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Review
. 2023 May 11;13(5):820.
doi: 10.3390/biom13050820.

The Induction Mechanism of Ferroptosis, Necroptosis, and Pyroptosis in Inflammatory Bowel Disease, Colorectal Cancer, and Intestinal Injury

Ping Zhou  1   2 , Shun Zhang  1   2 , Maohua Wang  1   2 , Jun Zhou  1   2
Affiliations
Review

The Induction Mechanism of Ferroptosis, Necroptosis, and Pyroptosis in Inflammatory Bowel Disease, Colorectal Cancer, and Intestinal Injury

Ping Zhou et al. Biomolecules. .

Abstract

Cell death includes programmed and nonprogrammed cell death. The former mainly includes ferroptosis, necroptosis, pyroptosis, autophagy, and apoptosis, while the latter refers to necrosis. Accumulating evidence shows that ferroptosis, necroptosis, and pyroptosis play essential regulatory roles in the development of intestinal diseases. In recent years, the incidence of inflammatory bowel disease (IBD), colorectal cancer (CRC), and intestinal injury induced by intestinal ischemia-reperfusion (I/R), sepsis, and radiation have gradually increased, posing a significant threat to human health. The advancement in targeted therapies for intestinal diseases based on ferroptosis, necroptosis, and pyroptosis provides new strategies for treating intestinal diseases. Herein, we review ferroptosis, necroptosis, and pyroptosis with respect to intestinal disease regulation and highlight the underlying molecular mechanisms for potential therapeutic applications.

Keywords: colorectal cancer; ferroptosis; inflammatory bowel disease; intestinal injury; necroptosis; pyroptosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of ferroptosis. Ferroptosis is mainly related to disorders of amino acid metabolism, accumulation of lipid peroxides, and disorders of iron ion metabolism. Xc complex imports cystine for the synthesis of glutathione. GPX4 uses glutathione to prevent the accumulation of lipid-reactive oxygen species. The classical Fenton reaction between Fe3+ and Fe2+ produces abundant reactive oxygen species. Decreased iron stores or increased iron intake can lead to iron overload and eventually iron death. In addition, other signaling pathways and regulators control ferroptosis sensitivity. For example, erastin can bind to porin 2/3 on the outer mitochondrial membrane, causing mitochondrial dysfunction and the release of many oxidative substances, ultimately leading to ferroptosis.
Figure 2
Figure 2
Mechanisms of necroptosis. Death receptors (TNFR, TLR, and IFNR) bind to their corresponding ligands (as shown) and are activated to trigger necroptosis. Upon caspase-8 or cIAP depletion, they promote the assembly of the RIPK1–RIPK3–MLKL signaling complex, resulting in the phosphorylation of MLKL (p-MLKL). Phosphorylated MLKL translocates to the plasma membrane to initiate membrane damage and form macropores. Ultimately, MLKL pores lead to necroptosis by allowing ion influx, cell swelling, membrane lysis, and subsequent uncontrolled release of intracellular substances. Due to membrane damage, potassium efflux can further activate NLRP3 through NEK7, increasing the release of inflammatory mediators. Recent studies have also found inhibitory factors of necroptosis, such as Nec-1 and SMYD2.
Figure 3
Figure 3
Mechanisms of pyroptosis. Sensing pathogens or DAMPs by inflammatory vesicles promotes the formation of an inflammatory vesicle complex that involves NLRP3/NLRC4/AIM2/Pyrin, ASC, and caspase-1 in the classical pathway. In the nonclassical pathway, LPS leads to caspase-11 activation. Activated caspase-1 and caspase-11 shear GSDMD and form GSDMD-NT. Some chemotherapeutic agents can induce the activation of caspase-3 and caspase-8. Then, activated caspase-3 and caspase-8 can cleave GSDME and GSDMC and form GSDME-NT with GSDMC-. In mouse macrophages, Yersinia pestis infection inhibited TAK1 activity, which caused the cleavage of GSDMD by caspase-8. GSDMB-NT, GSDMC-NT, GSDMD-NT, and GSDME-NT can oligomerize and translocate to the plasma membrane, thus forming cellular pores, causing cytoplasmic swelling, and releasing proinflammatory cytokines and cellular contents.
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Grants and funding

This research was funded by the National Natural Science Foundation of China, grant number 81873930, and the Sichuan Science and Technology Program, grant number 2022YFS0632 and 2020YJ0189.