Because of the reactivity of this and other aliphatic and aromatic aldehydes, cells have developed mechanisms to detoxify these molecules. Accumulation of 4HNE, which can induce cellular injury, may be caused by deficiencies in the process of toxic product elimination. Oxidative stress increases HNE-adducted proteins. This increase is partially reduced by the conjugation of HNE with GSH that forms the glutathione conjugate of HNE, which is a substrate of the multidrug resistant associated protein, MRP1. Perfusion of the rat heart with HNE leads to the formation and efflux of GS-HNE, suggesting a role for MRP1 in the clearance of GS-HNE from cardiac tissue. We have previously observed that MRP1 likely mediates the saturable efflux of the glutathione conjugate of HNE observed upon infusion of HNE to the perfused heart that protects the cardiomyocytes. However, under conditions of oxidative stress, accumulated 4HNE modifies and regulates enzymes involved in mitochondrial energy production, which results in the increased ROS generation and diminished protein degradation that may activate autophagic pathways. Despite advances in research and treatment, lung cancer remains one of the leading causes of death globally, with fiveyear survival rates as low as 15%. While the majority of lung cancers develop in smokers, other carcinogens including asbestos may contribute to lung cancer development. The contribution of asbestos to lung cancer in persons exposed to both tobacco and asbestos is difficult to quantify because of interactions between the two agents in initiating and promoting neoplastic changes. Apart from a history of exposure, there are no clinicopathologic criteria distinguishing asbestos-related and tobacco-related lung cancers. Recently, we and others have reported gene expression profiles that can potentially differentiate between these subtypes. Although lung cancer histopathologic subtypes observed in persons with and without asbestos exposure are similar, evidence is accruing that primary adenocarcinomas and squamous cell carcinomas of the lung arise by distinctly different carcinogenic pathways and display different sensitivities to targeted therapies. We recently identified ADAM28 as a candidate oncogene in asbestos-related lung adenocarcinomas. Here we compare gene expression between asbestos-related and non-asbestos related primary lung squamous cell carcinomas. Our aims were 1) to determine whether SCC gene expression profiles differed between individuals with and without evidence of prior asbestos exposure as determined by pulmonary asbestos lung fiber count, and 2) to discover and validate candidate gene expression biomarkers of ARLC-SCC that could be potential diagnostic markers. The exact contribution of asbestos to lung cancer burden in modern times is difficult to ascertain with certainty.