How certain nutrients may influence cell recycling, iron-related cell death, and energy production in heart and metabolic diseases

Oxidative stress has been extensively recognized as a significant factor in the pathogenesis of atherosclerosis, particularly through the oxidation of LDL, the activation of redox-sensitive transcription factors, and the reduction of bioavailability of endothelial nitric oxide (2, 33). Nevertheless, traditional antioxidant frameworks have not yielded consistent clinical advantages, indicating that the role of redox biology in cardiovascular pathology is more intricate than merely an excess of ROS (34). Novel findings have identified ferroptosis as a pivotal mechanism underlying vascular and myocardial damage (5). In atherosclerotic lesions, the accumulation of iron, the presence of membranes rich in polyunsaturated fatty acids, and the reduced activity of glutathione peroxidase 4 establish a conducive environment for the initiation of ferroptotic signaling (35). Endothelial cells subjected to oxidized lipids demonstrate elevated levels of lipid-derived ROS and mitochondrial impairment, while macrophage foam cells exhibit dysregulation of iron homeostasis that may exacerbate plaque instability (36). Experimental investigations have revealed that inhibitors of ferroptosis mitigate endothelial dysfunction and the progression of atherosclerotic lesions, thereby emphasizing its functional significance rather than a mere epiphenomenal correlation (6). In the framework of MI–reperfusion, the sudden reintroduction of oxygen instigates a surge of mitochondrial ROS and iron-mediated lipid peroxidation, thereby rendering cardiomyocytes susceptible to ferroptotic cell death (37). In contrast to apoptosis and necrosis, ferroptosis is characterized by extensive damage to membrane lipids and is intricately associated with mitochondrial metabolic dysfunctions (38). However, notable discrepancies persist within the literature: biomarkers indicative of ferroptosis are defined in a heterogeneous manner, and the interaction between ferroptosis and other forms of cell death remains insufficiently elucidated. An essential deficiency exists in the synthesis of iron metabolism, mitochondrial bioenergetics, and lipid remodeling within a comprehensive systems-level redox paradigm.

Mitochondrial quality control, with a particular emphasis on mitophagy, is critical for sustaining cardiac homeostasis due to the heart’s exceptional energetic requirements. The PINK1/Parkin signaling pathway, among other mechanisms, facilitates the selective elimination of impaired mitochondria, thereby mitigating excessive ROS generation and conserving bioenergetic efficiency (4). In the context of cardiometabolic diseases, compromised mitophagy results in the accumulation of dysfunctional mitochondria, which exacerbates oxidative stress and predisposes cells to ferroptosis and apoptosis. In atherosclerotic blood vessels, impaired mitophagy within endothelial and smooth muscle cells incites inflammatory activation and phenotypic transformation. Likewise, in ischemic myocardial tissue, inadequate mitophagic flux worsens post-ischemic remodeling and contractile impairment (39). Conversely, excessive or unregulated mitophagy may also jeopardize mitochondrial mass and energy production, underscoring the necessity for precise regulation of mitophagy as opposed to indiscriminate activation (40). Current review frequently characterizes mitophagy as a distinct protective mechanism; however, recent evidence indicates the presence of bidirectional crosstalk with ferroptosis. Deficiencies in mitochondrial turnover result in heightened lipid ROS production and disrupt iron–sulfur cluster homeostasis, which may diminish the threshold for ferroptotic cellular demise. In contrast, ferroptotic stress could compromise mitochondrial dynamics and membrane integrity, thereby exacerbating the impairment of mitophagic recognition. Notwithstanding the accumulation of mechanistic insights, translational investigations that connect the modulation of mitophagy to clinical outcomes in cardiovascular health are notably limited, and there is a lack of standardized methodologies for quantifying mitophagic flux within human tissues.

The healthy human heart demonstrates exceptional metabolic adaptability, efficiently transitioning between fatty acid oxidation and glucose metabolism contingent upon substrate availability and energetic requirements. In the context of ischemic heart disease, this adaptability is progressively diminished. Prolonged metabolic stress and redox imbalance alter substrate preference, hinder pyruvate dehydrogenase activity, and decrease the efficacy of oxidative phosphorylation, ultimately resulting in energetic insufficiency (3, 41). During episodes of acute ischemia, diminished oxygen levels inhibit mitochondrial respiration and heighten dependence on anaerobic glycolysis. Following reperfusion, the swift reactivation of the electron transport chain in the presence of accumulated reducing equivalents leads to a surge in ROS (42), which contributes to mitochondrial permeability transition and subsequent cell death. Ongoing mitochondrial dysfunction subsequent to infarction fosters adverse remodeling and exacerbates the progression of heart failure. Importantly, the reprogramming of mitochondrial metabolism exhibits critical intersections with both ferroptosis and mitophagy. Alterations in the flux of the tricarboxylic acid cycle significantly affect the availability of NADPH (43), which serves as a pivotal factor in the regeneration of glutathione and the detoxification of lipid peroxides. Dysregulated metabolism of fatty acids results in modifications to the composition of membrane lipids, potentially heightening vulnerability to peroxidative damage. Concurrently, inadequate mitophagy restricts the replacement of metabolically deficient mitochondria, thereby entrenching cardiomyocytes in a state characterized by oxidative inefficiency. Current research endeavors often examine mitochondrial metabolism, ferroptosis, or mitophagy in a discrete fashion. Nonetheless, the progression of cardiometabolic diseases is indicative of integrated disruptions across these interconnected domains. A perspective grounded in redox reprogramming underscores that mitochondrial dysfunction operates as both a contributor to and a consequence of oxidative stress, positing that the restoration of metabolic flexibility necessitates a comprehensive modulation of iron homeostasis, control of lipid peroxidation, and mitochondrial turnover. This integrative comprehension furnishes the conceptual framework for the strategic targeting of nutrient-derived modulators that have the capacity to concurrently influence redox signaling, mitophagy, and mitochondrial bioenergetics.

