Glutathion peroxidase 4 (GPX4) and Ribosomal Protein L40 (RPL40) participate in arsenic induced progression of renal cell carcinoma by regulating the NLRP3 mediated classic pyroptosis pathway

Epidemiological studies have demonstrated that long-term exposure to high‑arsenic water increases the risk of kidney Cancer. Kidney dysfunction can lead to the accumulation of metabolic waste and chronic inflammation, with the latter being a significant factor in tumor development. Therefore, it is crucial to investigate how environmental arsenic exposure affects renal function and inflammation, as well as its potential influence on the progression of renal carcinoma. Additionally, Pyroptosis plays an essential role in immune responses and the maintenance of cellular homeostasis. However, the role and mechanisms of Pyroptosis in arsenic-induced kidney Cancer progression remain unexplored. Our findings indicated that low-dose arsenic exposure reduces Pyroptosis and promotes abnormal proliferation of renal tubular epithelial cells, while high-dose exposure enhances Pyroptosis and damages renal tissue structure in mouse models. Mechanistically, in vitro studies confirmed that low-dose arsenic exposure promotes the progression of renal cell carcinoma by downregulating NLRP3 and inhibiting Pyroptosis, whereas high-dose exposure has the opposite effect. Proteomics analysis identified GPX4 and RPL40 as key proteins mediating Pyroptosis induced by low and high doses of arsenic, respectively. Furthermore, GPX4 and RPL40 were shown to regulate the malignant progression of renal cell carcinoma through their effects on NLRP3-mediated Pyroptosis. This study reveals that arsenic exposure induces Pyroptosis via NLRP3, leading to renal injury and influencing the malignant progression of renal Cancer. Notably, GPX4 and RPL40 regulate this progression under low and high-dose arsenic exposure, respectively.

Arsenic; GPX4; NLRP3; Pyroptosis; RPL40; Renal clear cell cancer.