Prophylactic C-terminal Occludin–derived peptide attenuates LPS-induced airway inflammation via barrier preservation and mitochondrial ROS regulation

Occludin is a key tight junction protein that contributes to epithelial barrier integrity and inflammatory regulation. Although its structural roles are well characterized, the physiological relevance of its C-terminal domain in airway inflammation remains poorly defined. Occludin expression was statistically reduced in inflamed human lung tissues. In BEAS-2B cells, occludin overexpression suppressed LPS-induced IL-8 release, restored barrier integrity, and reduced F-actin remodeling, whereas C-terminal deletion abolished these effects. The C-terminal occludin peptide (391∼412) significantly decreased IL-8 production, improved barrier function, and suppressed cytoskeletal changes, while a mutant peptide was ineffective. Transcriptomic analyses identified occludin as a central suppressor of inflammatory signaling. Mechanistically, the peptide inhibited p38 activation, preserved mitochondrial structure, and reduced mtROS production. In vivo , peptide pretreatment improved survival, lowered IL-1β, IL-6, IL-8, and TNF-α levels, and reduced goblet cell hyperplasia and inflammatory infiltration. Immune profiling further revealed restored T-cell populations, reduced myeloid expansion, and enhanced M2 alveolar macrophage polarization. The occludin C-terminal–derived peptide exerts robust anti-inflammatory, barrier-protective effects, and a modulator of mitochondrial redox balance representing a promising therapeutic candidate for LPS-induced and potentially broader inflammatory lung diseases. • Occludin expression is significantly reduced in inflamed human lung tissues. • A synthetic peptide derived from the occludin C-terminal region effectively reduces LPS-induced inflammation. • Occludin C-terminal peptide improves survival, decreases pro-inflammatory cytokines, reduces pathological lung changes, and rebalances redox homeostasis, and promoting M2 alveolar macrophage polarization.