Pharmacological inhibition of SREBP1 suppresses pancreatic cancer growth via inducing GPX4-mediated ferroptosis.

Pancreatic cancer (PC) is highly malignancy with poor survival. Ferroptosis offers a novel therapeutic target for cancer treatment and glutathione peroxidase 4 (GPX4) shields tumor cells from ferroptosis damage. Although Sterol regulatory element-binding protein 1 (SREBP1) has been implicated in the development of pancreatic cancer, its underlying mechanisms remain unclear. This research aims to explore the role of SREBP1 in ferroptosis by using its inhibitor Fatostatin. In this study, Fatostatin was found to inhibit the proliferation and clonogenicity of pancreatic cancer cell lines. This was accompanied by a reduction in intracellular lipid synthesis, increased iron accumulation, elevated levels of reactive oxygen species (ROS), and accumulation of malondialdehyde (MDA). The JASPAR database shows that there is a binding site of the SREBP1 on the promoter region of GPX4. What's more, it was verified that SREBP1 can transcriptionally regulate GPX4 by CHIP. In vivo experiments further revealed that Fatostatin could suppress the growth of subcutaneous tumors in nude mice. In conclusion, our study suggests that Fatostatin may inhibit pancreatic cancer cell proliferation by inducing ferroptosis through the SREBP1/GPX4 pathway. These findings shed light on the therapeutic potential of Fatostatin and lay the groundwork for future investigations into its mechanism of action in pancreatic cancer.