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Background:Acute lung injury (ALI) is characterized by an acute inflammatory process,and oxidative stress in the lung tissue leads to a lack of effective therapeutics.This study aimed to identify whether the overexpression of transcription factor EB (TFEB)regulates mitophagy to protect against lipopolysaccharide (LPS)-induced ALI.Methods:We detected the expression of inflammatory factors,cytochrome c (Cyt.c) and nicotinamide adenine dinucleotide phosphate (NADPH),and autophagy-related proteins and observed the changes in lung histopathology induced by ALI in rats and the changes in the cell ultrastructure of primary alveolar type Ⅱ epithelial cells induced by changing the expression of TFEB in the context of ALI.Results:The overexpression of TFEB could reduce the expression of proinflammatory factors,such as IL-1 and IL-6,and increase the expression of anti-inflammatory factors,such as IL-10,both in vitro and in vivo.In addition,the overexpression of TFEB could reduce the Cyt.c and NADPH levels both in vivo and in vitro.The overexpression of TFEB could upregulate the expression of autophagy-related proteins,such as lysosomal-associated membrane protein 1 (LAMP1),microtubule-associated protein light chain 3B (LC3B),and Beclin both in vivo and in vitro,and promote mitochondrial autophagy.The overexpression of TFEB significantly improved the histopathologic changes induced by LPS-induced ALI in rats.However,low TFEB expression produced the opposite results.Conclusion:TFEB overexpression can decrease inflammation and mitochondrial damage in the lung tissue and alveolar epithelial cells through regulating mitochondrial autophagy to protect against LPS-induced ALI.Therefore,TFEB is likely a potential therapeutic target in LPS-induced ALI.