Electronic Nicotine Delivery Systems (ENDS) including electronic cigarettes (e-cigarettes; e-cigs) are battery-operated heating devices which convert e-cigs liquid (e-liquid) into an inhalable vapors. These devices were marketed as a safer alternative to conventional tobacco cigarettes and therefore gained rapid popularity amongst all age groups in the United States (U.S.). With significant rise in life threatening lung illness cases linked to e-cigs in past few months, there is a recent surge to investigate the health effects of vaping. Since e-cigs are the products of new era compared to conventional smoking, there is only limited clinical data available in terms of the health effects of vaping. In this regard, PI's LBRN Pilot project focused to determine the effect of tobacco-flavored e-cigs vapor condensate (TF-ECVC) on the inflammatory responses and the expression/regulation of immunoproteasomes in human lung epithelial cells which can be rescued by Urolithin (Uro) A and Uro C (gut metabolites of ellagitannins and ellagic acid). Our findings reveal that Uro A rescues TF-ECVC mediated increases the production of inflammatory cytokines and chemokines; and expression of immunoproteasome subunits. Earlier reports also demonstrate that exposure to lipopolysaccharide results in compartmentalization of ubiquitin ligases, activation of proteasome and proteasome-mediated ERK activation in macrophage raft fractions. While, abundance of 20S proteasome subunits with high proteolytic activity has also been reported in exosomes released by tumor-associated macrophages. Our preliminary findings also revealed that proteome profile of lipid rafts isolated from TF-ECVC challenged cells (48h) contained several proteins associated with ubiquitin/proteasome pathway in the cargo. While exosomes isolated from the serum of secondhand smoke exposed C57Bl/6 mice showed significant accumulation of lipid rafts associated proteins. We therefore, hypothesize that modulation of lipid rafts may play critical role in compartmentalization/ activation of proteasome/immuno-proteasome subunits and downstream signaling TF-ECVC challenged human primary and adenocarcinoma lung epithelial cells. We will enrich the membrane rafts with n-3 PUFA or modulate the assembly of lipid rafts using Uro A, Uro C or chemical agent methyl-β-cyclodextrin (cholesterol depleting agent) to determine TF-ECVC responses in terms of .compartmentalization/ activation of proteasome/immuno-proteasome subunits and downstream signaling in rafts and exosomes.