Abstract
BACKGROUND: Sepsis-induced acute lung injury (ALI) is a life-threatening condition with high mortality and limited effective treatments. Aging of alveolar type II (AT2) epithelial cells and mitochondrial dysfunction are key contributors to ALI pathogenesis. Ginsenoside Rb1, a major bioactive component of ginseng, has shown potential in modulating cellular senescence and mitochondrial health. This study aimed to evaluate the therapeutic efficacy of Rb1-loaded lung tissue-derived decellularized extracellular matrix hydrogel (dECM-gel) in alleviating sepsis-induced ALI. METHODS AND RESULTS: Rb1-loaded dECM-gel was formulated and characterized for its rheological properties. In vitro, primary AT2 cells were treated with lipopolysaccharide (LPS) to mimic ALI conditions. The impact of Rb1-loaded dECM-gel on cellular senescence, mitochondrial function, and oxidative stress was assessed using β-galactosidase staining, JC-1 dye for mitochondrial membrane potential, ATP quantification assays, and transmission electron microscopy. Results demonstrated that Rb1-loaded dECM-gel significantly reduced AT2 cell senescence, improved mitochondrial function via activation of the mitochondrial unfolded protein response (mtUPR), and alleviated mitochondrial structural damage. In vivo, a murine model of sepsis-induced ALI was used to evaluate therapeutic outcomes. Treatment with Rb1-loaded dECM-gel improved lung histopathology, decreased oxidative stress, and reduced apoptosis, largely through activation of the AMPK/SIRT1 signaling pathway. CONCLUSION: Rb1-loaded dECM-gel mitigates sepsis-induced ALI by enhancing mtUPR and activating the AMPK/SIRT1 pathway, offering a promising therapeutic strategy for lung injury. These findings underscore the potential of ginsenoside-based biomaterials in the clinical management of ALI.