The onset of AF is closely linked to myocardial dysfunction, driven by electrophysiological abnormalities and disturbances in ion exchange, which lead to electrical remodeling and arrhythmias caused by ectopic pacing. Emerging research suggests a potential connection between these electrical disturbances and mitochondrial dysfunction (Muszyński and Bonda, 2021). Mitochondria, essential for ATP production through the electron transport chain, are particularly vulnerable to ferroptosis, an organelle-specific form of cell death.

Cell membrane proteins regulate ion flux across the membrane, orchestrating vital biochemical processes. During ferroptosis, mitochondrial dysfunction disrupts ion gradients and membrane potential, leading to altered cardiac electrical conduction and the development of arrhythmias (Galaris et al., 2019). However, the precise mechanisms behind these processes require further investigation.

Mitochondria make up approximately 30% of the volume of myocardial cells and are essential for energy production, supplying about 90% of the energy required for cardiac contraction (Schaper et al., 1985; Harris and Das, 1991). Mitochondrial dysfunction can significantly impair both systolic and diastolic heart function. Studies have shown that such dysfunction disrupts ATP production, leading to the accumulation of ROS, which in turn disturbs calcium homeostasis and membrane excitability in myocardial cells, contributing to the development of AF (Clark and Mach, 2017).

Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a crucial nuclear transcription coactivator involved in mitochondrial biogenesis, energy metabolism, and the regulation of oxidative stress and inflammation (Chandrasekaran et al., 2015). Inhibition of PGC-1α results in mitochondrial dysfunction, oxidative stress, and intracellular calcium overload, ultimately triggering AF (Sahin et al., 2011; Summermatter et al., 2013). Patients with atrial fibrillation often show mitochondrial alterations, including abnormal ATP levels, elevated HSP60 expression, mitochondrial ATP depletion, reduced respiration and membrane potential, and abnormal morphology. These changes mirror those seen in other cardiac conditions such as myocardial infarction, heart failure, dilated cardiomyopathy, ischemic heart disease, hypertensive heart disease, and diabetic cardiomyopathy (Guzmán et al., 2014; Eirin et al., 2014). Ferroptosis is marked by mitochondrial constriction, loss of cristae, and outer membrane disruption (Kagan et al., 2020). Irregular mitochondrial morphology involves fragmentation (Chen et al., 2010), swelling, decreased density, cristae disarray (Cogliati et al., 2013), and disintegration (Guzmán et al., 2014). These structural changes impair mitochondrial respiratory function, hinder ATP synthesis, and compromise cardiac contractility. Additionally, prolonged mitochondrial calcium buffering delays calcium uptake, further disrupting mitochondrial respiration (Jeganathan et al., 2017; Wiersma et al., 2019).

Ferroptosis is induced through the mitochondrial voltage-dependent anion channel, activation of mitogen-activated protein kinase, and inhibition of the cystine/glutamate transporter (Xie et al., 2016). Mitochondria are central to iron synthesis, utilization, and degradation, thus maintaining iron homeostasis and supporting both material and energy metabolism. They regulate iron sensitivity across various metabolic pathways, with proteins such as ferritin, mitochondrial ferritin 1/2, and NEET playing key roles in iron regulation. Additionally, ASCF2 and CS are involved in mitochondrial lipid metabolism, while glutamine and other metabolic pathways are also influenced by mitochondrial function. Therefore, understanding mitochondrial responses during ferroptosis is crucial for clarifying its role in the initiation and progression of AF.

Oxidative stress results from an imbalance between antioxidant and oxidative systems, significantly affecting iron homeostasis. The Fenton reaction is the primary source of oxidative stress in ferroptosis (Shen et al., 2018; Wang et al., 2018).

A key feature of oxidative stress is the elevation of ROS, which occurs when the body’s antioxidant defenses are insufficient to neutralize oxidizing substances. This leads to the accumulation of free radicals and other oxidative species, causing cellular damage. Oxidative stress is a well-established factor in the onset and progression of numerous diseases. Research shows that iron overload promotes glutathione (GSH) depletion, ROS production, lipid peroxidation, and the synthesis of ferroptosis markers such as GPX4 and the cystine-glutamate antiporter (SLC7A11). It also inhibits ACSL4 and reduces mitochondrial membrane potential (MMP). Ferroptosis can exacerbate mitochondrial oxidative stress through the NRF2-ARE pathway (Chen et al., 2022). Furthermore, iron overload induces lipid peroxidation, mitochondrial ROS production, and further decreases MMP.

