In general, the regulation of iron homeostasis in cardiomyocytes is similar to that in other systemic cells of the body (Fig. 1).

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.

Physiologically, transferrin (TF) binds two molecules of ferric ions, and subsequently, they bind to the receptor of TF, transferrin receptor protein 1 (TFR1) [21]. It is this process that initiates and mediates the uptake of ferric irons by cells. In addition to this pathway, iron influx into cells can occur via the DMT-1 protein, L/T-type calcium channels at the cardiac plasma membrane, and zinc transporters [21]. Subsequently, ferric irons undergo a reduction reaction mediated by the metal reductase STEAP3 (six-transmembrane epithelial antigen of prostate) to become ferrous irons [22]. Ferrous irons are detached from transferrin in endocytic lysozymes and released into the cytoplasm by natural resistance associated macrophage protein 2 (NRAMP2), involved in the composition of labile iron pools in the cytosol [21]. Apo-transferrin and TFR1 are recycled and transported back to the cell surface.

The ferrous iron in the cytoplasm binds to the ferritin heavy chain (FTH), oxidizes to a ferric state, and forms ferritin-bound iron [22]. Iron, on the other hand, is released from the FTH by nuclear receptor coactivator 4 (NCOA4) mediated degradation of ferritin, a process known as ferritinophagy [22]. Through the above cycle, cells maintain iron homeostasis by storing excess iron ions or releasing iron ions into the cytoplasm for use when iron is needed. In addition, the excess iron can also be removed from the cell through ferroportin (FPN) [22]. In physiological conditions, labile iron is kept at very low levels, preventing the production of excessive reactive oxygen species (ROS) [21]. Nevertheless, intracellular iron overload can significantly increase the labile iron pool, resulting in the hazardous accumulation of ROS and ferroptosis.

The amino acid metabolism pathway in ferroptosis prominently features GSH, a tripeptide composed of cysteine, glutamate, and glycine, and is ubiquitous in cells. GSH plays a crucial role in reducing harmful per-oxidants generated by cell metabolism to harmless lipid alcohols [23]. It exists in two forms: a reduced form (GSH) and an oxidized form (G-S-S-G, glutathione disulfide) [23]. Extracellular cystine and intracellular glutamate enter and exit the cell in a 1:1 ratio via the cystine/glutamate reverse transporter respectively, named system X${}_{\text{𝑐}}$${}^{-}$, containing two subunits (solute carrier family 3 member 2 (SLC3A2) and solute carrier family 7 member 11 (SLC7A11)) [24]. The cystine transported into the cell is used for the biosynthesis of GSH [23]. As a vital functional cofactor of glutathione peroxidase 4 (GPX4), GSH is converted to GSSH catalyzed by GPX4, a process synchronized to the conversion of L-OOH to L-OH [23, 25]. Concurrently, NADPH is converted to NADP${}^{+}$, which is catalyzed by glutathione reductase [23]. Notably, GPX4 can maintain the balance of intracellular redox state and can also remove excessive accumulation of harmful peroxidation products in cells [24, 25]. Thus, GPX4 plays an integral role in preventing ferroptosis in cells [24, 25]. Depletion of GSH or reduced glutathione synthesis (e.g., cysteine deficiency) leads to reduced or inactivated GPX4 content, which in turn promotes ferroptosis in cells [22, 24, 25, 26]. In addition, Erastin can deplete intracellular cystine by inhibiting system X${}_{\text{𝑐}}$${}^{-}$, eventually depleting GSH and inactivating GPX4, leading to ferroptosis [13]. In conclusion, GPX4 is an important antioxidant in cells and plays a unique role in the prevention and treatment of ferroptosis. Additionally, some metabolic pathways, such as mevalonate, are also involved in the process of ferroptosis through the production of squalene, isopentenyl pyrophosphate, coenzyme Q10 and other biomolecules with anti-pyrophosphate activity, which also affect ferroptosis [14]. Amino acid metabolism and lipid metabolism in ferroptosis is shown Fig. 1.

Phospholipids, an important component in maintaining the fluidity of the cell membrane, is also damaged through ferroptosis [25, 26]. Polyunsaturated fatty acids (PUFAs) in phospholipids, such as docosahexaenoic acid and arachidonic acid (AA), are the main substances that mediate intracellular signal transduction and are also vulnerable to peroxidation damage during ferroptosis [25]. It has been shown that the acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) are involved in the biosynthesis of polyunsaturated fatty acids in phospholipids [27]. Phosphatidylethanolamines combine with AA and adrenal acid (AdA) to synthesize PUFAs under the catalysis of ACSL4 and CoA; and free PUAFs become bound to membrane phospholipids through the activity of LPCAT3 [28, 29]. Acylation of PUFAs by ACSL4, which increases the PUFA content of phospholipids, is thought to be a specific factor for ferroptosis [27]. After synthesis, PUAFs become embedded into the phospholipids of the cell membrane, and are subsequently oxidized by lipoxygenases (LOXs) to become L-OOH [25]. Compounds including Fe-S and H${}_2$O${}_2$ supplied by mitochondria participate in the Fenton reaction in the cell, in which Fe${}^{2+}$ is oxidized to Fe${}^{3+}$ and the reactive free radical ($\cdot$OH) is generated, which in turn is converted to L-OOH [30]. Normally, the intracellular production of trace lipid hydrogen can be reduced to lipid alcohols by GPX4, thereby maintaining the stability of cells to avoid the damage of ROS. However, ferroptosis is driven by iron-dependent LPO, and plays a pivotal role linking ferroptosis to various diseases and abnormal metabolic states [31]. When lipid metabolism in cardiomyocytes is altered through the lipoxygenase and Fenton reaction pathways, malignant LPO will occur in the cells, and GPX4 will become depleted, resulting in ferroptosis [28, 30, 31]. Moreover, LPO could damage the cardiac cell membrane by contributing to ferroptosis [26, 28]. LPO is also involved in the inflammatory response, which may play an important molecular and pathological role in the occurrence of AF, and the details will be explained in the next section.

An additional characteristic of ferroptosis is a large release of oxidized lipid mediators [39]. Undergoing ferroptosis makes cells more immunogenic, as they release DAMPs and pro-inflammatory factors that drive the tissue environment toward an inflammatory state [9, 40]. As a DAMP, HMGB1 plays a vital role in the formation of and pathological mechanism behind inflammation, as well as amplifying the inflammatory response [14]. Once released by the cell, HMBG1 gains immune-stimulating properties and acts as an adjuvant, promoting an immune response by binding to pattern recognition receptors and activating inflammation [9, 14, 40]. Furthermore, neutralizing anti-HMBG1 antibodies attenuates the macrophage inflammatory response induced by ferroptosis [41]. A possible association between ferroptosis and inflammation is shown in Fig. 2.

Fig. 2.

The relationship between ferroptosis and inflammation. In response to cellular stress or stimulation, phospholipase A2 (PLA2) and phospholipase C2 (PLC2) break down cell membrane phospholipids into AA. The polyunsaturated fatty acid AA is produced by catabolism under the stimulation of cellular oxidative stress and LPO. Subsequently, cyclooxygenases (COXs) metabolize AA to prostaglandins (PGs) and thromboxanes (TXs), which can induce an inflammatory response. Simultaneously, LOXs convert AA into hydroxyeicosatetraenoic acids (HETEs), leading to the production of leukotrienes (LTs) and lipoxins (LXs). Additionally, LOXs can also exacerbate ferroptosis by enhancing LPO and releasing ROS. As the core of ferroptosis, LPO perpetuates a vicious cycle by promoting further AA decomposition through substances like nitric oxide (NO) and tumor necrosis factor-alpha (TNF-$\alpha$), exacerbating ferroptosis. In addition, ferroptosis can also promote the metabolism of COX-2-induced AA by upregulating prostaglandin-endoperoxide synthase 2 (PTGS2), the gene encoding COX-2. Ferroptotic cells release DAMPs and inflammatory cytokines, activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-$\kappa$B) to promote aseptic inflammation. Consequently, PGs, TXs, LTs, LXs, DAMPs and other inflammatory cytokines contribute to inflammation. ROS, reactive oxygen species; AA, arachidonic acid; PLA2, phospholipase A2; PLC2, phospholipase C2; COX, cyclooxygenase; PTGS2, prostaglandin-endoperoxide synthase 2; PG, prostaglandin; TXs, thromboxane synthetase; HETE, hydroxyeicosatetraenoic acid; LT, leukotriene; LX, lipoxin; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; GSH, glutathione; GPX4, glutathione peroxidase 4; NF-$\kappa$B, nuclear factor kappa B; TNF-$\alpha$, tumor necrosis factor-$\alpha$; LPO, lipid peroxidation; LOXs, lipoxygenases.

