Anesthetic propofol inhibits ferroptosis and aggravates distant cancer metastasis via Nrf2 upregulation

The impact of anesthetic management on the prognosis of patients with cancer undergoing surgery is controversial. Circulating tumor cells (CTCs) play critical roles during cancer metastasis and can be released in large quantities during surgery. The ferroptosis of CTCs is related to metastasis. Whether anesthetics affect distant metastasis by increasing the survival of CTCs is unknown. To test this hypothesis, mice were inoculated with cancer cells via tail vein injection before treatment with propofol or sevoflurane for 2 h. After 2 weeks, more metastases were observed in the propofol group compared with the sevoflurane and vehicle groups. Then, we used the ferroptosis inhibitor ferrostatin-1 to explore the effect of ferroptosis on metastasis. Similar to propofol, pretreatment with ferrostatin-1 significantly increased CTC survival in mouse lungs at 24 h and the tumor burden at 10 weeks post-inoculation. Moreover, propofol protected cancer cells from RSL3-induced ferroptosis in vitro, as evidenced by decreases in intracellular levels of reactive oxygen species (ROS), lipid peroxide, and ferroptosis markers. Further studies showed that propofol treatment upregulated the expression of nuclear factor erythroid 2‐related factor 2 (Nrf2) and its downstream target genes, including HO-1, NQO1, and SLC7A11. Finally, the targeted knockdown of Nrf2 abolished the anti-ferroptosis effect of propofol. Collectively, we demonstrated the risk of a specific type of anesthetic, propofol, in promoting cancer cell metastasis through Nrf2-mediated ferroptosis inhibition. These findings may guide the choice of anesthetic for surgical removal of tumors.