Autosomal dominant polycystic kidney disease (ADPKD) is distinguished by the presence of bilateral renal cysts, the early onset of hypertension, endothelial dysfunction, systemic inflammation, and expedited atherosclerosis, thereby augmenting cardiovascular risk and facilitating the progression to end-stage renal disease. A controlled, prospective investigation assessed a cohort of 59 ADPKD patients diagnosed with chronic kidney disease at stages G2/G3, among whom 33 individuals received a daily dosage of 1.6 g of ALA for a duration of 6 months. ALA was found to significantly enhance various metabolic parameters (including glucose, insulin, HOMA-IR, and uric acid), improve endothelial function (evidenced by an increase in flow-mediated dilation and a reduction in the renal resistive index), stabilize acid–base balance, and mitigate oxidative stress (indicated by a decrease in NADPH oxidase 2), in addition to boosting psychocognitive outcomes (measured by the Mini-Mental State Examination, Hamilton Depression Rating Scale, and Beck Depression Inventory-II). No statistically significant alterations were recorded in intima-media thickness, ankle-brachial index, interleukin-6 (IL-6), interleukin-1 beta (IL-1β), or tumor necrosis factor-alpha (TNF-α). ALA demonstrates a profile of safety as an antioxidant and anti-inflammatory agent, exhibiting cardiovascular and cognitive advantages in the early stages of ADPKD (44) (Table 1). Postmenopausal females experience an augmented susceptibility to atherosclerosis as a consequence of the decline in estradiol levels. Although hormone replacement therapy demonstrates immediate cardiovascular advantages, it concomitantly poses elevated risks for stroke and malignancies, underscoring the imperative for safer therapeutic alternatives. Shen et al. assessed the efficacy of ALA, a robust natural antioxidant, in mitigating atherosclerosis utilizing Ldlr^−/− murine models and human aortic endothelial cells (HAECs). ALA markedly diminished atherosclerotic lesions precipitated by ovariectomy and a high-fat diet, reinstated the expression of estrogen receptors (ERα, ERβ), attenuated monocyte adhesion, inhibited apoptosis, decreased ROS through the downregulation of Nox4 and p22phox, and obstructed NF-κB activation in HAECs. ALA may represent a promising therapeutic strategy for the management of postmenopausal atherosclerosis (45).

The objective of a study was to determine the effects of TNFα (10 ng/mL) on vascular smooth muscle cells (VSMCs) over a duration of 24 h, both in the presence and absence of ALA (2 mM), employing two-dimensional gel electrophoresis and DNA microarray methodologies. Proteins up-regulated by TNFα, such as plasminogen activator inhibitor-2 and cyclin-dependent kinase 3, exhibited down-regulation upon treatment with ALA, whereas proteins down-regulated by TNFα, including keratin 19 and Rho GDP dissociation inhibitor alpha, demonstrated restoration in the presence of ALA. The analysis of gene expression corroborated these alterations to some extent, thereby elucidating the underlying mechanisms of atherosclerosis and the protective function of ALA (46). Amom et al. aimed to examine the protective properties of ALA in hypercholesterolemic New Zealand White rabbits. Eighteen rabbits were categorized into three distinct groups: normal control (N), high-cholesterol diet (HCD), and HCD + ALA groups (4.2 mg/kg body weight) over a period of 10 weeks. Blood samples were procured for the evaluation of lipid profiles and malondialdehyde (MDA) levels, while aortas were subjected to analysis for intimal lesions. ALA supplementation resulted in a significant decrease in total cholesterol, LDL, and MDA concentrations when compared to the HCD group. Histological assessments revealed a reduction in the formation of atheromatous plaques. These findings suggested that ALA exhibits both lipid-lowering and anti-atherosclerotic properties, thereby mitigating oxidative stress and the progression of athero-lesions in hypercholesterolemic rabbits (47). The infectious burden is implicated in the pathogenesis of atherosclerosis through common inflammatory pathways; however, interventions aimed at mitigating atherosclerosis under these circumstances remain inadequately investigated. Lee et al. demonstrated the effects of ALA in C57BL/6 mice subjected to a hypercholesterolemic diet over a duration of 12 weeks, with the administration of lipopolysaccharide in the first week to simulate infectious stimuli. ALA administration resulted in a significant reduction in serum cholesterol levels, inflammatory cytokines, and atherosclerotic lesions, while simultaneously enhancing atherosclerotic biomarkers. From a mechanistic perspective, ALA was found to impede the proliferation and migration of VSMCs stimulated by platelet-derived growth factor through the Ras-MEK1/2-ERK1/2 signaling pathway (48).

Hyperglycemia-induced oxidative stress plays a pivotal role in the progression of atherosclerosis and the onset of cardiovascular complications associated with diabetes. An investigation assessed the influence of ALA (1.65 g/kg) in streptozotocin-induced diabetic apoE^(−/−) murine models and their nondiabetic counterparts subjected to a high-fat dietary regimen. Following a duration of 20 weeks, ALA exhibited a substantial reduction in markers of oxidative stress, inhibited elevations in plasma total cholesterol levels, curtailed the development of atherosclerotic lesions, and alleviated health decline associated with diabetes. Furthermore, ALA resulted in a decrease in plasma glucose concentrations and facilitated the recovery of pancreatic insulin-producing cells, thereby suggesting protective effects on beta-cell functionality (49). The aim of a study was to assess the protective properties of ALA (4.2 mg/kg/day) in New Zealand White rabbits subjected to a 1% HCD over a duration of 10 weeks. Blood specimens were obtained for the evaluation of lipid profiles and MDA quantification, while aortic tissues were scrutinized for the presence of intimal lesions. The administration of ALA resulted in a statistically significant decline in MDA, total cholesterol, and LDL concentrations in comparison to the high-cholesterol control group. Histopathological examination indicated a reduction in atheromatous plaque development within the ALA-treated cohort (50).

Zhang et al. assessed the effects of ALA in apoE^−/− and apoE/LDL receptor-deficient murine models subjected to either a Western-type diet or a standard chow diet, with or without the inclusion of 0.2% ALA over a duration of 10 weeks. The administration of ALA resulted in a significant reduction of atherosclerotic lesions, approximately 20% in the aortic sinus and between 40 and 55% in both the aortic arch and thoracic aorta. These observed outcomes were correlated with a reduction of around 40% in body weight gain, diminished serum triglycerides and VLDL levels, decreased accumulation of aortic macrophages, lowered expression of adhesion molecules, and a reduction in proinflammatory cytokines. The anti-obesity, antihypertriglyceridemic, and anti-inflammatory properties of ALA are likely responsible for its antiatherogenic effects, indicating its potential role as a preventive and therapeutic adjunct in the management of atherosclerotic vascular disease (51). The objective of a research was to determine the effects of combined flaxseed oil (FO) and ALA supplementation in rats fed a high-fat diet for 10 weeks. ALA was dissolved in FO at 8 g/kg, with varying proportions in the diet. FO+ALA supplementation significantly enhanced plasma antioxidant defenses, increasing SOD, CAT, GPx activities, and GSH levels, while reducing lipid peroxidation. It improved lipid profiles by lowering TG, TC, and LDL-C and increasing the HDL-C/LDL-C ratio. FO+ALA also reduced inflammatory markers IL-6 and CRP (52). Another study engineered LA nanoparticles (LA NPs) through a self-assembly process, utilizing the inherent antioxidant and anti-inflammatory characteristics of LA to enhance bioavailability and mitigate the potential toxicity associated with traditional nanomedicines. In models of inflammatory macrophages, LA NPs demonstrated superior anti-inflammatory efficacy compared to free LA. In a murine model of atherosclerosis, LA NPs diminished plaque development, alleviated oxidative stress, restricted macrophage infiltration, and reduced levels of inflammatory cytokines, as substantiated by ultrasound and immunofluorescence evaluations (53). Another study aimed to elucidate whether ALA exerts an inhibitory effect on the expression of fractalkine that is stimulated by TNF-alpha in rat VSMCs. Analyses conducted using Northern and Western blot techniques revealed that TNF-alpha significantly enhanced fractalkine expression, which was notably attenuated by ALA. Gel shift assays suggested that the inhibitory mechanism of ALA operates, at least in part, through the NF-κB signaling pathway (54).

In a study, it was assessed the impact of ALA (60 mg/kg/day over a period of 21 days) on the expression levels of ICAM-1 within T2DM rat models. A total of 18 male rats were systematically allocated into three distinct groups: control, T2DM, and T2DM + ALA. The expression of ICAM-1 in the abdominal aorta was evaluated through immunohistochemical techniques and subsequently quantified utilizing image analytical methods. T2DM rats demonstrated a statistically significant elevation in both the area and intensity of ICAM-1 expression when compared to control subjects, whereas ALA administration resulted in a pronounced reduction in ICAM-1 expression in relation to untreated T2DM counterparts (55). AL-Kaisei et al. evaluated the prophylactic effects of ALA (300 mg/kg/day for a duration of 60 days) in a cohort of 30 Sprague–Dawley rats, which were stratified into control, T2DM, and T2DM + ALA groups. The condition of T2DM was elicited through the administration of intraperitoneal streptozotocin injections (40–45 mg/kg) over a period of 3 days. The subjects assigned to the T2DM group exhibited significant elevations in glucose levels, lipid profiles, insulin resistance, and the presence of coronary atherosclerotic plaques. Conversely, the rats that received ALA treatment demonstrated diminished glucose and lipid levels, enhanced insulin sensitivity, and maintained antioxidant enzyme activity (GH-PX), with an absence of coronary atherosclerotic lesions (56). Overall, ALA demonstrates significant cardiovascular and anti-atherosclerotic properties through a multitude of interrelated molecular pathways. ALA mitigates oxidative stress by effectively scavenging ROS and augmenting antioxidant mechanisms, comprising SOD, CAT, GPx, GSH, and the activation of Nrf2. It modulates inflammatory signaling pathways by inhibiting the activation of NF-κB, downregulating pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, as well as suppressing adhesion molecules including ICAM-1 and fractalkine in both VSMCs and endothelial cells. Furthermore, ALA enhances lipid metabolism by reducing levels of total cholesterol, LDL, and VLDL, while simultaneously improving HDL ratios. In experimental models of atherosclerosis and myocardial infarction, ALA diminishes apoptosis through the Bax/Bcl-2 and caspase signaling pathways, inhibits macrophage senescence and infiltration, promotes M2b macrophage polarization, and facilitates autophagy, thereby collectively preserving vascular integrity and myocardial functionality. These multifaceted mechanisms underscore ALA’s role as a pleiotropic cardioprotective agent.

Ischemic cardiomyopathy (ICM) is characterized by oxidative stress, inflammatory processes, and apoptotic mechanisms that contribute to the dysfunction of the left ventricle and the development of myocardial fibrosis. A double-blind, randomized, placebo-controlled study investigated the efficacy of ALA (administered at a dosage of 600 mg/day for a duration of 3 months) as an adjunctive therapeutic intervention in a cohort of 67 diabetic patients diagnosed with ICM. A total of 60 participants successfully completed the trial (ALA n = 30; placebo n = 30). The administration of ALA resulted in a statistically significant reduction in the levels of inflammatory biomarkers including TNF-α, CRP, TGF-β1, and MMP-2 when compared to the placebo group. Notable improvements were observed in echocardiographic parameters, with a significant increase in left ventricular ejection fraction and a reduction in left ventricular end-systolic diameter, left ventricular end-diastolic diameter, and left atrial diameter (57) (Table 2). The aim of a study was to determine the impacts of ALA (100 mg/kg/day) and mitoquinone (MitoQ, 10 mg/kg/day) preconditioning, both independently and in conjunction, on ischemia–reperfusion injury (IRI) in geriatric Wistar rats (22–24 months). Parameters including myocardial infarct size, oxidative stress biomarkers, mitochondrial functionality, the expression of mitochondrial dynamics-related genes (Mfn1, Mfn2, Foxo1, Drp1, Fis1), hemodynamic variables, and serum lactate dehydrogenase (LDH) levels were rigorously evaluated. The combined administration of ALA and MitoQ notably diminished oxidative stress, reduced LDH concentrations, and lessened infarct size, while concurrently enhancing mitochondrial functionality and reinstating the expression of genes associated with mitochondrial dynamics. The co-administration partially rectified the hemodynamic alterations induced by IRI, thereby illustrating a superior cardioprotective effect in the context of aging hearts compared to the monotherapy interventions (58). Another research endeavored to elucidate the effects of ALA in the context of ischemia/reperfusion injury (I/RI) utilizing H9c2 cardiomyocyte cell lines and rat models subjected to hypoxic/reoxygenation conditions or ligation of the left anterior descending coronary artery. The administration of ALA significantly augmented cellular viability, diminished apoptosis, inhibited the production of ROS and levels of MDA, and enhanced the enzymatic activity of superoxide dismutase. Furthermore, ALA treatment resulted in a reduction of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and modulated the expression of apoptotic proteins through a decrease in Bax levels and an increase in Bcl-2 levels. On a mechanistic level, ALA was observed to inhibit the cytoplasmic translocation of high mobility group box 1 (HMGB1), thereby attenuating the activation of the HMGB1/toll-like receptor 4 (TLR4)/NF-κB signaling pathway (59).

Gholami et al. assessed the impact of ALA and ischemic postconditioning (IPostC) on the occurrence of arrhythmias in a model of type-II diabetes mellitus induced in rats. The diabetic condition was established through the administration of a high-fat diet combined with low-dose streptozotocin. Myocardial I/R was performed utilizing the Langendorff apparatus, with ALA (100 mg/kg/day) being provided for a duration of 5 weeks prior to I/R, while IPostC was implemented at the onset of reperfusion. Although IPostC administered in isolation exhibited negligible anti-arrhythmic effects, the synergistic application of ALA preconditioning alongside IPostC markedly diminished the incidence of premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation. This observed cardioprotective effect was correlated with an upregulation of connexin-43 expression and elevated nitric oxide concentrations, suggesting that ALA enhances the therapeutic efficacy of IPostC in diabetic myocardial tissues (60). Mokhtari et al. examined the potential of ALA preconditioning to reinstate the protective effects conferred by IPostC in a model of type-II diabetic rats. The induction of diabetes was achieved through the administration of a high-fat diet in conjunction with low-dose streptozotocin, followed by a regimen of ALA (100 mg/kg/day) for a duration of 5 weeks prior to the ischemia/reperfusion (I/R) procedure. The hearts were subjected to I/R using a Langendorff apparatus, with IPostC being implemented at the onset of reperfusion. The combination of ALA and IPostC resulted in a significant reduction of infarct size, a downregulation of autophagy markers LC3 and p62 at both mRNA and protein levels, and a decrease in mitochondrial ROS as well as membrane depolarization (61). The objective of a research was to elucidate the cardiovascular implications of ALA in isolated rat hearts subjected to IRI utilizing a Langendorff apparatus. ALA was observed to elevate sulfane sulfur concentrations, which play a pivotal role in the release of hydrogen sulfide (H₂S). It is well-established that H₂S mitigates post-reperfusion arrhythmias and affords protection to cardiomyocytes against hypoxia-induced apoptosis, in part by facilitating the activation of ATP-sensitive potassium (K(ATP)) channels. The findings demonstrated that ALA markedly enhanced cardiac function and diminished the incidence of arrhythmias, particularly at a concentration of 10⁻⁷ M. These cardioprotective effects were completely negated by glibenclamide, a specific inhibitor of K(ATP) channels (62).

Cao et al. examined the impact of ALA on the autophagic process within an in vitro hypoxia/reoxygenation (H/R) paradigm of MI/reperfusion injury, utilizing H9c2 cardiomyocyte cell lines. The evaluation of autophagy, a critical mechanism implicated in myocardial I/R damage, was conducted through the quantification of Beclin-1 expression, the ratio of LC3II to LC3I, as well as the assessment of green fluorescent protein-tagged LC3 fusion proteins. The presence of autophagic vacuoles in cells subjected to H/R conditions was substantiated by transmission electron microscopy. The administration of ALA prior to exposure significantly diminished autophagic markers, enhanced cellular viability, and reduced the incidence of overall cell death (63). Deng et al. determined the impacts and underlying mechanisms of ALA in a rat model subjected to in vivo MI/R injury. The subjects underwent a duration of 30 min of ischemia, followed by a period of reperfusion, and were administered ALA as a pretreatment. The application of ALA resulted in a significant attenuation of LDH and CK release, a reduction in infarct size, a limitation of cardiomyocyte apoptosis, and an enhancement of cardiac function. Furthermore, it was observed that ALA diminished TNF-α release and neutrophil infiltration within the injured myocardial tissue. Mechanistically, ALA facilitated the phosphorylation of Akt, promoted the nuclear translocation of Nrf2, and augmented the expression of HO-1, while not influencing the activation of p38MAPK or the production of nitric oxide. The inhibition of PI3K was found to negate these protective effects (64). The purpose of a research was to examine whether the cardioprotective properties of ALA are facilitated through the activation of aldehyde dehydrogenase 2 (ALDH2) in the context of IRI. Employing isolated rat hearts and cultured cardiomyocytes, the researchers evaluated cardiac functionality, apoptosis, oxidative stress indicators, and the activity of ALDH2. The conditions of ischemia–reperfusion and hypoxia-reoxygenation resulted in an exacerbation of cardiac dysfunction, increased apoptosis, heightened levels of ROS, and elevated concentrations of toxic aldehydes (specifically, 4-HNE and MDA). Administration of ALA prior to the injury significantly augmented ALDH2 activity, ameliorated cardiac function, and mitigated oxidative stress and apoptosis. These protective effects were negated in the presence of inhibitors targeting ALDH2 or PKCε (65).

Wang et al. analyzed the protective effects and underlying mechanisms of ALA in the context of MI/R injury in a rat model. MI/R notably elevated the activity of creatine kinase (CK), intensified oxidative stress, diminished the activity of antioxidant enzymes, and facilitated apoptosis and inflammation in a time-dependent manner. The administration of ALA 30 min prior to reperfusion significantly mitigated these alterations. ALA diminished the production of ROS, reinstated the antioxidant defense mechanisms, and inhibited apoptotic and inflammatory responses. These results indicated that ALA confers protection against MI/R-induced cardiac injury via antioxidant, anti-apoptotic, and anti-inflammatory pathways. The study enhances our comprehension of ALA’s pharmacological properties and endorses its prospective therapeutic application in I/RI and cardiovascular diseases (66). Ko et al. employed isolated Langendorff-perfused rat hearts to scrutinize IR injury and the contributions of non-enzymatic antioxidants. A 40-min ischemic interval succeeded by reperfusion resulted in considerable myocardial injury, evidenced by elevated LDH efflux, diminished contractile strength, and lowered ascorbic acid (vitamin C) concentrations. The levels of reduced glutathione and alpha-tocopherol (vitamin E) exhibited stability except under exacerbated IR circumstances. Administration of schisandrin B (Sch B) or ALA as a pretreatment for 3 days conferred protection against IR injury. Sch B demonstrated superior enhancement of contractile recovery, whereas ALA was more proficient in attenuating LDH efflux. Both interventions elevated myocardial concentrations of vitamin C and E, indicating that cardioprotective mechanisms are, at least in part, associated with the modulation of non-enzymatic antioxidant defenses during episodes of oxidative stress (67). Coombes et al. explored the impacts of dietary antioxidant supplementation utilizing vitamin E (VE) and ALA on myocardial ischemia–reperfusion (I-R) responses in senescent male Fischer-334 rats. The subjects were administered either a control diet or a VE/ALA fortified diet for a duration of 14 weeks prior to being subjected to 25 min of ischemia, succeeded by 15 min of reperfusion. The ANTIOX-supplemented rats demonstrated markedly elevated peak arterial pressure during the reperfusion phase and exhibited protection against I-R-induced myocardial lipid peroxidation. Furthermore, heart homogenates derived from ANTIOX rats displayed a reduction in oxidative damage in vitro (68).