Previously, we discussed the metabolic pathways of ferroptosis, highlighting LPO as the underlying mechanism driving inflammation associated with ferroptosis. It is well known that PUFAs are the main components of cell membranes. PUFAs may play a crucial role in regulating inflammatory signaling and antioxidant pathways [42]. Increased intake of eicosapentaenoic acid and docosahexaenoic acid is beneficial in reducing the incidence of diseases characterized by elevated inflammation (including cardiovascular disease) [42]. PUFAs and their related metabolic enzymes have become key cellular and molecular factors resulting in inflammation [9]. PUFAs are also the most sensitive lipid in the process of ferroptosis [43, 44]. In one study, phosphatidylethanolamine (PE) was identified as a lipid associated with AF [45]. The authors suggested that PE impaired mitochondria and aggravated LPO by promoting the increase of oxidative products, triggering ferroptosis in atrial cells, and participating in atrial fibrosis [45]. Atrial cells with iron overload are in a state of cellular stress, accompanied by increased intracellular ROS, while AA is released by phospholipase C (PLC) or phospholipase A2 (PLA2) from phospholipids of the cell membrane. Additionally, AA can be oxidized by LOX, cyclooxygenase (COX) and cytochrome P450 monooxygenase, and metabolized into a variety of bioactive inflammatory mediators, such as leukotrienes (LTs), prostaglandins (PGs), and hydroxyeicosatetraenoic acid [9, 14]. These substances all contribute to the inflammatory response.

There are six LOX isoforms in the human body [43], which play an essential role in the cellular oxidation of ferroptosis. This family of lipid-peroxidases that catalyzes the peroxidation of PUFAs to produce lipid hydrogen peroxide products [43]. Furthermore LOX oxidizes AA into hydroperoxyl-intermediates including hydroperoxyeicosatetraenoic acids (HPETE) and hydroxyeicosatetraenoic acids (HETE), which are then metabolized into leukotrienes (LTs), lipotoxins (LXs) and other pro-inflammatory substances [9, 14, 44]. LOX, in addition to acting through enzyme-catalyzed lipid peroxidation, also alerts immune cells through LOX-derived proinflammatory metabolites, including LTB4/LTC4/LTD4 and LTE4, indirectly sensitizing the cell to ferroptosis [46].

COX is a key rate-limiting enzyme for the conversion of AA to PG. Two isoenzymes COX-1 and COX-2 have been found to play a key role in this process [47]. While COX-1 is widely expressed in various cell types, COX-2 is typically less expressed in normal tissues and mainly functions in activating macrophages and other inflammatory cells [47]. The gene prostaglandin endoperoxide synthase 2 (PTGS2) encodes COX enzymes, which are responsible for metabolizing AA found within cell membranes into a range of inflammatory factors including prostaglandin E2 (PGE2) [9]. Studies have shown that ferroptosis can directly increase the expression of PTGS2, and then encode more COX-2, accelerating AA metabolism, and ultimately promoting the secretion of inflammatory factors [9, 48]. Thus, inflammation induced by ferroptosis may be related to the increase of PTGS2 expression and PGE2 release.

