Targeting HMGB1/RAGE Axis with Metformin: a Potential Anti-Metastatic Strategy in Lung Adenocarcinoma

Lung cancer remains the leading cause of cancer-related mortality worldwide, with metastasis and resistance to therapy posing significant treatment challenges. HMGB1/RAGE signalling axis plays a central role in the process of metastasis. In this study, we investigated the potential of metformin, a well-known antidiabetic agent, to inhibit HMGB1/RAGE-mediated EMT and migration in A549 lung adenocarcinoma cells. Our findings demonstrate that recombinant HMGB1 increases RAGE expression and its localization to the cell membrane. Treatment with HMGB1 also elevates the levels of mesenchymal marker vimentin, enhancing the mi-gratory capacity of A549 cells. All these effects were notably suppressed by co-treatment with metformin. These results suggest that metformin disrupts HMGB1/RAGE interaction and signalling, thereby inhibiting EMT and migration. Collectively, our data support the hypothesis that metformin binds HMGB1 and prevents its interaction with RAGE, contributing to its antitumour effects. This highlights a novel anti-metastatic mechanism of metformin and underscores its potential as a complementary therapeutic strategy for targeting tumour progression in lung cancer.