lncRNA CASC9 stabilizes MUC1 by binding to U2AF2 to inhibit cellular ferroptosis and alleviate LPS-induced cell injury.

Background: Sepsis-induced acute lung injury (ALI) is a critical condition with a limited number of treatment options. The regulatory role of long noncoding RNA cancer susceptibility candidate 9 (lncRNA CASC9) in ferroptosis, a specific type of cell death, has been linked to this condition.

Methods: In this study, HPAEpiCs were treated with lipopolysaccharide (LPS) to model sepsis-induced acute lung injury. Various assays were employed, including RNA immunoprecipitation (RIP) and RNA pull-down to investigate lncRNA CASC9 interactions with U2 small nuclear RNA auxiliary factor 2 (U2AF2) and Mucin 1 (MUC1), Cell Counting Kit-8 (CCK-8) for cell viability, ELISA for inflammatory cytokines, Calcein-AM/PI staining for live/dead cell visualization, Reagent kit detection of lipid reactive oxygen species (ROS) and Malondialdehyde (MDA) assays for oxidative stress markers, iron and Glutathione (GSH) assays for redox status, qPCR for gene expression, and Western blot for protein levels.

Results: The expression of lncRNA CASC9 was significantly decreased in LPS-induced cell models. Overexpression of lncRNA CASC9 reduced ferroptosis, as indicated by improved cell viability, decreased inflammatory cytokines, and restored redox homeostasis (reduced MDA and ROS, and iron levels, and increased GSH level). The lncRNA CASC9 interacts with U2AF2 to stabilize MUC1 mRNA, enhance MUC1 expression and reduce ferroptosis. Knockdown of U2AF2 reversed these effects, highlighting lncRNA CASC9's regulatory role in ferroptosis via MUC1 stabilization. MUC1 overexpression similarly reduced LPS-induced ferroptosis, supporting the protective role of the lncRNA CASC9/U2AF2/MUC1 pathway.

Conclusion: This study demonstrated that lncRNA CASC9 regulates sepsis-induced ALI by stabilizing MUC1 mRNA through U2AF2 interaction, thereby inhibiting ferroptosis.