Skip to main page content (VSports)
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in VSports app下载. gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely V体育官网. .

Review
. 2022 Nov 30;23(23):15031.
doi: 10.3390/ijms232315031.

Emerging Potential Mechanism and Therapeutic Target of Ferroptosis in PDAC: A Promising Future (V体育2025版)

Chang Li  1   2 , Xunzhe Yin  1 , Zuojia Liu  1 , Jin Wang  3
Affiliations
Review

Emerging Potential Mechanism and Therapeutic Target of Ferroptosis in PDAC: A Promising Future

Chang Li et al. Int J Mol Sci. .

Abstract

Pancreatic cancer (PC) is a devastating malignant tumor of gastrointestinal (GI) tumors characterized by late diagnosis, low treatment success and poor prognosis VSports手机版. The most common pathological type of PC is pancreatic ductal adenocarcinoma (PDAC), which accounts for approximately 95% of PC. PDAC is primarily driven by the Kirsten rat sarcoma virus (KRAS) oncogene. Ferroptosis was originally described as ras-dependent cell death but is now defined as a regulated cell death caused by iron accumulation and lipid peroxidation. Recent studies have revealed that ferroptosis plays an important role in the development and therapeutic response of tumors, especially PDAC. As the non-apoptotic cell death, ferroptosis may minimize the emergence of drug resistance for clinical trials of PDAC. This article reviews what has been learned in recent years about the mechanisms of ferroptosis in PDAC, introduces the association between ferroptosis and the KRAS target, and summarizes several potential strategies that are capable of triggering ferroptosis to suppress PDAC progression. .

Keywords: KRAS; PDAC; ferroptosis; therapy; tumorigenesis. V体育安卓版.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the collection and analysis of data and in the writing of the manuscript, or in the decision to publish the results V体育ios版.

