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ZKSCAN3 mitigates lipopolysaccharide-induced acute lung injury by restraining excessive autophagy via activation of the mTOR pathway

   
@article{JTD125615,
	author = {Lei Zhang and Xinyu Yang and Yiwei Li and Xueshan Bu},
	title = {ZKSCAN3 mitigates lipopolysaccharide-induced acute lung injury by restraining excessive autophagy via activation of the mTOR pathway},
	journal = {Journal of Thoracic Disease},
	volume = {0},
	number = {0},
	year = {2026},
	keywords = {},
	abstract = {Background: Acute lung injury (ALI) is a critical condition marked by dysregulated inflammation and autophagic imbalance. Zinc-finger with KRAB and SCAN domains 3 (ZKSCAN3) is a master transcriptional repressor of autophagy, yet its role in ALI pathogenesis remains unclear.Methods: ALI was induced in C57BL/6 mice and A549 alveolar epithelial cells by lipopolysaccharide (LPS). ZKSCAN3 was overexpressed using plasmid transfection to evaluate its therapeutic potential. Lung injury was assessed by histopathology, wet-to-dry ratio (W/D ratio), and inflammatory cytokine levels [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6]. Autophagic activity was evaluated via transmission electron microscopy(TEM), immunofluorescence, and western blotting for LC3-II, Beclin-1, and P62. The involvement of the mTOR pathway was investigated by examining the phosphorylation status of mTOR.Results: ZKSCAN3 expression was significantly downregulated in both LPS-induced lung tissues and A549 cells. Overexpression of ZKSCAN3 markedly alleviated LPS-induced pulmonary edema, alveolar damage, and the surge of pro-inflammatory cytokines. Mechanistically, ZKSCAN3 overexpression suppressed excessive autophagic flux, as evidenced by a decreased LC3-II/LC3-I ratio and Beclin-1 expression, and increased accumulation of P62. Furthermore, this protective effect was associated with a notable increase in mTOR phosphorylation, indicating reactivation of the mTOR-autophagy inhibitory axis.Conclusions: Our findings reveal that downregulation of ZKSCAN3 contributes to the pathogenesis of LPS-induced ALI. Restoration of ZKSCAN3 exerts a protective effect by reining in excessive autophagy, through activation of the mTOR signaling pathway. This positions the ZKSCAN3-mTOR axis as a potential therapeutic target for ALI.},
	issn = {2077-6624},	url = {https://jtd.amegroups.org/article/view/125615}
}