Platinum-based chemotherapy is still widely applied for the treatment of advanced non-small cell lung cancer (NSCLC). However, acquired chemoresistance compromises the curative effect of this drug. In this study, we found that glucose-6-phosphate dehydrogenase (G6PD), a critical enzyme of the pentose phosphate pathway, contributed to cisplatin resistance in NSCLC. The experimental results showed that transforming growth factor beta 1 (TGFβ1) increased the expression of G6PD by activating the forkhead box protein M1-high mobility group AT-hook 1-G6PD (FOXM1-HMGA1-G6PD) transcriptional regulatory pathway, in which TGFβ1 inhibited the ubiquitination and degradation of FOXM1 protein. Additionally, HMGA1 induced TGFβ1 expression, and neutralized TGFβ1 in the culture medium downregulated HMGA1 levels, suggesting the existence of a TGFβ1-FOXM1-HMGA1-TGFβ1 positive feedback loop and its role in maintaining G6PD expression. Further investigations showed that exogenous TGFβ1 enhanced the cisplatin resistance of NSCLC cells, while disrupting the FOXM1-HMGA1-G6PD pathway, thereby sensitizing the cells to cisplatin. Consistently, the TGFβ1-FOXM1-HMGA1-G6PD axis was confirmed in NSCLC tissues, and overactivation of this axis predicted poor survival in NSCLC patients. Collectively, the results of this study demonstrate that the TGFβ1-FOXM1-HMGA1-TGFβ1 positive feedback loop plays a crucial role in the cisplatin resistance of NSCLC by upregulating the expression of G6PD, providing a potential therapeutic target to restore chemosensitivity in cisplatin-resistant NSCLC.
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