New Mechanistic Insights Into Nobiletin’s Protective Effects Against LPS‐Induced Hyperinflammatory Acute Lung Injury in Rats: Targeting miR‐200, AT1R/p38 MAPK, and HMGB1/NF‐κB mTOR Pathways

Abstract

Background Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe inflammatory lung disorders associated with high morbidity and mortality. Dysregulation of the renin–angiotensin system (RAS) and proinflammatory pathways play an indispensable role in ALI progression. Aim This study aimed to investigate the protective potential of nobiletin (NOB) in mitigating ALI and hyperinflammatory lung injury. Material and Methods The study enrolled 32 male albino rats allocated into four groups: (Control, NOB, lipopolysaccharide [LPS], and NOB + LPS groups). Rats received NOB 20 mg/kg by oral gavage for 1 week; on the seventh day, a single dose of 15 mg/kg LPS was given by intranasal instillation. After 24 h of LPS administration, plasma and lung tissue samples were analyzed for inflammatory cytokines, mitochondrial complex‐I, oxidative stress markers, and molecular signaling pathways. Results NOB administration significantly downregulated miR‐200 expression, associated with ACE2 activation and attenuated AT1R‐mediated inflammatory responses. It also decreased NF‐κB and p38 MAPK signaling, reducing pulmonary and systemic levels of tumor necrosis factor‐alpha (TNF‐α), interleukin‐6 (IL‐6), granulocyte monocyte‐colony stimulating factor (GM‐CSF), and interleukin‐17A (IL‐17A). Additionally, NOB improved the high mobility group box 1 (HMGB1)/NF‐κB/mammalian target of rapamycin (mTOR) pathway, and increased mitochondrial complex‐I may be consistent with improved tissue preservation. Conclusion NOB exerts protective effects against ALI by improving inflammatory cytokine, oxidative stress, miRNA‐200, mitochondrial complex‐I, and ACE2, highlighting its potential as a protective candidate for ALI and hyperinflammatory‐associated lung injury.