Mavacamten alleviates sepsis-induced acute respiratory distress syndrome by modulating the PI3K/AKT/autophagy axis: a...

Sepsis-induced acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung condition with high mortality and no specific pharmacological treatments. The complex spatial heterogeneity of the lung during sepsis hinders the discovery of effective therapies. This study aimed to use spatial transcriptomics to map the septic lung's molecular landscape to identify and validate a novel therapeutic agent.

We performed spatial transcriptomics on lung tissues from mice subjected to cecal ligation and puncture (CLP) to model sepsis. A computational drug screen identified Mavacamten. In vitro, lipopolysaccharide-stimulated murine alveolar epithelial cells were used to assess Mavacamten's effects on inflammation and cell injury. In vivo, CLP mice received Mavacamten, and we assessed survival, lung function, pulmonary edema, histology, and inflammatory markers. The underlying mechanism was investigated by analyzing the PI3K/AKT/mTOR pathway and autophagy markers. Statistical analyses included ANOVA, t-tests, and Kaplan-Meier analysis.

Spatial transcriptomics revealed distinct cellular clusters that were dramatically rearranged during sepsis. In vitro, Mavacamten significantly attenuated lipopolysaccharide-induced inflammation, cellular injury, and oxidative stress. In the CLP mouse model, Mavacamten treatment markedly improved 7-day survival, restored arterial oxygenation, reduced pulmonary edema, and lessened histological lung injury. Mavacamten also significantly lowered local and systemic pro-inflammatory cytokine levels. Mechanistically, Mavacamten reversed the sepsis-induced inhibition of autophagy and suppressed the activation of the PI3K/AKT/mTOR signaling pathway in lung tissues.

Mavacamten confers robust protection against sepsis-induced ARDS in a preclinical model by mitigating inflammation and lung injury, leading to improved survival. Its therapeutic action is mediated by inhibiting the PI3K/AKT pathway and restoring protective autophagy. Mavacamten is a promising candidate for repurposing in the treatment of sepsis-induced ARDS.