Acute lung injury (ALI) is a severe complication of sepsis, yet the role of lncRNA NORAD in its pathogenesis remains unclear. Using LPS-stimulated BEAS-2B and HBEC3-KT cells as well as cecal ligation and puncture (CLP)-induced ALI models in C57BL/6 mice, we found that NORAD expression was markedly upregulated and promoted cell injury characterized by reduced viability, enhanced apoptosis, increased cytokine secretion, and aggravated lung damage. Mechanistic studies combining dual-luciferase and RIP assays revealed that NORAD directly bound miR-150-5p to derepress STAT1, leading to elevated STAT1, p-STAT1, and p-p65 levels and activation of JAK/STAT and NF-κB signaling. Silencing NORAD alleviated lung injury in vitro and in vivo, as evidenced by improved cell survival, decreased concentration of total protein in bronchoalveolar lavage fluid (BALF), reduced inflammatory response, lower wet/dry (W/D) ratio, diminished caspase-3 levels, and decreased histological injury scores in CLP mice. Furthermore, knockdown of miR-150-5p or overexpression of STAT1 abolished the protective effects of NORAD inhibition, whereas overexpression of miR-150-5p or knockdown of STAT1 mitigated the injury-promoting effects of NORAD overexpression. These findings demonstrate that NORAD exacerbates sepsis-induced ALI via the miR-150-5p/STAT1 axis, providing new insights into potential therapeutic targets for sepsis-related lung injury.
Liu et al. (Tue,) studied this question.