Sepsis-induced acute lung injury: AUF1 regulates pyroptosis via ETS2/ZDHHC21-mediated STING palmitoylation : A therapeutic target for lung injury.

BACKGROUND: Sepsis-induced acute lung injury (ALI) is characterized by excessive inflammation and pyroptosis of lung epithelial cells. AU-rich element binding factor 1 (AUF1) is a key RNA-binding protein involved in mRNA decay and regulation of inflammatory responses. Understanding AUF1's role in ALI could reveal novel therapeutic targets. METHODS: We employed both in vivo (cecal ligation and puncture, CLP) and in vitro (lipopolysaccharide, LPS-treated cells) models of sepsis-induced ALI. Survival rates, lung histopathology, and expression levels of ZDHHC21, STING palmitoylation, and pyroptosis markers (c-Caspase-1, GSDMD-N, IL-18, IL-1β) were assessed. Knockdown and overexpression experiments for ZDHHC21, ETS2, and AUF1 were conducted. RNA immunoprecipitation (RIP) and RNA pulldown assays evaluated AUF1 binding to ETS2 mRNA, while mRNA decay was analyzed using actinomycin D. RESULTS: In ALI models, ZDHHC21 expression, STING palmitoylation, and pyroptosis markers were significantly increased. Inhibition of NLRP3/AIM2 improved survival and reduced lung injury without affecting ZDHHC21 levels. Knockdown of ZDHHC21 reduced STING palmitoylation and pyroptosis. ETS2 was upregulated in ALI and directly activated ZDHHC21 transcription. AUF1 expression was downregulated in ALI, leading to decreased decay of ETS2 mRNA and elevated ETS2/ZDHHC21/STING axis activity. Overexpression of AUF1 reversed these changes, reducing STING palmitoylation and pyroptosis. AUF1 directly bound and promoted the decay of ETS2 mRNA. CONCLUSION: AUF1 mitigates sepsis-induced ALI by promoting ETS2 mRNA decay via the ETS2/ZDHHC21 axis, thereby reducing STING palmitoylation and pyroptosis in lung epithelial cells. Targeting the AUF1/ETS2/ZDHHC21/STING pathway offers a promising therapeutic strategy for improving outcomes in sepsis-induced ALI. Future studies should validate these findings in human samples and explore upstream regulators of AUF1.