Abstract

Cigarette consumption remains a preeminent global public health concern, as prolonged exposure to cigarette smoke is fundamentally implicated in the etiology of chronic pulmonary diseases and the manifestation of various malignancies. Apigenin, a bioactive dietary flavonoid widely distributes in botanical sources such as celery, demonstrates significant histoprotective effect. Nevertheless, the underlying mechanism governing apigenin's ability to counteract incipient pulmonary injury induced by cigarette smoke extract (CSE) remains to be delineated. By employing a novel CSE exposure system to establish reproducible in vivo and in vitro injury models, this study demonstrated that apigenin administration dose-dependently attenuates pulmonary apoptosis, as evidenced by the restoration of the Bax/Bcl-2 ratio and the suppression of Caspase-3 activation. Furthermore, apigenin treatment reversed the CSE-induced downregulation of PPARγ and its downstream effector, FATP2. Apigenin also restored intestinal mucosal integrity, promoted the enrichment of the probiotic Clostridia vadinBB60 group, and elevated intestinal difluprednate levels, which strongly correlated with increased glucocorticoid receptor (GR) expression in lung tissue. Mechanistically, apigenin facilitated the recruitment of PGC1α to PPARγ, thereby promoting PPARγ nuclear translocation and subsequent FATP2 activation in CSE-challenged MLE-12 cells. In RAW264.7 macrophages, difluprednate mediated GR nuclear translocation, subsequently suppressing the mRNA expression of the pro-inflammatory cytokines IL-1β and IL-6. Collectively, these findings identify apigenin as a dual-pathway modulator that bridges PPARγ/FATP2-mediated metabolic homeostasis with GR-dependent anti-inflammatory signaling, highlighting its therapeutic potential against smoking-related pulmonary dysfunction and supporting its application as a functional food intervention.