Figures

Figure 1
Figure 1
The core mechanism of ferroptosis. Ferroptosis is mainly caused by iron-dependent lipid peroxidation (PLOOH). The xc- system imports cystine into cells with the 1:1 counter-transport of glutamate. GPX4 converts GSH to GSSG and reduces PLOOH, thereby blocking the lipid peroxidation chain reaction and inhibiting ferroptosis. Several proteins (including TFR1, NCOA4, ATG5, and ATG7) mediate ferritinophagy and promote iron accumulation in ferroptosis through the regulation of iron metabolism. Fe2+ can greatly induce PLOOH through the Fenton reaction, which then induces ferroptosis. Increasing PUFA synthesis can increase the sensitivity to ferroptosis, which is mainly regulated by ACSL4 and LPCAT3. Abbreviations: SLC7A11,zd solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2; GSH, glutathione; GSSG, glutathione disulfide; GPX4, glutathione peroxidase 4; PLOOH, phospholipid hydroperoxide; ROS, reactive oxygen species; H2O2, hydrogen peroxide; Fe2+, ferrous iron; Fe3+, ferric iron; TFR1, transferrin receptor 1; NCOA4, nuclear receptor coactivator 4; ATG5, autophagy-related 5; ATG7, autophagy-related 7; PUFAs, polyunsaturated fatty acids; PUFA-CoA, polyunsaturated fatty acyl-coenzyme a; PL-PUFA, polyunsaturated phospholipid; ALOX, lipoxygenase; LPCAT3, lysophosphatidylcholine acyltransferase 3; ACSL4, acyl coenzyme A (CoA) synthetase long-chain family member 4; ER, endoplasmic reticulum.
Figure 2
Figure 2
KRAS of ferroptosis in PDAC. The depletion of GPX4 or the release of H2O2 from PLOOH causes the release of 8-OHG, which leads to the activation of cytokine production in macrophages and promotes tumor growth. Ferroptotic PDAC cells can also release the KRASG12D protein, activating the RAS-RAF-MEK-ERK pathway, thereby inducing AGER-dependent macrophage M2 polarization and producing immunosuppressive cytokines in the tumor microenvironment and inhibiting apoptosis from promoting tumor cell growth. By contrast, the depletion of SLC7A11 in PDAC cells or the administration of cyst(e)inase suppresses tumor growth by releasing HMGB1 to initiate T cells and thus generate antigen-specific adaptive immune responses. Abbreviations: 8-OHG, 8-hydroxy-2′-deoxyguanosine; AGER, advanced glycosylation end product-specific receptor; GPX4, glutathione peroxidase 4; GSH, glutathione; H2O2, hydrogen peroxide; HMGB1, high mobility group box 1; PDAC, pancreatic ductal adenocarcinoma; SLC7A11, solute carrier family 7 member 11; PLOOH, phospholipid hydroperoxide.
Figure 3
Figure 3
Mechanism of ferroptosis involved in PDAC. Ferroptosis is an iron-dependent cell death driven by lipid peroxidation. There are multiple ways to regulate the level of ferroptosis in PDAC cells, such as transcription factors, autophagic degradation and metabolic pathways. System xc- and GPX4 act as the key regulators in the process of ferroptosis in PDAC. AMPK-Beclin1 pathway trigger ferroptosis by inhibiting system xc-. Irisin serves as a suppressor of ferroptosis by increasing the accumulation of lipid reactive oxygen and the depletion of GSH. NCOA4 accumulates in lysosomes and then promotes ferritinophagy, leading to iron accumulation and, ultimately, ferroptosis. ARF6 increases the expression of ASCL4 and induces ferroptosis by increasing the expression of PLOOH. ALDH2 decreases 4-HNE production in PDAC cells and blocks the ferroptosis pathways by reducing oxidative stress ROS. Abbreviations: GSH, glutathione; GPX4, glutathione peroxidase 4; PDAC, pancreatic ductal adenocarcinoma; AMPK, AMP-activated protein kinase; NCOA4, nuclear receptor coactivator 4; ACSL4, acyl coenzyme A (CoA) synthetase long-chain family member 4; ALDH2, aldehyde dehydrogenase 2; 4-HNE, 4-hydroxy-2-nonenal; ROS, reactive oxygen species.
Figure 4
Figure 4
Ferroptosis in the treatment of PDAC. KrasG12D mutations can inhibit PDAC cell apoptosis by blocking ferroptosis. There are many therapeutic ways to cure PDAC by inducing ferroptosis in PDAC cells, such as targeted therapy, immunotherapy, nanomedicine, and radiotherapy. Abbreviations: PDAC, pancreatic ductal adenocarcinoma.
See this image and copyright information in PMC

"V体育ios版" References

    1. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA-Cancer J. Clin. 2021;71:209–249. doi: 10.3322/caac.21660. - DOI - PubMed
    1. Kleeff J., Korc M., Apte M., La Vecchia C., Johnson C.D., Biankin A.V., Neale R.E., Tempero M., Tuveson D.A., Hruban R.H., et al. Pancreatic cancer. Nat. Rev. Dis. Primers. 2016;2:22. doi: 10.1038/nrdp.2016.22. - DOI - PubMed
    1. Mizrahi J.D., Surana R., Valle J.W., Shroff R.T. Pancreatic cancer. Lancet. 2020;395:2008–2020. doi: 10.1016/S0140-6736(20)30974-0. - DOI - PubMed
    1. Quinonero F., Mesas C., Doello K., Cabeza L., Perazzoli G., Jimenez-Luna C., Rama A.R., Melguizo C., Prados J. The challenge of drug resistance in pancreatic ductal adenocarcinoma: A current overview. Cancer Biol. Med. 2019;16:688–699. doi: 10.20892/j.issn.2095-3941.2019.0252. - DOI - PMC - PubMed
    1. Ischenko I., D’Amico S., Rao M., Li J.Y., Hayman M.J., Powers S., Petrenko O., Reich N.C. KRAS drives immune evasion in a genetic model of pancreatic cancer. Nat. Commun. 2021;12:15. doi: 10.1038/s41467-021-21736-w. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances