Bazedoxifene attenuates lipopolysaccharide-induced acute lung injury by inhibiting NLRP3 inflammasome activation of macrophages in mice.

Acute Lung Injury (ALI) is a common clinical emergency. Currently, most available treatments are primarily supportive, highlighting the urgent need for effective therapeutic strategies. A key driver of ALI pathogenesis is the uncontrolled pulmonary inflammatory response. Bazedoxifene (BAZ), approved by the FDA since 2013 for postmenopausal osteoporosis, has demonstrated anti-inflammatory properties in chronic inflammatory diseases. However, the effects of BAZ on ALI remain unclear. The NLRP3 inflammasome, a critical pattern recognition receptor, contributes to ALI progression by sensing diverse damage signals and amplifying the inflammatory cascade. In this study, we found that BAZ pretreatment alleviated lipopolysaccharide (LPS) -induced lung inflammation in ALI mice and suppressed NLRP3 inflammasome activation in mouse macrophages. Given that dysregulation of mitochondrial dynamics is a known trigger for NLRP3 inflammasome activation under inflammatory stress, we further explored this relationship. Our results indicated that BAZ attenuated LPS-induced ALI by curbing excessive mitochondrial fission and promoting mitochondrial fusion in macrophages. In conclusion, our study reveals that BAZ confers protective effects against LPS-induced ALI by modulating mitochondrial dynamics to inhibit NLRP3 inflammasome activation, providing new perspectives for the development of ALI therapies.