Benzo[a]pyrene-induced METTL3 overexpression accelerates renal cell carcinoma progression via m6A modification of LTB4R mRNA and enhanced Treg infiltration

Abstract

Benzo[ a ]pyrene (BaP) is a widespread environmental pollutant and a representative polycyclic aromatic hydrocarbon with well-established carcinogenic properties. However, the molecular mechanisms through which BaP promotes renal cell carcinoma (RCC) progression, particularly those involving epigenetic modifications and immune modulation, remain poorly understood. In this study, we integrated transcriptomic data from The Cancer Genome Atlas (TCGA) and the Comparative Toxicogenomics Database (CTD) to identify BaP-related N6-methyladenosine (m⁶A)-associated genes in RCC. We established an m⁶A-based prognostic signature, defined molecular subtypes, and further validated the key axis using benzo[ a ]pyrene-7,8-diol-9,10-epoxide (BPDE)-induced in vitro malignant transformation models, BaP-exposed mouse xenograft models, and human RCC specimens. We found that BaP exposure upregulated methyltransferase-like 3 (METTL3) expression and increased global m⁶A levels. Mechanistically, METTL3-mediated m⁶A modification of leukotriene B4 receptor 1 (LTB4R) mRNA was recognized by the m⁶A reader protein insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which stabilized LTB4R mRNA and thereby increased LTB4R expression. The METTL3/LTB4R axis promoted BPDE-induced malignant phenotypes, including the proliferation, migration, and invasion of renal epithelial cells. Moreover, LTB4R-overexpressing tumor cells recruited regulatory T cells (Tregs), and co-culture with Tregs further enhanced malignant behaviors through the METTL3/LTB4R axis. In vivo, METTL3 inhibition or knockout suppressed tumor growth, whereas LTB4R overexpression reversed these effects. Our findings demonstrate that BaP exposure promotes RCC progression through METTL3-mediated m⁶A modification of LTB4R and Treg infiltration, providing new insights into the epitranscriptomic mechanisms of environmental carcinogenesis and identifying the METTL3/LTB4R axis as a potential therapeutic target for BaP-associated RCC.