MiR-23a-3p targets and regulates SLC7A11, promoting oxidative stress and ferroptosis, which contribute to the progression of AF (Liu et al., 2022). The key to mitigating oxidative stress injury lies in upregulating antioxidant-related genes and proteins, such as FTH1, GPX4, SLC7A11, and various antioxidant enzymes, to restore redox homeostasis (Stockwell et al., 2020).

GPX4 is a critical antioxidant enzyme that inhibits lipid peroxidation and reduces ROS accumulation (Thomas et al., 1990). When ROS levels rise or cystine levels decrease, cellular GSH levels drop, impairing GPX4 activity and promoting ferroptosis (Li et al., 2020a; Seiler et al., 2008). Studies have identified a correlation between GPX4 variants, especially rs713041, and cardiovascular diseases (Strauss et al., 2018; Admoni et al., 2019). Additionally, GPX4 variants may be linked to the onset of postoperative AF, along with changes in myocardial GPX4 content and activity (Berdaweel et al., 2022). These findings above indicate that ferroptosis could play a role in the initiation and progression of AF, potentially serving as a prognostic marker.

Mitochondrial aldehyde dehydrogenase (ALDH2) inhibits ACSL4, a key enzyme in lipid peroxidation, thereby preventing ferroptosis and improving cardiac systolic function (Zhu et al., 2022a). Conversely, alcohol is a known risk factor for AF with the ALDH2 heterozygous defect allele (*1/*2), who regularly consume alcohol, are at increased risk of AF due to slower alcohol metabolism and enhanced ferroptosis (Yamashita et al., 2022).

The formation of arrhythmogenic lesions may be driven by diastolic calcium leakage from the sarcoplasmic reticulum (SR), caused by hyperphosphorylation of the ryanodine receptor (RyR). This promotes delayed depolarization and triggers activity that favors AF (Chan et al., 2019). Both reentry and rapid focal activity contribute to frequent atrial depolarization and electrical remodeling, characterized by reduced conduction velocity and a shortened atrial refractory period, which sustain AF (Lenaerts et al., 2009). Electrical remodeling is linked to SR calcium overload, elevated cytoplasmic Ca²⁺ levels, reduced expression of inward calcium channels, increased rectifier potassium current, and altered connexin expression (Wang et al., 2017).

Excessive ethanol consumption significantly elevates ferroptosis-promoting proteins (e.g., PTGS2, ACSL4, P53) and reduces anti-ferroptosis proteins (e.g., GPX4, FTH1) in the atrium, leading to substantial atrial damage. This damage includes increased susceptibility to AF, impaired atrial conduction, atrial enlargement, and heightened fibrosis markers (Yu et al., 2023). The SIRT1-Nrf2-HO-1 signaling pathway may provide therapeutic insights by inhibiting ferroptosis and protecting the atrium from injury.

Recent research on ferroptosis has highlighted its regulatory effects on ion channels, which play a critical role in the development of AF. Cardiac rhythm generation is closely linked to the functional dynamics of ion channels.

During ferroptosis, lipid peroxides accumulate on the cell membrane, increasing surface tension and activating Piezo1 and TRP channels (Hirata et al., 2023). This lipid oxidation also enhances the permeability of cations such as Na⁺ and Ca²⁺, leading to their efflux from the cell. As a result, intracellular Na⁺ and Ca²⁺ concentrations rise, while K⁺ levels decrease. Additionally, membrane lipid oxidation reduces the activity of Na⁺/K⁺-ATPase, further disrupting monovalent cation gradients. This study emphasizes the crucial role of altered cation permeability—mediated by Piezo1, TRP channels, and Na⁺/K⁺-ATPase activity—in the initiation of ferroptosis.

During episodes of atrial fibrillation, progressive atrial enlargement is a key feature closely associated with atrial mechanical overload. In human atrial fibroblasts, at least two stretch-activated ion channels (SACs) are involved: Piezo1, a non-selective cation channel activated directly by mechanical stretch, and BKCa, a calcium-dependent, potassium-selective channel (Emig et al., 2021). In individuals with non-persistent atrial fibrillation, both the activity and expression of Piezo1 are significantly increased, suggesting its predominant role over other channels compared to sinus rhythm. In response to atrial mechanical stimulation, BKCa activity rises as a secondary response to Piezo1. In contrast, patients with persistent atrial fibrillation exhibit a reduction in BKCa activity. Additionally, the upregulation of TRP channels is implicated in both electrical and structural cardiac remodeling. TRP channels, which are non-selective cation channels with varying calcium permeability, consist of six subtypes expressed in different cell types (Yue et al., 2015). TRP channels contribute to endothelial cell apoptosis and cardiac fibrosis through fibroblast differentiation, playing a role in the onset and progression of various cardiovascular diseases (Yue et al., 2011). Multiple TRP subtypes have been shown to participate in atrial electrical remodeling in AF patients, though through different mechanisms (Yue et al., 2015). A study examining leukocyte TRP channels found significantly higher expression in patients with nonvalvular AF compared to controls (Düzen et al., 2017), suggesting that Piezo1 and TRP channels may serve as critical targets for ferroptosis, promoting the onset and progression of AF.

