The development of novel therapeutics for non-small cell lung cancer (NSCLC) is urgently needed. Epithelial to mesenchymal transition (EMT) is a developmental cellular program that determines tumor aggressiveness by causing metastasis and chemoresistance, but no drug is approved to target it. Metabolic pathways represent attractive therapeutic targets for cancer, also for controlling EMT (Ramesh et al. Trends in Cancer 2020). This work aimed at identifying metabolic pathways with a potential regulatory role on EMT in NSCLC. By an EMT-focused large-scale transcriptomics analysis on NSCLC patients’ datasets, we found that EMT can be inhibited by metabolites belonging to the class of short chain fatty acids propionate and butanoate. These are small non-toxic metabolites produced by commensal microbiota potentially safe for therapeutic use. Treatment of lung cancer cell lines with sodium propionate (SP): 1) reduced EMT markers and in vitro migration, 2) impaired their metastatic ability once injected in immune-deficient mice and lymph nodal metastasis in a CRISPR/Cas9-based mouse model of NSCLC, and 3) sensitized towards cisplatin, backbone for cytotoxic chemotherapy in advanced-stage patients. Mechanistically, RNA-sequencing, ChIP-sequencing and histones PTM profiling indicated chromatin remodeling via p300-mediated histone acetylation as the mechanism behind EMT attenuation. Additional work is currently ongoing to understand the role of lung microbiota on lung cancer EMT. This class of metabolites could be tested for chemoprevention of metastasis and for breaking EMT and chemotherapy resistance. Targeting EMT could have important implications in reducing the devastating effects of aggressive NSCLCs. Potential implications for breast cancer research and treatment are discussed.