Inflammation is also related to oxidative stress, which can trigger a range of pro-inflammatory (such as tumor necrosis factor-$\alpha$ [TNF-$\alpha$]) and transcription factors (such as NF-$\kappa$B) [14]. Due to the deficiency or inactivation of GPX4, or the introduction of an inducer of ferroptosis, there are increased levels of lipid-ROS and LPO in the cell, resulting in ferroptosis [49]. It is known that GPX4 can play a role in cytoprotection by reducing the production of cellular lipid hydroperoxide [50]. Furthermore, GPX4 alleviates ferroptosis and inflammation by inhibiting the oxidation of AA and activation of the NF-$\kappa$B pathway [51]. This also reduces the production of inflammatory factors caused by LPO, which is known to polarize macrophages by increasing modified low-density lipoproteins (LDL), promoting inflammation [14]. Ferroptosis can also lead to the polarization of macrophages into the M1 type through increases of ROS, TNF-$\alpha$ and IL-1$\beta$ [52]. Notably, the M1 macrophages have pro-inflammatory properties [52]. As previously discussed, the decrease in intracellular GPX4 content and the imbalance of intracellular redox state aggravate the sensitivity of cells to ferroptosis and simultaneously increase the production of intracellular inflammatory factors. Excess ROS consumes the pool of intracellular antioxidants, consequently increasing inflammation, LPO production, and ferroptosis aggravation producing a cytotoxic feedback loop [49, 51, 52]. By inhibiting LPO that is central to ferroptosis (such as inhibiting PE), the ferroptosis inflammatory response can be suppressed, and decreasing AF progression [45]. Consequently, these enzymatic targets may lead to a potential mechanism for the prevention and treatment of AF [45].

It has been suggested that inflammatory atrial cardiomyopathy, also known as atrial myocarditis, increases AF susceptibility through tissue fibrosis, electrophysiological remodeling, autonomic nerve remodeling, and other mechanisms [53]. At present, a number of studies found that inhibition of NF-$\kappa$B and COX-2 signaling may reduce the release of PGE2, NO, and other inflammatory mediators, which could exert anti-inflammatory activity [54, 55, 56]. One study also found that PGE2 regulated the polarization of macrophages through the NF-$\kappa$B signaling pathway, thereby affecting the inflammatory response [57]. Furthermore, signaling pathways such as NF-$\kappa$B, TNF-$\alpha$ and NLRP3 inflammasome are central to the inflammatory response orchestrated by innate immune cells. They are mainly responsible for the maturation and release of cytokines, and can also independently participate in the pathogenesis of AF [53, 56, 57, 58]. By targeting the NF-$\kappa$B signaling pathway, ferroptosis related diseases could potentially be reversed [58, 59]. In addition, LPO is implicate in activating the NLRP3 inflammasome [58], further emphasizing the interplay between inflammasomes, ferroptosis, and AF. As shown in Fig. 3, NF-$\kappa$B, TNF-$\alpha$, and NLRP3 inflammasomes exemplify key inflammatory pathways, highlighting their role in linking ferroptosis and AF. Table 2 (Ref. [36, 45, 60, 61, 62, 63]) summarizing the relevant literature currently reported on ferroptosis and AF.

Fig. 3.

The interplay between inflammation, ferroptosis, and AF. Ferroptosis can influence atrial cells through inflammation, with atrial inflammation being a crucial contributor to both the onset and persistence of AF. This figure outlines a possible mechanism by which intracellular ferroptosis induces and sustains AF through inflammatory pathways. Key factors in AF induction include reentry and ectopic firing, which are associated with the abnormal release of Ca${}^{2+}$, excessive intake of K${}^{+}$, and the release of various inflammatory factors resulting in atrial fibrosis. Central to this process are TNF-$\alpha$, NF-$\kappa$B, and NLRP3 inflammasome, each playing a vital and irreplaceable role. TSP-1, thrombospondin 1; SR, sarcoplasmic reticulum; GPX4, glutathione peroxidase 4; IL-6, interleukin 6; IL-18, interleukin 18; TGF-$\beta$, transforming growth factor-$\beta$; LPO, lipid peroxidation; ERP, effective refractive period; IL-1$\beta$, interleukin 1$\beta$ ; DAMPS, damage-associated molecular patterns; TLR4, toll-like receptor 4; Myd88, myeloid differentiation factor 88; P38-MAPK, p38 mitogen activated protein kinases; TNFR1/2, tumor necrosis factor-α receptor type 1/2; NF-$\kappa$B, nuclear factor kappa B; TNF-$\alpha$, tumor necrosis factor-$\alpha$; NLRP3, NOD-like receptor thermal protien domain associated protein 3; RyR2, ryanodine receptor 2; DADs, depolarization after delays; Casp1, caspase-1; AF, atrial fibrillation.