Coombes et al. evaluated the impacts of vitamin E (VE) and ALA supplementation on cardiac functionality, dysrhythmias, and biochemical alterations during in vivo ischemia–reperfusion (I-R) in 4-month-old female Sprague–Dawley rats. The subjects were administered either a control diet or a VE/ALA-enriched diet over a duration of 14 weeks. Notwithstanding the considerable elevation of myocardial VE concentrations in the supplemented cohort, no discernible differences were detected in cardiac performance or the frequency of ventricular dysrhythmias during I-R. Nevertheless, indicators of lipid peroxidation were significantly diminished in the supplemented rats, suggesting a protective role of antioxidants against oxidative stress without influencing cardiac functionality (69). Another study shown the ramifications of ALA and its reduced derivative, dihydrolipoic acid (DHLA), on cardiac IRI at both the organ and mitochondrial tiers. Isolated rat cardiac tissues were exposed to global ischemia followed by reperfusion with varying concentrations of ALA. Administration of low-dose ALA (0.5 μM) facilitated hemodynamic recovery, whereas high-dose ALA (10 μM) exacerbated recovery and extended rhythm disturbances. DHLA administration to isolated mitochondria did not mitigate respiratory dysfunction but significantly diminished mitochondrial superoxide (O2•−) generation. Furthermore, DHLA indirectly modulated O2•− production through the redox-cycling mechanism of ubiquinone (70). Overall, ALA demonstrates cardioprotective properties in the context of myocardial I/R injury through a diverse array of molecular mechanisms. ALA alleviates oxidative stress by effectively scavenging ROS, augmenting the activity of antioxidant enzymes, and modulating non-enzymatic antioxidants, including vitamins C and E. It attenuates apoptosis by manipulating the ratios of Bax to Bcl-2, constraining mitochondrial membrane depolarization, and activating critical signaling pathways such as ALDH2, PI3K/Akt, and Nrf2/HO-1. ALA diminishes inflammation through the inhibition of TNF-α, IL-6, IL-1β, and the HMGB1/TLR4/NF-κB signaling cascade. It enhances mitochondrial functionality by regulating genes pertinent to mitochondrial dynamics (Mfn1/2, Drp1, Fis1) and decreasing mitochondrial ROS. Furthermore, ALA influences autophagy (LC3, p62, Beclin-1), promotes H₂S release via K(ATP) channels, and works in concert with ischemic postconditioning and antioxidants such as vitamin E or MitoQ, collectively improving cardiac performance, decreasing infarct size, and averting arrhythmias during I/R injury.

MI is linked to significant morbidity and mortality, while the macrophage senescence-associated secretory phenotype (SASP) is integral to the healing process following infarction. An investigation explored the correlation between ALA and macrophage senescence through the application of single-cell RNA sequencing (GSE163465↗), molecular assessments, coculture methodologies, and experimental animal models. The findings demonstrated an age-independent augmentation in senescent macrophages during MI, marked by increased levels of H2A X, CCL7, IL-1β, and CDKN1A, alongside diminished SOD2, signifying oxidative stress and mitochondrial impairment. ALA administration inhibited the degradation of SIRT1, facilitated the nuclear translocation of Nrf2, decreased the production of ROS and autophagy flux, and mitigated the expression of SASP (71) (Table 3). The aim of a study was to determine the impact of concomitant supplementation with ALA and mitoquinone (MitoQ) on cardiac functionality in aged rats following MI. The experimental rats were subjected to a 30-min occlusion of the left anterior descending artery, followed by a subsequent 24-h reperfusion period, subsequent to receiving ALA and MitoQ for a duration of 2 weeks prior to the induction of ischemia. The dual intervention resulted in a statistically significant enhancement of cardiac function in comparison to control subjects. These observed advantages were correlated with notable declines in pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and markers of apoptosis (Bax, caspase-3, cytochrome c), in addition to a reduced incidence of TUNEL-positive cells (72). Gholami et al. evaluated the synergistic impacts of ALA and ischemic postconditioning (Post) on myocardial infarction and apoptosis in rats suffering from chronic type II diabetes that were subjected to I/R injury. The diabetic condition was established through a high-fat diet and administration of streptozotocin, with rats receiving ALA for a duration of 5 weeks prior to the I/R event. Although Post alone did not exhibit a statistically significant reduction in infarct size or levels of LDH, ALA administered alone demonstrated protective properties. Importantly, the combined administration of ALA and Post treatment significantly reduced apoptotic markers, such as Bax, the Bax/Bcl2 ratio, and cleaved caspase-3, while simultaneously enhancing Bcl2 expression. Additionally, histopathological assessments showed marked improvements (73).

