The ATG14-SIRT1 Axis Modulates NF-Κb Pathway Activation and Inflammatory Responses in Acute Lung Injury

Acute lung injury (ALI) is characterized by dysregulated inflammation and tissue damage. Autophagy-related gene 14 (ATG14) is a key autophagy regulator, but its role in ALI remains incompletely understood.

LPS-induced ALI was investigated in mice and lung epithelial cells. Autophagy, ATG14 acetylation, NF-κB pathway activation, and cytokine production were evaluated by histology, western blotting, immunoprecipitation, ELISA, electron microscopy, mass spectrometry, and molecular docking. ATG14 knockdown/overexpression and SIRT1 overexpression were used to explore mechanisms.

LPS induced excessive autophagy, increased ATG14 expression and acetylation in lung tissue, reduced epithelial ATG14 levels through TLR4-dependent proteasomal degradation in vitro, reduced SIRT1 levels, and enhanced NF-κB pathway activity. SIRT1 interacted with ATG14 and suppressed its acetylation. Peptide docking supported the structural feasibility of SIRT1 recognition of ATG14 regions containing K78 and K178, with the K178-containing region showing a more compatible orientation near the SIRT1 catalytic surface. ATG14 inhibition or SIRT1 restoration reduced NF-κB pathway activity, cytokine production, and lung inflammation in vitro and in vivo.

The ATG14-SIRT1 axis modulates autophagy-inflammation crosstalk in ALI and may represent a potential therapeutic target.