Mitochondrial dysfunction is a significant feature of ferroptosis, contributing to the occurrence and progression of AF. A recent review concluded that the effect of the NLRP3 inflammasome on ferroptosis was achieved by changing the level of ROS [100]. Similarly, the induction of the NLRP3 inflammasome by abnormal intracellular ROS levels also contributes to ferroptosis [100]. The excessive production of ROS is not only related to the inflammatory response, but is also associated with the degree of mitophagy in ferroptotic cells. Mammalian target of rapamycin (mTOR), a serine-threonine kinase, is an important regulator of cell metabolism and growth, and also participates in the regulatory mechanism of ferroptosis. Tristetraprolin and mTOR are participants in intracellular iron homeostasis, regulating iron-containing genes and the mRNA stability of the transferrin receptor 1 [101].

An experimental study has found that the ablation of the NLRP3 inflammasome can improve a series of aging-related metabolic features (including cardiac aging-related inflammation and fibrosis) [102]. This may be related to the activation of autophagy, reduction of the insulin-like growth factor 1 (IGF-1) pathway and the phosphatidyl inositol 3 kinase/protein kinase B/mammalian target of rapamycin (PIK3/AKT/mTOR) pathway [102]. Another study found that mTOR was also a profibrotic signal involved in the excessive inflammatory response and fibrotic remodeling of AF through the C-X-C chemokine ligand 12/C-X-C chemokine receptor type 4 (CXCL12/CXCR4) axis [103]. Further research also links mTOR activation with fibroblast proliferation, increased fibroblast-to-myofibroblast transformation, and cardiac collagen synthesis [104], highlighting mTOR’s involvement in AF. Over-activated mTOR stimulates the NLRP3 inflammasome, recruits pro-inflammatory factors, and contributes to AF pathogenesis by promoting fibrosis and altering atrial cell electrophysiology. Consequently, mTOR has emerged as a potential therapeutic target for AF, with its inhibition potentially reducing AF incidence.

In contrast to these favorable results, a study found that when mTOR was inhibited in cardiomyocytes, iron accumulation occurred in the cells, leading to iron overload [100]. This inhibition of mTOR promoted mitophagy, which often coincides with cell autophagy, triggering the degradation of ferritin and potentially inducing ferroptosis [100]. Sirtuin3, a classical NDA${}^{+}$-dependent mitochondrial protein deacetylase, is responsible for deacetylating mitochondrial proteins subjected to oxidative stress and regulating cellular metabolism [105]. Research has shown that Sirtuin3 enhanced the phosphorylation of AMP-activated protein kinase (AMPK), which inhibited the activity of mTOR and ultimately promoting both autophagy and ferroptosis [105]. Researchers also found that the mTOR pathway was inhibited in AF patients aged 60 to 70 years, with mTOR-related genes downregulated in atrial tissue [106]. These results suggest that inhibition of mTOR and its related pathways may contribute to cardiac ferroptosis and the onset of AF. Therefore, mTOR may be a pivotal link between ferroptosis, inflammation and AF.

The experimental evidence regarding the roles of mTOR and autophagy in the context of ferroptosis, inflammation, and AF is not straightforward. To address these contradictory findings, it is hypothesized that the level of mTOR inhibition and the degree of mitophagy act as a double-edged sword. Under high stress conditions, such as decreased GSH intake, decreased GPX4, and iron overload, cells experience a significant imbalance in intracellular redox metabolism, leading to intracellular LPO. At the same time, large amounts of ROS are also produced within mitochondria. Mild autophagy can be beneficial for cells, helping to remove necrotic organelles and substances exerting anti-inflammatory effects. Mitophagy, the targeted removal of damaged mitochondria, can decrease ROS production and subsequently inhibit the activation of the NLRP3 inflammasome [102].

mTOR, a critical regulator of inflammation and autophagy, exhibits contrasting effects depending on its activity level. Overactivation of mTOR induces the recruitment of inflammatory factors and promotes fibrosis [103, 104]. Conversely, mild inhibition of mTOR induces mitophagy, which aids in ROS clearance and provides cellular protection [102]. However, excessive inhibition of mTOR will lead to severe mitophagy, which will lead to cell death, ferritin degradation and ferroptosis [105]. Additionally, studies have also found that GPX4 overexpression can improve mitochondrial dysfunction [107]. There was evidence that inhibition of GPX4 resulted in LPO as well as ROS accumulation and promoted autophagy [107]. Thrombospondin 1 is thought to inhibit autophagy [107]. Overexpression of GPX4 promoted the production of thrombospondin-1 [107]. Therefore, GPX4 could block autophagy by releasing thrombospondin 1, which eventually attenuated cardiac fibrosis [107]. GPX4 was also thought to alleviate fibrosis by reducing intracellular LPO and inhibiting the TGF-$\beta$ pathway [107]. In summary, GPX4 protects against ferroptosis while also alleviating fibrosis. The relationship between inflammation, ferroptosis and AF is multi-dimensional, and there are many key nodes that dominate the role of ferroptosis in the pathogenesis of AF.

