Unraveling the Potential Pathogenic Role of Squalene Synthase (SQS) in Lung Cancer Using Enzyme Inhibitors as Molecular Tools

Squalene synthase (SQS) is a key enzyme in the mevalonate pathway, catalyzing the first committed step in cholesterol biosynthesis. Several small-molecule SQS inhibitors have been developed thus far, initially aiming at treating hypercholesterolemia. Although their development for cardiovascular diseases was limited after clinical trials compared with statins, the potential of SQS as an anticancer target has recently gained renewed attention. Nevertheless, the evaluation of SQS inhibitors as anticancer agents has been rudimentary thus far. Herein, we attempted to provide some clear evidence of the potential of this enzyme as a "druggable" target in lung cancer. Accordingly, two chemically diverse SQS inhibitors were used as pharmacological tools and tested in different cancer-cell-based assays, providing some groundwork for their mechanistic underpinning in cancer cells. Lastly, in vivo studies corroborated the potent effect of SQS inhibition on lung inflammation and tumor burden, rendering SQS as a viable and promising drug target against lung cancer.