EGCG alleviates obesity-exacerbated lung cancer progression by STAT1/SLC7A11 pathway and gut microbiota.

Leptin is a nutritional cytokine, and it is closely related to the progression of cancer. However, the detailed effect of leptin in lung cancer remains poorly known. We found leptin-induced A549 cell proliferation, migration, and invasion, which was reversed by epigallocatechin gallate (EGCG) from green tea. Currently, we found that leptin-triggered M2 polarization of tumor-associated macrophages was inhibited by EGCG. Then, to investigate the underlying mechanism effect of leptin on A549 cells was studied. Aberrant activities of STAT1 are implicated in cancer development. Based on the cancer genome atlas data, STAT1 acted as an oncogene in lung cancer and EGCG greatly reduced STAT1 expression in A549 cells. Ferroptosis is an iron-dependent nonapoptotic cell death. STAT1 served as a transcriptional activator for SLC7A11. EGCG restrained lung cancer cell growth induced by leptin via targeting STAT1-SLC7A11 mediated ferroptosis. A high-fat diet (HFD) feeding condition was combined with a multi-dose urethane-induced lung tumorigenesis model using C57BL/6J mice. Obesity was induced with a 60 kcal% HFD feeding. Serum leptin levels increased in urethane-administered and HFD-fed mice. Compared to the control diet-fed mice, the HFD-fed mice exhibited increased lung tumor burden and typical pro-tumorigenic STAT1 activation in lung tissues after urethane administration. In addition, HFD alters the gut microbiome by decreasing the abundance of Clostridia and by increasing the abundance of Deltaproteobacteria and Epsilonproteobacteria while EGCG exhibited a reversed effect. These findings suggested that leptin promoted the development of lung tumorigenesis in vitro and in vivo via mediating activation of the STAT-SLC7A11 pathway and gut microbiota.