory macrophages that regulate diverse inflammatory diseases. This study aimed to investigate the role of LACC1 in lipopolysaccharide (LPS)-induced acute lung injury (ALI) and to elucidate its underlying regulatory mechanisms. Single-cell RNA sequencing of bronchoalveolar lavage fluid (BALF) from patients with ALI was performed to characterize LACC1 expression patterns in pulmonary macrophages. Then, LACC1 conditional knockout mouse model was established to investigate the in vivo function of LACC1 during LPS-induced lung injury. ln vitro function of LACC1 was further explored using LACC1-silenced THP-1 cells. RNA sequencing was conducted to profile gene expression changes in LACC1-knockdown THP-1 cells, followed by GO and KEGG enrichment analysis. Key downstream molecules and signaling pathways modulated by LACC1 were validated by Western blot and qRT-PCR. Single-cell RNA sequencing analysis based on BALF of ALI patients revealed that LACC1 expression was markedly elevated in pulmonary macrophages. Conditional knockout of LACC1 in macrophages exacerbated LPS-induced pulmonary inflammation. In vitro, LACC1 knockdown in THP-1 cells markedly exacerbated the inflammatory response after LPS treatment. RNA sequencing identified LPAR3 as a key downstream target, and enrichment analysis indicated significant involvement of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway followed by LACC1 knockdown. Western blot analysis confirmed that LACC1 knockdown reduced LPAR3 expression and inhibited PI3K/AKT/mTOR pathway activation. LACC1 might exert a protective effect against LPS-induced lung injury by suppressing inflammatory responses via modulation of LPAR3/PI3K/AKT/mTOR signaling pathway.