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Review
. 2024 May 21;10(1):242.
doi: 10.1038/s41420-024-02007-1.

Ferroptosis exacerbates hyperlipidemic acute pancreatitis by enhancing lipid peroxidation and modulating the immune microenvironment

Xinyi Gu #  1 , Zhicheng Huang #  1 , Xiuzhiye Ying #  1 , Xiaodie Liu  1 , Kaiyi Ruan  2 , Sijia Hua  1 , Xiaofeng Zhang  3   4   5 , Hangbin Jin  3   4   5 , Qiang Liu  6   7   8 , Jianfeng Yang  9   10   11   12
Affiliations
Review

Ferroptosis exacerbates hyperlipidemic acute pancreatitis by enhancing lipid peroxidation and modulating the immune microenvironment

Xinyi Gu et al. Cell Death Discov. .

Abstract

Abnormal activation of ferroptosis worsens the severity of acute pancreatitis and intensifies the inflammatory response and organ damage, but the detailed underlying mechanisms are unknown. Compared with other types of pancreatitis, hyperlipidemic acute pancreatitis (HLAP) is more likely to progress to necrotizing pancreatitis, possibly due to peripancreatic lipolysis and the production of unsaturated fatty acids. Moreover, high levels of unsaturated fatty acids undergo lipid peroxidation and trigger ferroptosis to further exacerbate inflammation and worsen HLAP. This paper focuses on the malignant development of hyperlipidemic pancreatitis with severe disease combined with the core features of ferroptosis to explore and describe the mechanism of this phenomenon and shows that the activation of lipid peroxidation and the aberrant intracellular release of many inflammatory mediators during ferroptosis are the key processes that regulate the degree of disease development in patients with HLAP. Inhibiting the activation of ferroptosis effectively reduces the intensity of the inflammatory response, thus reducing organ damage in patients and preventing the risk of HLAP exacerbation. Additionally, this paper summarizes the key targets and potential therapeutic agents of ferroptosis associated with HLAP deterioration to provide new ideas for future clinical applications.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Ferroptosis, lipid peroxidation, and acute pancreatitis.
During enzymatic lipid peroxidation, free unsaturated fatty acids are anchored and lengthened at the cell membrane by ACSL4 and LPCAT3, and newly produced long-chain unsaturated fatty acids enter the cytosol to cause calcium overload, which exacerbates pancreatic injury by decreasing ATP production, inducing inflammatory responses, and activating pancreatic enzyme pathways at inappropriate times. In addition, ALOX5 catalyzes the binding of free iron ions to unsaturated fatty acids and the gradual production of inflammatory mediators such as LTs to exacerbate the severity of AP. During nonenzymatic lipid peroxidation, the catabolic products of unsaturated phospholipids use the Fenton reaction to increase cell membrane damage and inappropriately activate pancreatic enzymes to cause SAP (PUFA, polyunsaturated fatty acid; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; AA, arachidonic acid; ALOX5, arachidonate-5-lipoxygenase; 5-HPETE, 5-hydroperoxyeicosatetraenoic acid; LT, leukotriene; PLOO-, phospholipid peroxyl radical; PLOOH, phospholipid hydroperoxide).
Fig. 2
Fig. 2. Ferroptosis regulates lipid peroxidation.
A FSP1 binds to the lipid bilayer and oxidizes NADPH, which increases the conversion of CoQ10 to CoQ10H2 to scavenge ROS, thus inhibiting lipid peroxidation. FSP1 activates ESCRT-III to capture Ca2+ and attenuates cytosolic damage in adenohypophysial cells. B NRF2 downregulates the severity of ferroptosis through the upregulation of NQO1 and HO-1 and increases NADPH expression. C FSP1 and NRF2 can not only alleviate the severity of SAP by inhibiting ferroptosis, but also alleviate pancreatic acinar cell damage by reducing calcium ion overload and ROS levels. (FSP1 fibroblast-specific protein, ESCRT-III endosomal sorting complex required for transport-III, NRF2 nuclear factor erythroid 2-related factor, NQO1 quinone oxidoreductase 1, HO-1 heme oxygenase-1, DAMP damage-associated molecular pattern, GSH glutathione, GPX4 glutathione peroxidase 4).
Fig. 3
Fig. 3. Ferroptosis and SAP-associated inflammatory cells.
DAMPs released after ferroptosis bind to TLR4 to increase the production of NETs to exacerbate pancreatic injury. Macrophages use TLR2 to recognize oxidized phospholipids and then phagocytose ferroptotic cells and progressively release HMGB-1, which promotes M1 macrophage polarization to enhance inflammatory responses. GPX4 downregulation promotes immune responses in Th1 and Th17 cells to increase the severity of inflammation. In contrast, low METTL3 expression increases GPX4 expression, which subsequently reduces NET formation by inhibiting ferroptosis. RSL3 alleviates the AP-associated inflammatory response by reducing M1 macrophage polarization through the inhibition of iNOS expression. GPX4 upregulation inhibits the proinflammatory effects of Th1 and Th17 cells (DAMP, damage-associated molecular pattern; TLR4, Toll-like receptor 4; TLR9, Toll-like receptor 9; NETs, neutrophil extracellular traps; HMGB-1, high mobility group box-1; TLR2, Toll-like receptor 2; GPX4, glutathione peroxidase 4; iNOS, inducible nitric oxide synthase; METTL3, methyltransferase-like 3; RSL3, an inhibitor of GPX4).
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