Wang et al. examined the implications of ALA in the context of MI, with particular emphasis on the modulation of macrophage activity and the subsequent cardiac recuperation. Myocardial infarction was experimentally induced in murine models via ligation of the left anterior descending artery, and macrophages were exposed to conditions of hypoxia alongside stimuli promoting M1 polarization. Treatment with ALA facilitated the transition toward M2b macrophage polarization while concurrently attenuating the production of pro-inflammatory cytokines under hypoxic circumstances. Additionally, ALA treatment resulted in a diminution of ROS generation and the preservation of mitochondrial membrane potential in vitro. The supernatants derived from ALA-treated macrophages exhibited a capacity to diminish apoptosis and autophagy in hypoxic cardiomyocytes. On a mechanistic level, ALA effectively inhibited the activation of the HMGB1/NF-κB signaling cascade (74). Xie et al. demonstrated an innovative drug delivery mechanism to augment the therapeutic potency of ALA in the context of acute myocardial infarction (AMI). In light of LA’s swift elimination and extensive biodistribution, the researchers meticulously crafted a controlled-release thin film (ALA@PLGA) employing poly(lactic-co-glycolic acid) through the process of electrospinning. This advanced system facilitated prolonged localized release of ALA, thereby proficiently neutralizing ROS within the compromised myocardial tissue. In vitro experiments demonstrated that ALA@PLGA significantly diminished oxidative stress and apoptosis in cardiomyocytes subjected to hydrogen peroxide treatment. In murine models of AMI, the epicardial application of this film markedly enhanced cardiac functionality and mitigated fibrosis throughout the ventricular remodeling phase. Furthermore, it effectively reduced oxidative stress, cellular senescence, DNA damage, inflammatory responses, apoptosis, and ferroptosis (75). The aim of a study was to explore the ramifications of ALA in individuals diagnosed with T2DM, particularly those possessing a prior history of non-Q myocardial infarction, a demographic characterized by elevated risks of recurrent myocardial infarction and cardiovascular mortality. A cohort comprising 112 patients undergoing conventional therapeutic regimens which included ACE inhibitors, β-blockers, statins, antiplatelet agents, and oral hypoglycemic medications, was assessed. Following a four-month regimen of ALA supplementation, participants exhibited notable decreases in systemic inflammatory markers, such as C-reactive protein, IL-6, and TNF-α, whereas the concentrations of the anti-inflammatory cytokine IL-10 exhibited no significant alterations (76).

Ozgun et al. examined the cardioprotective properties of LA in the context of isoproterenol-induced myocardial infarction in both diabetic and non-diabetic rat models. The induction of diabetes was accomplished via the administration of streptozotocin, followed by a regimen of LA (10 mg/kg/day) for a duration of 14 days prior to the induction of myocardial injury. The administration of isoproterenol resulted in heightened cardiac necrosis, leukocyte infiltration, and serum lipid peroxidation, concomitantly leading to a reduction in the activities of paraoxonase and lactonase. In non-diabetic rats afflicted with myocardial infarction, LA markedly attenuated cardiac necrosis, inflammation, and lipid peroxidation, while also reinstating the activities of antioxidant enzymes. Conversely, in diabetic rats subjected to myocardial infarction, LA did not demonstrate a statistically significant improvement in either histopathological or biochemical parameters (77). Another study determined the therapeutic efficacy of ALA in the context of myocardial damage linked to obstructive sleep apnea syndrome, which is characterized by intermittent hypoxia (IH). In vivo studies demonstrated that exposure to IH compromised cardiac function in murine models, whereas administration of ALA significantly ameliorated cardiac performance. Mechanistically, ALA was found to activate the Nrf2 signaling pathway and facilitate autophagy. In vitro experiments revealed that IH induced apoptotic processes and decreased viability in H9C2 cardiomyocytes, while ALA enhanced Nrf2 nuclear translocation, activated downstream antioxidant signaling pathways, augmented autophagy, and inhibited apoptotic events. The suppression of Nrf2 through the application of ML385 resulted in a reduction of autophagy and attenuated the cardioprotective effects of ALA, thereby corroborating the role of Nrf2 in this context (78). Another study assessed the efficacy of daily administration of ALA in providing protection against AMI and the ensuing left ventricular remodeling (LVR). In murine subjects that were pre-treated with ALA for a duration of 7 days prior to the induction of coronary artery occlusion, a significant reduction in infarct size was observed in comparison to the control group. In a distinct study focusing on LVR, the initiation of ALA treatment 1 day post-AMI and its continuation over an extended period resulted in notable improvements in left ventricular end-systolic volume and ejection fraction at both 28 and 56 days following the infarction event. Moreover, survival rates demonstrated a marked enhancement in the cohort of mice that received ALA treatment (79). Collectively, the aggregated findings from these studies elucidate that ALA confers cardioprotective properties via a complex interplay of antioxidant, anti-inflammatory, anti-apoptotic, and mitochondrial-regulatory mechanisms. ALA diminishes the production of ROS, facilitates Nrf2 nuclear translocation, and enhances the expression of downstream antioxidant defenses, thus mitigating damage induced by oxidative stress. It attenuates inflammatory signaling pathways by inhibiting the HMGB1/NF-κB cascade and reducing the levels of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. ALA mitigates apoptosis through the modulation of the Bax/Bcl-2 ratio, decreasing the activation of caspase-3, and maintaining the integrity of mitochondrial membrane potential. Additionally, it fosters advantageous M2b, inhibits the SASP, and regulates the dynamics of autophagic flux. In conjunction with other therapeutic strategies (e.g., in combination with MitoQ or ischemic postconditioning), ALA synergistically enhances cardiac function and diminishes infarct size. Prolonged delivery systems further augment its therapeutic efficacy in the context of myocardial infarction and associated cardiac injuries.

Cellular studies consistently demonstrate ALA’s ability to attenuate oxidative injury across diverse cardiovascular-relevant cell types, including cardiomyocytes, endothelial cells, and smooth muscle cells. Unlike compounds that rely solely on direct antioxidant scavenging, ALA enhances intracellular antioxidant systems by regenerating glutathione, vitamin C, and vitamin E. This is accompanied by activation of Nrf2-dependent transcriptional programs, as shown by reporter assays and gene-expression profiling. Methodologically, mitochondrial membrane potential assays, Seahorse respirometry, and ROS quantification techniques repeatedly show improved mitochondrial integrity and reduced oxidative burden after ALA treatment. These findings position ALA as a broader metabolic modulator rather than a simple antioxidant. Animal studies extend these findings by demonstrating functional improvements in cardiac performance and vascular physiology. In rodent models of ischemia–reperfusion injury, diabetic cardiomyopathy, and hypertension, ALA supplementation reduces myocardial infarct size, improves endothelial relaxation, and enhances mitochondrial enzyme activity—particularly within pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes. Biochemical analyses consistently report decreases in lipid peroxidation markers (e.g., MDA) and increases in endogenous antioxidant enzyme activities. Notably, ALA’s redox-cycling capacity distinguishes it from non-redox-active antioxidants, enabling sustained protection under high oxidative load.

