Focus on the Role of Inflammation as a Bridge between Ferroptosis and Atrial Fibrillation: A Narrative Review and Novel Perspective

In this comprehensive review, we examine the intricate interplay between inflammation, ferroptosis, and atrial fibrillation (AF), highlighting their significant roles in AF pathophysiology and pathogenesis. Augmented inflammatory responses are pivotal to AF, potentially leading to atrial remodeling and reentry phenomena by impacting calcium channels and atrial tissue fibrosis. A strong correlation exists between inflammatory cytokines and AF, underscoring the importance of inflammatory signaling pathways, such as NOD-like receptor thermal protien domain associated protein 3 (NLRP3) inflammasome, Nuclear Factor kappa B (NF- $\kappa{}$ B) signaling, and Tumor necrosis factor- $\alpha{}$ (TNF- $\alpha{}$ ) signaling in AF development. Ferroptosis, a non-apoptotic regulated mode of cell death, has been widely studied in relation to cardiovascular diseases including heart failure, myocardial infarction, cardiomyopathy, and reperfusion injury. The interaction between ferroptosis and inflammation is complex and mutually influential. While significant progress has been made in understanding the inflammation-AF relationship, the role of inflammation as a conduit linking ferroptosis and AF remains underexplored. The specific pathogenesis and key molecules of atrial fibrosis caused by ferroptosis are still not fully understood. Here we review the role of inflammatory signaling in ferroptosis and AF. We elucidated the association between ferroptosis and AF, aiming to unveil mechanisms for targeted inhibition of atrial cell fibrosis and to propose novel therapeutic strategies for AF. This exploration is vital for advancing our knowledge and developing more effective interventions for AF, a condition deeply intertwined with inflammatory processes and ferroptotic pathways.

Keywords

atrial fibrillation

ferroptosis

inflammation

Highlights

1. A robust association is present in the relationship between ferroptosis and atrial fibrillation (AF).
2. Inflammation may play a role of cohesion between ferroptosis and AF.
3. The ferroptosis of atrial cells can be blocked by targeted inhibition of the inflammatory response or inhibition of exosomes (the two promote each other), which may be a new target for AF in clinical applicat

Funding

82370324/National Natural Science Foundation of China

20204Y0449/Shanghai Municipal Health Commission Health Industry Clinical Research Youth Program

Figures

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Fig. 1.

Metabolic Pathways associated with ferroptosis in cardiomyocytes. Iron metabolism and cell signaling in cardiomyocytes: Nonheme iron is transported into the cell by TF and its receptor, TFR1. Subsequently, the endosome is acidified by ATPases, inducing the STEAP metalloreductase family to reduce ferric to ferrous iron. Ferrous iron is released into the cytoplasm by NRAMP2, while TF and TFR1 are transported back to the cell membrane for reuse. Ferrous iron that is transported to the cytoplasm is oxidized to ferric iron, which is bound to ferritin and used in enzymatic reactions or stored for later use. Saturated ferritin is degraded by NCOA4-mediated autophagy, a process known as ferritinophagy, and eventually, the ferrous iron produced by degradation and the ferrous iron released from endosomes form an intracellular labile iron pool. In GSH metabolism, the X ${}_{\text{c}}$ ${}^{-}$ system comprises of two subunits (SLC3A2 and SLC7A11) and functions as a cystine/glutamate antiporter on the cell membrane. It is responsible for transporting cystine into the cell and glutamate out of the cell. Cystine is broken down inside the cell to cysteine, which is used to synthesize GSH. GSH is converted to GSSH catalyzed by GPX4, and at the same time, L-OOH is converted to L-OH. In Lipid metabolism, PUFAs within the cell membrane are catalyzed by LOXs and oxidized to L-OOH. The mitochondria produce Fe-S and H ${}_{2}$ O ${}_{2}$ . In the Fenton reaction, ferrous iron is oxidized, and H ${}_{2}$ O ${}_{2}$ is dehydrogenated to H ${}_{2}$ O. The Fenton reaction generates hydroxyl radicals ( $\cdot{}$ OH), a type of reactive free radical, which are eventually converted to L-OOH. The L-OOH produced in this process, along with that generated by glutathione peroxidase 4 (GPX4) metabolism, further exacerbates ROS and LPO accumulation within the cell. TF, transferrin; TFR1, transferrin receptor 1; STEAP3, six-transmembrane epithelial antigen of prostate 3; NRAMP2, natural resistance associated macrophage protein 2; NCOA4, nuclear receptor coactivator 4; GSH, glutathione; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; GSSH, glutathione disulfide; GPX4, glutathione peroxidase 4; L-OOH, lipid hydroperoxide; L-OH, lipid alcohol (or lipid hydroxide); PUFAs, polyunsaturated fatty acids; LOXs, lipoxygenases; Fe-S, iron-sulfur; H ${}_{2}$ O ${}_{2}$ , hydrogen peroxide; H ${}_{2}$ O, water; $\cdot{}$ OH, hydroxyl radical; ROS, reactive oxygen species; LPO, lipid peroxidation; FPN, ferroportin.

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Rev. Cardiovasc. Med. Print ISSN 1530-6550 Electronic ISSN 2153-8174