Metformin's hidden power: Unveiling its role in melanoma suppression through endo-lysosome pH and autophagy regulation.

Metformin, a widely used agent for type 2 diabetes treatment, has been found to reduce the risk of cancer in patients with diabetes in recent years. In preclinical studies, researchers found that metformin, when used alone, exhibits anti-tumor effects both in vitro and in vivo. However, the anti-tumor mechanisms of metformin remain to be further explored. In this study, we found that metformin alkalized endo-lysosome pH and inhibited autophagy by targeting the endosomal transmembrane protein NHE6 (Na+-H+ Exchanger 6), thereby inhibiting melanoma cell growth and survival. In contrast, the knockout of NHE6 in B16F10 cells acidified the endo-lysosomal pH and activated autophagy, which in turn reversed the metformin-induced pH and autophagy regulation and blunted the anti-tumor effects of metformin both in vitro and in vivo. Interestingly, knockout of NHE6 also suppressed B16F10 cell growth and survival. However, NHE6 could be rescued by restoration of endo-lysosome pH, suggesting that activation or inhibition of autophagy by pH interference might be detrimental to the fate of B16F10 cells. Taken together, we conclude that metformin could suppress melanoma progression by inhibiting autophagy based on endo-lysosome pH regulation. In addition, we also found the potential role of NHE6 in the progression of melanoma, which is worth further study as novel theoretical evidence for future melanoma pathogenesis and targeted therapy research.