In our study of the connection between inflammation and ferroptosis in AF, we focused on the activation of the NF-$\kappa$B pathway, TNF-$\alpha$ and the NLRP3 inflammasome as representatives of inflammatory response to elucidate the relationship between ferroptosis and AF. Atrial inflammation is one of the important factors leading to the occurrence and maintenance of AF. Although AF is closely related to atrial fibrosis induced by atrial inflammation, there are two different types of atrial fibrosis: “reactive” fibrosis and “reparative” fibrosis [108]. Moreover, these two types of fibrosis have different effects on the induction of AF. “Reactive” fibrosis is characterized by thickening of the normal fibrous connective tissue surrounding the muscle bundles while the muscle bundles itself is structurally intact [108, 109]. When myocardial cell necrosis occurs, such as in a myocardial infarction, apoptosis, and ferroptosis, the replacement of dead cardiomyocytes by fibrous tissue is the important pathological feature of “reparative” fibrosis which is largely irreversible [108, 109, 110].

In contrast, “reactive” fibrosis can impair cardiac longitudinal conduction, but only when thicker interstitial collagen chains are present between atrial myocytes [111]. “Reparative” fibrosis, however, creates conduction blocks due to cell death and disrupted muscle bundles. Furthermore, the uneven distribution of cardiomyocytes and collagen fibers disrupts the continuity of atrial electrical signals, potentially leading to local circuit formation and promoting reentry mechanisms [111, 112]. In addition to irreversible atrial fibrosis, abnormal atrial ion channels caused by inflammation are another important mechanism leading to the occurrence of AF. It can be concluded that ferroptosis, as a type of cell death related to the heart, plays a detrimental role in inducing the inflammatory response and atrial fibrosis.

Given the central role of iron metabolism in cardiac health, we sought to identify the key molecules in the inflammatory signaling pathway associated with ferroptosis, to explore new targets for AF treatment, and to search for possible highly affinity and selective inhibitors for these targets. A study indicated that ferroptosis caused by iron overload is involved in new-onset AF in sepsis, a systemic inflammatory response, with ferroportin potentially playing a key mediating role [61]. In vitro experiments on atrial cells exposed to excessive alcohol revealed an increased susceptibility to AF, marked by elevated levels of ferroptosis-promoting molecules such as P53 and ACSL4 [62]. Icariin was shown to inhibit ferroptosis in atrial cells, reducing atrial inflammation and oxidative stress by activating the atrial SIRT1-Nrf-2-HO-1 signaling pathway [62].

Contrasting our hypothesis that ferroptosis leads to AF onset, another study proposed that AF could induce ferroptosis, especially in maintaining persistent AF [63]. This research involved rapid atrial pacing in experimental dogs, leading to the secretion of exosomes by atrial cells and cardiac fibroblasts [63]. The exosome inhibitor GW4869 reduced atrial inflammation and collagen deposition in the experimental group. In addition, they found that exosomes secreted by cardiac fibroblasts promoted ferroptosis in h9c2 cells, and that miR-23a-3p encapsulated in the exosomes may be the key molecule responsible for ferroptosis [63]. Therefore, specific inhibitors of miR-23a-3p can be regarded as a potential therapeutic target to disrupt the ferroptosis-AF cycle [63]. The above evidence strongly suggests that ferroptosis and AF are closely linked and may be complemented by atrial inflammation. These findings offer new potential targets, such as inhibiting signaling molecules or inflammatory factors in ferroptosis-related pathways. In conclusion, ferroptosis is intimately linked with AF, atrial inflammation, subsequent atrial fibrosis, and ion channel abnormalities, all of which play significant roles in this intricate process.