Human studies, although more variable, generally support the cardiometabolic benefits observed in preclinical models. Clinical trials in diabetic and metabolic-syndrome populations show improvements in endothelial function, reductions in oxidative stress biomarkers, and enhanced insulin sensitivity—an outcome relevant to cardiovascular risk. Variability in dosing regimens and oral bioavailability, however, introduces heterogeneity in effect size. Nonetheless, the consistency of redox-related improvements across trials suggests a robust underlying mechanism. Collectively, evidence across experimental systems supports ALA as a multifaceted modulator of mitochondrial redox biology in cardiovascular disease. By combining direct antioxidant actions, regeneration of endogenous defense systems, metabolic cofactor activity, and activation of cytoprotective signaling pathways, ALA occupies a unique therapeutic niche among mitochondrial-targeted interventions. Future comparative trials and dose-standardized clinical studies will be critical to defining its optimal application in cardiovascular prevention and therapy.

ALA, UA, and EGT each demonstrate modulation of ferroptosis, albeit through distinct molecular pathways. Research indicates that UA has the capacity to mitigate ferroptotic cell death in ischemia–reperfusion scenarios by promoting Nrf2 nuclear translocation and activating downstream antioxidant gene expression, thereby curtailing lipid peroxidation and iron-dependent ROS production (80). ALA, traditionally recognized for its antioxidant properties, indirectly attenuates ferroptotic signaling by enhancing glutathione concentrations and Nrf2 activity, which serves to inhibit iron-catalyzed lipid radical formation (92). EGT, characterized as a thiol-based antioxidant, effectively scavenges lipid peroxides and stabilizes iron–sulfur clusters, thereby exhibiting protective effects against ferroptosis in both cardiomyocytes and vascular endothelial cells (93). In comparison, the inhibition of ferroptosis by UA appears to be most directly associated with transcriptional reprogramming, while ALA and EGT predominantly fortify redox buffering mechanisms.

A further dimension of mechanistic differentiation among these compounds emerges when evaluating their effects on iron transport systems and ferroptosis-modulating antioxidant enzymes that set the threshold for lipid peroxide propagation. In addition to facilitating glutathione recycling, ALA has been reported to regulate cellular iron balance by influencing both iron uptake and export processes. Specifically, it suppresses DMT1 expression while increasing ferroportin and ferritin heavy chain levels, thereby lowering the intracellular labile iron pool and reducing Fenton reaction–mediated lipid radical generation. At the same time, ALA enhances GPX4 activity via NRF2-dependent pathways, strengthening phospholipid hydroperoxide detoxification and supporting mitochondrial membrane stability under oxidative stress. Together, these actions establish ALA as an indirect yet functionally significant modulator of ferroptosis susceptibility at the convergence of glutathione metabolism and iron handling.

In contrast, UA appears to inhibit ferroptotic signaling mainly through transcriptional activation of endogenous cytoprotective antioxidant pathways rather than through direct regulation of intracellular iron stores. In cardiometabolic ischemia–reperfusion models, UA has been shown to stimulate Nrf2 nuclear translocation and induce downstream effectors such as HO-1, thereby reducing mitochondrial ROS accumulation and lipid peroxidation while maintaining cardiomyocyte survival. This gene-level enhancement of intrinsic antioxidant defenses indicates that UA acts upstream of lipid peroxidation execution by reshaping stress-responsive transcriptional networks that determine ferroptotic sensitivity.

EGT, by comparison, operates through a distinct mechanism as a mitochondria-directed thiol antioxidant with strong affinity for redox-active transition metals. Its uptake via the OCTN1 (SLC22A4) transporter enables selective intracellular accumulation within mitochondria and regions of oxidative damage. In these compartments, EGT helps preserve iron–sulfur cluster integrity, buffer labile iron pools, and directly scavenge lipid-derived peroxyl radicals. Through this combination of metal chelation and radical-neutralizing activity, EGT is particularly suited to disrupt early ferroptotic initiation processes driven by mitochondrial ROS amplification and iron-dependent phospholipid oxidation in cardiomyocytes and vascular endothelial cells.

Collectively, these findings indicate that ALA, UA, and EGT exert anti-ferroptotic effects at partially distinct regulatory points along the ferroptosis cascade. UA primarily strengthens transcriptional antioxidant defense programs; ALA integrates glutathione-dependent peroxide detoxification with control of iron transport pathways; and EGT directly stabilizes mitochondrial redox-active iron and modulates lipid radical propagation dynamics. This complementary distribution of activity, spanning upstream transcriptional regulation, intermediary antioxidant buffering, and downstream lipid peroxide propagation, supports the rationale that simultaneous targeting of these ferroptosis-relevant nodes may offer a mechanistically synergistic approach to mitigating cardiometabolic ferroptotic injury.

Mitophagy serves to eliminate impaired mitochondria, thereby sustaining cellular homeostasis. UA initiates mitophagy through the Nrf2–p62 signaling pathway, thereby enhancing mitochondrial quality following cellular injury (94). ALA promotes mitophagic flux via Parkin-dependent mechanisms, thereby safeguarding mitochondrial integrity in the context of oxidative stress (95). EGT facilitates mitophagy indirectly by preserving mitochondrial redox equilibrium (96). UA presents the most compelling evidence for the induction of targeted mitophagy in the context of cardiometabolic stress.

A further point of mechanistic differentiation becomes evident when the actions of these compounds are viewed within the hierarchical organization of mitochondrial quality-control networks rather than as isolated triggers of mitophagy. Among them, UA most consistently exhibits direct activation of mitophagic machinery through coordinated engagement of the Nrf2–p62 signaling axis and subsequent recruitment of Parkin-dependent mitochondrial clearance pathways. In ischemia–reperfusion and metabolic injury models referenced in this manuscript, UA-induced increases in mitophagic flux correlate with recovery of mitochondrial membrane potential, attenuation of mitochondrial ROS amplification, and improved ATP production. These findings support its role as an upstream regulator of mitochondrial turnover, extending beyond simple redox stabilization. By contrast, ALA appears to promote mitophagy chiefly by sustaining the redox conditions necessary for effective mitochondrial quality-control signaling rather than by directly initiating mitophagic cascades. Experimental studies indicate that ALA facilitates Parkin translocation to damaged mitochondria under oxidative stress while preserving glutathione-dependent antioxidant capacity and limiting lipid peroxide accumulation that might otherwise disrupt mitophagy progression. Through these integrated actions, ALA enhances completion of mitophagic flux and prevents the persistence of dysfunctional mitochondria that drive ferroptosis-prone metabolic remodeling in cardiometabolic tissues.

