Polydatin mitigates cigarette smoke-induced pulmonary apoptosis by regulating Bim via FoxO3 post-translational modifications and modulating the gut microenvironment

Cigarette smoke-mediated chronic pulmonary damage constitutes a critical predisposing factor for chronic obstructive pulmonary disease and lung cancer pathogenesis. Polydatin, a naturally occurring stilbenoid characterized by its potent anti-inflammatory and antioxidant properties, has yet to be fully elucidated regarding its protective role and the underlying molecular mechanisms in CSE-induced pulmonary injury. Cigarette smoke extract (CSE)-induced lung injury murine models and MLE12 cells were treated with polydatin or other conditions. The investigation encompassed both intravital and extracorporeal modalities. Evaluations included pulmonary index, histopathology, oxidative stress markers, transcriptomic sequencing, protein expression (AKT/FoxO3/Bim), apoptosis (TUNEL), intestinal metabolomics, 16S rRNA microbiota profiling, and immunohistochemical staining of colon tissue. The administration of polydatin dose-dependently in vivo alleviated CSE-induced systemic impairments including weight loss, pulmonary edema, and oxidative stress concurrently demonstrating high biocompatibility and low systemic toxicity. Furthermore, it modulates the intestinal microecology by depleting g__Pantoea and g__Enterococcus abundance, concurrently restoring mucosal barrier integrity via the enhancement of ZO-1 and Occludin levels. Mechanistic analysis demonstrated that polydatin directly interacts with AKT1 at the Thr308 residue, thereby reversing the CSE-induced attenuation of AKT1 and FoxO3 (Ser253) phosphorylation. This restoration facilitates the nuclear-to-cytoplasmic translocation of FoxO3 and subsequent downregulation of the pro-apoptotic protein Bim. This regulatory cascade effectively curtails apoptosis and DNA fragmentation, with a concomitant decrease in Bax and Cleaved-Caspase 3 expression. In conclusion, polydatin exerts suitable protective effects against CSE-induced pulmonary injury by attenuating apoptosis through the AKT-FoxO3-Bim signaling cascade and simultaneously orchestrating the gut microenvironment. These findings highlight the potential of polydatin as a promising natural therapeutic agent for lung disorders.