JMJD6-DGAT1 axis-mediated lipogenesis is involved in arsenic-induced oncogenic phenotypes of uroepithelial cells.

Arsenic is a widespread global pollutant, and its exposure increases the risk of bladder cancer. However, the exact mechanism involved is still unclear. Here, we explored the mechanisms of arsenic-induced lipid metabolism reprogramming in malignant phenotypes, focusing on the regulatory role of acylglycerol-acyltransferase 1 (DGAT1), a key enzyme in the final step of triglyceride synthesis. The effects of continuous exposure to arsenic for 12 weeks on the lipid metabolism were assessed in vivo. We observed that arsenic exposure increased lipogenesis and upregulated DGAT1 expression in rat uroepithelial cells. In vitro studies showed that chronic exposure to arsenic upregulated DGAT1 to store de novo synthesized-fatty acid into triglycerides and lipid droplets. Under arsenic exposure, inhibition of DGAT1 led to excessive fatty acid into the mitochondria for β-oxidation, inducing ferroptosis and suppressing cell proliferation. Additionally, we identified that Jumonji domain-containing 6 (JMJD6) as a key transcriptional regulator of DGAT1 and highlighted the role of JMJD6 in regulating DGAT1 in lipid metabolism remodeling during arsenic-induced malignant phenotype of uroepithelial cells. This study provides new clue for the mechanisms of arsenic carcinogenesis and proposes a reliable reference for mitigating arsenic toxicity.