%A Wenjing Zhou, Jing Zhang, Mingkun Yan, Jin Wu, Shuo Lian, Kang Sun, Baiqing Li, Jia Ma, Jun Xia, Chaoqun Lian %T Orlistat induces ferroptosis-like cell death of lung cancer cells %0 Journal Article %D 2021 %J Front. Med. %J Frontiers of Medicine %@ 2095-0217 %R 10.1007/s11684-020-0804-7 %P 922-932 %V 15 %N 6 %U {https://journal.hep.com.cn/fmd/EN/10.1007/s11684-020-0804-7 %8 2021-12-15 %X

Aberrant de novo lipid synthesis is involved in the progression and treatment resistance of many types of cancers, including lung cancer; however, targeting the lipogenetic pathways for cancer therapy remains an unmet clinical need. In this study, we tested the anticancer activity of orlistat, an FDA-approved anti-obesity drug, in human and mouse cancer cells in vitro and in vivo, and we found that orlistat, as a single agent, inhibited the proliferation and viabilities of lung cancer cells and induced ferroptosis-like cell death in vitro. Mechanistically, we found that orlistat reduced the expression of GPX4, a central ferroptosis regulator, and induced lipid peroxidation. In addition, we systemically analyzed the genome-wide gene expression changes affected by orlistat treatment using RNA-seq and identified FAF2, a molecule regulating the lipid droplet homeostasis, as a novel target of orlistat. Moreover, in a mouse xenograft model, orlistat significantly inhibited tumor growth and reduced the tumor volumes compared with vehicle control (P<0.05). Our study showed a novel mechanism of the anticancer activity of orlistat and provided the rationale for repurposing this drug for the treatment of lung cancer and other types of cancer.