DUSP1 alleviates LPS-induced acute lung injury by inhibiting the SHP2-JNK axis and mitochondrial apoptosis.

Background: Lipopolysaccharide (LPS) induces acute lung injury (ALI), a condition characterized by oxidative stress, inflammation, and apoptosis, ultimately leading to respiratory failure. Dual-specificity phosphatase 1 (DUSP1), a key regulator of MAPK signaling, may offer protection against inflammatory damage.

Objective: This study aimed to investigate the protective effects of DUSP1 overexpression against LPS-induced inflammatory injury and to explore the underlying molecular mechanisms using both in vitro and in vivo models.

Methods: Cellular and murine ALI models were established using LPS. DUSP1 was overexpressed via plasmid transfection for in vitro experiments and viral vectors for in vivo studies. Cell viability, apoptosis, reactive oxygen species (ROS), and pro-inflammatory cytokine levels (IL-1β, IL-6, TNF-α) were assessed. In mice, lung injury was evaluated through bronchoalveolar lavage fluid (BALF) analysis, lung mechanics, and histopathology. DUSP1-SHP2 interactions were predicted using bioinformatics and validated through co-immunoprecipitation. JNK pathway activation was analyzed by Western blotting, and dual-luciferase reporter assays confirmed the regulatory interaction between DUSP1 and SHP2.

Results: In vitro, DUSP1 overexpression significantly enhanced cell viability while reducing apoptosis, ROS, malondialdehyde (MDA), and inflammatory cytokines in LPS-stimulated cells. In vivo, DUSP1 overexpression substantially alleviated LPS-induced lung injury, evidenced by decreased BALF protein, reduced lung water content, lower airway resistance, improved pulmonary function, and less tissue damage. Mechanistically, DUSP1 directly interacted with SHP2, inhibiting its phosphorylation, which in turn suppressed the phosphorylation of p53 and JNK. DUSP1 overexpression also downregulated PINK1/Parkin-mediated mitophagy, key pro-apoptotic proteins (Cytochrome C, Caspase-3, Bax), and the NLRP3 inflammasome. Anisomycin treatment reversed these protective effects, confirming the dependence of DUSP1's protective action on JNK pathway inhibition.

Conclusion: DUSP1 overexpression alleviates LPS-induced lung inflammation and injury by targeting the SHP2-JNK axis and restoring mitochondrial homeostasis. These findings position DUSP1 as a promising therapeutic target for inflammatory lung disorders.