Polystyrene Microplastics Exposure Aggravates Clear Cell Renal Cell Carcinoma Progression via the NF‐κB and TGF‐β Signaling Pathways

Abstract Polystyrene microplastics (PS‐MPs) are increasingly associated with carcinogenesis. However, their specific role in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, the microplastics in ccRCC tissues and normal adjacent tissues (NAT) are detected utilizing Py‐GC/MS, LDIR, and SEM. Tumor functional assays are conducted to assess the effects of PS‐MPs on ccRCC cellular behaviors. Transcriptomic alterations induced by PS‐MPs are characterized via RNA‐sequencing (RNA‐seq) analysis. Key signaling pathways are investigated through immunoblotting, immunocytochemistry, and ELISA. PDO and CDX models are employed to evaluate the effects of PS‐MPs on ccRCC progression and intervention strategies. The results demonstrate that PS‐MPs are markedly abundant in ccRCC tissues compared to NAT. Cytoplasmic accumulation of PS‐MPs promotes malignant phenotypes in ccRCC cells. RNA‐seq analysis demonstrates significant enrichment of oncogenic pathways following PS‐MPs exposure. Mechanistic validation confirms PS‐MPs exposure activates the NF‐κB and TGF‐β pathways in ccRCC. In preclinical models, PS‐MPs accelerate ccRCC growth, which is attenuated by treatment with the pathway inhibitors. In conclusion, this study provides the first comprehensive evidence that PS‐MPs exacerbate ccRCC progression through activating the NF‐κB and TGF‐β pathways. These findings establish PS‐MPs as an environmental risk factor for ccRCC and identify potential therapeutic targets to counteract PS‐MPs‐mediated oncogenic effects.