Fisetin-loaded Nanoemulsion and Fecal Microbiome Extract Enhance In Vitro Inhibition of Non-Small Cell Lung Cancer Progression

Lung cancer (LC) remains the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. While conventional treatments such as chemotherapy and radiotherapy are highly established, adverse effects and therapy resistance necessitate the exploration of novel therapeutic strategies. This study investigates the in vitro anti-cancer potential of the flavonoid fisetin and its nanoemulsion formulation (FNE) in NSCLC, alongside fecal microbiome extract (FME) as a potential adjunct therapy. In vitro functional assays demonstrated that while pure fisetin powder did not significantly inhibit NSCLC cell proliferation, colony formation nor cell migration, FNE and FME exhibited notable cytotoxic effects. Protein array analysis identified significant downregulation of 22 key oncogenic proteins implicated in lung cancer tumour development, epithelial-mesenchymal transition, tumour microenvironment, immunomodulation, therapy resistance, and metastasis. Importantly, the computational analysis supported these results by identifying fisetin-associated genes that correspond to the experimentally downregulated proteins. Computational in silico analysis of fisetin-associated genes identified multiple lung cancer targets including IL6, SERPINE1, PDGFA, MMP3, MST1, MET, and ENPP2. These findings highlight the enhanced therapeutic efficacy achieved through a phytoceutical-loaded nanoemulsion and microbiome-modulated anti-cancer mechanisms, with improved outcomes when combining FNE and FME treatments. The integration of phytoceuticals and microbiome research represents a promising avenue for advancing NSCLC treatment strategies and overcoming current therapeutic limitations.