The Emerging Scenario of Ferroptosis in Pancreatic Cancer Tumorigenesis and Treatment

Abstract

Pancreatic cancer remains one of the most lethal forms of cancer. Currently, there is a lack of effective drug treatments for pancreatic cancer. However, as a newly discovered form of non-apoptotic cell death, ferroptosis has garnered increasing attention in relation to pancreatic cancer. Understanding the role of ferroptosis in the tumorigenesis and treatment of pancreatic cancer may enable more effective clinical trials and treatments for pancreatic cancer and may minimize side effects or restrict the emergence of drug resistance. In this review, we summarize the current knowledge regarding the process and underlying mechanisms of ferroptosis, as well as its dual role in both promoting tumorigenesis and facilitating treatment strategies for pancreatic cancer. Additionally, how ferroptosis is implicated in the development of pancreatitis and insulin resistance, indicating that ferroptosis may play an important role in the risk of pancreatitis- and insulin-resistance-related pancreatic cancers, is also addressed.

Keywords: drug resistance; ferroptosis; immunotherapy; pancreatic cancer; tumorigenesis.

Figure 1

Resistance system of ferroptosis. Ferroptosis is a form of non-apoptotic cell death caused by iron-dependent membrane lipid peroxidation. Cells have evolved at least four systems inhibiting ferroptosis with different subcellular localizations to decrease lipid peroxides. The system xc⁻-GSH-GPX4 axis can collaborate with the FSP1-CoQH2 axis on the plasma membrane and can also cooperate with the DHODH-CoQH2 axis on the mitochondrial membrane. The GCH1-BH4-DHFR axis also acts as a potent cellular antioxidant providing protection from ferroptosis in the absence of GPX4. Created with BioRender.com.

Figure 2

The iron, ROS, and lipid metabolism in ferroptosis. Free iron enters or exits cells through different transport pathways. Free iron mediates the production of ROS through the Fenton reaction to promote lipid oxidation and is involved in the ferroptosis process as cofactors of iron-dependent enzymes; the main sources of cellular ROS production are mETC and NOXs on the cell membrane; lipid droplets are the place where neutral lipids are stored in cells. Lipophagy induces autophagic degradation of lipid droplets and promotes the release of free fatty acid. Oxygenases, such as ALOX and POR, catalyze the oxidation of PUFAs and activate lipid peroxidation. Created with BioRender.com.

Figure 3

Ferroptosis in the progression of pancreatic cancer. Ferroptosis plays a dual role in pancreatic cancer: On the one hand, ferroptotic PDAC cells in KC mice with the pancreatic knockout Gpx4 will release 8-OHG or KRASG12D to promote the polarization of M2 macrophages and induce the release of related cytokines (e.g., IL6, IL10, ARG1, TGFB), thereby promoting the growth of pancreatic tumors. On the other hand, Slc7a11 knockout KPC mice not only inhibited the synthesis of CoA and GSH to induce ferroptosis, but subsequent ferroptosis cells also activated antigen-specific adaptive immune responses to inhibit tumors. B3GNT3 in PDAC cells inhibits ferroptosis to promote the growth of pancreatic tumors by mediating the protein stability of 4F2hc and enhancing the interaction between 4F2hc and xCT. The inhibition of GOT1 can promote ferroptosis through the enhancement of mitochondrial stress and the dysfunction of redox homeostasis. E2F1 inhibits ferroptosis and promotes malignant progression of pancreatic cancer by the transcriptional activation of PNO1. Created with BioRender.com.

Figure 4

Drug-induced ferroptosis in pancreatic cancer cells. ATF4 inhibits ferroptosis and increases gemcitabine resistance by promoting the transcriptional expression of HSPA5, thereby promoting the stability of GPX4. Low expression of FBW7 in tumors relieves its inhibition of NR4A1, thereby promoting the expression of SCD1 to inhibit ferroptosis and promote gemcitabine resistance. The anticancer and procancer effects of various drugs have been shown to be achieved by inducing/inhibiting ferroptosis. Created with BioRender.com.

Figure 5

Ferroptosis in pancreatitis. A large number of epidemiological studies have shown that pancreatitis is an important risk factor for pancreatic cancer. Recombinant SQSTM1 protein increases the production of PUFAs through the AGER-ACSL4 axis, leading to the occurrence of autophagy-dependent ferroptosis, thereby mediating the progression of AP. iMSCs and iAAT-MSCs ameliorate ferroptosis in acinar cells by regulating the FTH1-PDI-GPX4 axis, regulating ROS function and iron production. ARNTL prevents experimental acute pancreatitis by blocking the ferroptosis-mediated release of HMGB1. PSMD4 promotes GPX4 degradation to promote ferroptosis and pancreatic inflammation. Created with BioRender.com.

Figure 6

Ferroptosis in insulin resistance. Ferroptosis is essential for the occurrence of insulin resistance. METTL14- and YTHDF2-mediated m6A modification of PGC-1α promotes NRF1/GSTK1-dependent ferroptosis and hepatic insulin resistance. Ferroptosis can induce islet dysfunction, and ferroptosis inhibitors such as Fer-1 and DFO can reverse this process. Created with BioRender.com.