A study investigating sinoatrial node function in mice with chronic iron overload found that inhibition of the Ca_(V1.3) channel initially reduced the density of L-type calcium currents (I_(Ca,L)), causing a rightward shift in the voltage activation curve of I_(Ca,L) (Rose et al., 2011). These changes led to a decrease in spontaneous action potential generation in sinoatrial node cells, resulting in bradycardia, prolonged PR intervals, cardiac blocks, and AF.

In conclusion, ferroptosis-induced modulation of ion channels may contribute to the development of AF.

The ferroptosis inducer elastin can trigger autophagy through ROS generation. Autophagy plays a key role in regulating ferritin degradation and TFR1 expression, leading to increased intracellular iron levels and promoting ferroptosis (Park and Chung, 2019). This process involves a range of autophagic proteins that facilitate the degradation of damaged or excess cellular components. Double-membrane vesicles encapsulate these components, which then fuse with lysosomes for degradation (Klionsky, 2008; Yorimitsu and Klionsky, 2005). Autophagy serves both as an essential biological process, regulated by specific genes, and as a stress-responsive survival mechanism that may also contribute to cell death (Liu et al., 2013). Key autophagic proteins include BECN1 and light chain 3 β (LC3B). By engulfing ferritin through phagocytosis, autophagy elevates intracellular free iron levels, further promoting ferroptosis (Manz et al., 2016). Notably, the expression of BECN1 in valvular AF may offer a promising therapeutic target for future treatments of AF (Liu et al., 2021).

In a study of patients with postoperative atrial fibrillation (Garcia et al., 2012), significant accumulation of autophagic vesicles and lipofuscin deposits was observed in atrial tissue. Additionally, LC3B levels were reduced, indicating selective damage during the autophagic process. These findings suggest the presence of ultrastructural atrial remodeling associated with autophagy-related damage.

Nuclear receptor coactivator 4 (NCOA4) interacts directly with FTH1, facilitating the transport of ferritin to the autophagosome for degradation. This process triggers phagocytosis and ferritin breakdown, releasing large amounts of free iron. The resulting increase in cytoplasmic Fe²⁺ enhances the expression of exoflavin (SFXN1) on the mitochondrial membrane, promoting the transfer of Fe²⁺ into mitochondria (Dowdle et al., 2014; Bellelli et al., 2016). This leads to mitochondrial ROS production and ferroptosis, contributing to cardiac damage (Li et al., 2020b).

The IL-6/STAT3 signaling pathway regulates NCOA4-mediated ferritin phagocytosis, promoting ferroptosis in cardiomyocytes (Zhu et al., 2023). In a rapid atrial pacing (RAP)-induced AF animal model, activation of the IL-6/STAT3 pathway was observed in both peripheral blood and liver (Yaegashi et al., 2016). This activation increases fibrinogen expression, triggers the extrinsic prothrombin activation pathway, and induces a hypercoagulable state in AF.

Additionally, under Paraquat exposure, Protein 1 containing the Fun14 domain (FUNDC1)/JNK-mediated ferroptosis may contribute to cardiac and mitochondrial damage (Peng et al., 2022). Phosphorylation of FUNDC1 at the Ser17 site activates mitochondrial autophagy (Zhu et al., 2022b), a key process for eliminating dysfunctional or excess mitochondria and maintaining mitochondrial quality control (Pickles et al., 2018; Chang et al., 2021; Sun et al., 2022). Previous studies have highlighted the significant role of mitochondrial autophagy dysfunction in atrial muscle cells of patients with AF (Bravo-San Pedro et al., 2017). FUNDC1, a recently identified mitochondrial autophagy receptor, interacts directly with LC3B, a microtubule-associated protein (Chen et al., 2016; Lv et al., 2017).

Despite limited research on ferroptosis in AF, its pathogenesis, experimental validation, and drug mechanisms remain areas for extensive investigation. Therapeutic approaches targeting ferroptosis in atrial fibrillation may draw from research in other systemic diseases. Potential agents include experimental compounds like erastin and RSL3, drugs such as statins and artemisinin, ionizing radiation, and cytokines like IFNγ and TGF-β1, which may offer avenues for reversing AF (Chen et al., 2021).