Astaxanthin protects against acute lung injury via dual modulation of Ca2+/CaMKIIα/NLRP3 and TLR2/MyD88/NLRP3 pathways.
- 2026-01
- International immunopharmacology 168
- PubMed: 41176909
- DOI: 10.1016/j.intimp.2025.115776
Study Design
- Type
- Review
- Methods
- A murine model of lipopolysaccharide (LPS)-induced ALI was established and treated with two doses of AST (50 mg/kg and 100 mg/kg). In vitro, LPS-stimulated A549 cells were used.
Acute lung injury (ALI) is characterized by excessive inflammation, oxidative stress, and alveolar epithelial damage, often leading to severe pulmonary dysfunction. Astaxanthin (AST), a natural antioxidant, exhibits anti-inflammatory and cytoprotective properties in various disease models. However, its therapeutic potential and underlying molecular mechanisms in ALI remain poorly understood. A murine model of lipopolysaccharide (LPS)-induced ALI was established and treated with two doses of AST (50 mg/kg and 100 mg/kg). Lung histopathology, fibrosis, cytokine levels, oxidative stress markers, and immunohistochemical features were evaluated. In vitro, LPS-stimulated A549 cells were used to mimic ALI, and AST's effects on oxidative stress, inflammation, pyroptosis, and mitochondrial function were investigated. Network pharmacology and molecular docking identified potential AST targets, followed by functional rescue experiments involving NOD-like receptor protein 3 (NLRP3) or calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) overexpression and site-directed mutagenesis in vivo and in vitro. AST administration significantly improved lung histological structure, reduced collagen deposition and inflammatory cell infiltration, and lowered levels of IL-6, IL-1β, and oxidative stress levels in ALI mice. Mechanistically, AST inhibited calcium (Ca2+) influx and suppressed CaMKIIα expression, leading to downregulation of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cleaved caspase-1, thereby mitigating pyroptosis. Moreover, AST suppressed toll-like receptor 2/myeloid differentiation primary response 88 (TLR2/MyD88) signaling both in vivo and in vitro models. Molecular docking and mutational analyses identified Ser257 on CaMKIIα and Glu313 on TLR2 as shared binding sites for AST, critical for its inhibitory effects on inflammasome activation. Notably, the protective effects of AST were abolished in mice injected with Ser257 or Glu313 mutant constructs, highlighting the essential role of these residues in mediating its actions. AST attenuates LPS-induced ALI by suppressing NLRP3 inflammasome activation and pyroptosis through the Ca2+/CaMKIIα and TLR2/MyD88 pathways. These findings identify AST as a promising therapeutic candidate for ALI and provide new insights into targeting pyroptosis-related pathways in inflammatory lung disease.