EGT, in comparison, influences mitophagy primarily through maintenance of mitochondrial redox balance and preservation of iron–sulfur cluster stability rather than through direct stimulation of canonical mitophagy pathways. Its preferential intracellular uptake via the OCTN1 transporter enables mitochondrial accumulation at sites of oxidative stress, where it dampens ROS generation and mitigates mitochondrial injury that would otherwise provoke compensatory mitophagic activation. This pattern suggests that EGT acts principally as a mitochondrial protective agent, indirectly supporting mitophagy efficiency by maintaining structural and metabolic integrity under cardiometabolic stress. Collectively, these compounds appear to function at distinct yet complementary checkpoints along the mitophagy continuum. UA predominantly enhances the initiation of selective mitochondrial clearance; ALA supports the propagation and successful completion of mitophagic flux during oxidative stress; and EGT safeguards mitochondrial integrity upstream of mitophagy activation by limiting redox-driven damage. This functional stratification reinforces the concept that nutritionally derived redox modulators regulate mitochondrial quality control through coordinated but mechanistically differentiated pathways that together strengthen mitochondrial resilience in cardiometabolic disease.

Emerging data further indicate that improved mitophagic efficiency mediated by these agents may indirectly suppress ferroptotic signaling by curbing mitochondrial ROS amplification and subsequent lipid peroxidation. Within this integrated model, UA-driven mitophagy initiation, ALA-supported flux completion, and EGT-mediated mitochondrial stabilization converge to modulate the ferroptosis–mitophagy regulatory axis in cardiometabolic pathology through complementary mechanisms.

UA reinstates the mitochondrial membrane potential and ATP synthesis, thereby restoring fatty acid oxidation processes within ischemic myocardial tissue (80). ALA functions as a crucial cofactor for mitochondrial dehydrogenases, thereby augmenting the efficiency of the electron transport chain and mitigating ROS leakage (97). EGT is sequestered within mitochondria through organic cation transporters, thereby preserving redox equilibrium and enhancing respiratory efficiency (24). UA promotes metabolic reprogramming subsequent to injury, while ALA and EGT predominantly contribute to the maintenance of basal bioenergetic resilience.

A clearer mechanistic distinction among these compounds emerges when their effects are interpreted within the framework of mitochondrial metabolic flexibility rather than static measurements of respiratory efficiency alone. UA consistently demonstrates the strongest capacity to promote adaptive metabolic reprogramming following cardiometabolic stress by restoring mitochondrial membrane potential, enhancing oxidative phosphorylation efficiency, and facilitating recovery of fatty acid β-oxidation pathways in ischemic myocardial tissue. Across the experimental models discussed in this manuscript, these effects are closely associated with activation of mitochondrial quality-control signaling and improved coupling between substrate utilization and ATP production, supporting the interpretation that UA functions primarily as a regulator of injury-responsive metabolic remodeling rather than a basal respiratory cofactor.

In contrast, ALA exerts its principal effects on mitochondrial metabolism through its established role as an essential cofactor for mitochondrial α-ketoacid dehydrogenase complexes, including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, thereby facilitating efficient entry of glycolytic substrates into the tricarboxylic acid cycle and sustaining electron transport chain activity under oxidative stress conditions. In addition to enhancing substrate flux through central carbon metabolism, ALA-mediated regeneration of reduced glutathione limits mitochondrial ROS accumulation and preserves respiratory chain integrity, thereby maintaining redox-sensitive enzymatic activity required for sustained ATP synthesis in cardiometabolic tissues. These combined effects position ALA as a stabilizer of basal mitochondrial bioenergetic competence rather than a primary inducer of metabolic reprogramming following injury.

EGT differs mechanistically from both UA and ALA by exerting its metabolic effects predominantly through preservation of mitochondrial redox homeostasis and protection of iron–sulfur cluster–containing respiratory enzymes that are particularly vulnerable to oxidative disruption. Preferential intracellular accumulation through OCTN1-dependent transport enables EGT to localize within mitochondria and buffer ROS at sites of high metabolic flux, thereby supporting maintenance of electron transport chain efficiency and limiting oxidative impairment of complex I and complex III activity. Through stabilization of these redox-sensitive components of mitochondrial respiration, EGT appears to preserve metabolic resilience under conditions of cardiometabolic stress rather than directly promoting substrate-driven metabolic switching.

Importantly, these compounds appear to operate at complementary regulatory levels within the continuum of mitochondrial metabolic adaptation. UA primarily supports injury-responsive metabolic reprogramming through restoration of oxidative phosphorylation capacity and fatty acid utilization pathways, ALA maintains central carbon metabolic flux and enzymatic efficiency within the tricarboxylic acid cycle, and EGT preserves respiratory chain structural integrity through targeted mitochondrial redox buffering. This functional stratification suggests that nutritionally derived redox modulators collectively enhance mitochondrial metabolic flexibility by coordinating substrate utilization efficiency, respiratory chain stability, and ROS-dependent signaling thresholds that influence both mitophagy activation and ferroptosis susceptibility in cardiometabolic disease contexts.

Emerging evidence further indicates that preservation of mitochondrial metabolic flexibility by these compounds may indirectly suppress ferroptotic signaling by limiting mitochondrial ROS amplification and phospholipid peroxidation propagation while simultaneously reducing the burden of dysfunctional mitochondria requiring mitophagic clearance. Within this integrated framework, coordinated regulation of mitochondrial respiration by UA, ALA, and EGT represents a central mechanistic axis linking metabolic adaptation to redox-sensitive cardiometabolic protection.

ALA possesses the most comprehensive clinical evidence, demonstrating improvements in systemic inflammation and endothelial function among cardiometabolic patients (98). EGT display encouraging preclinical cardiometabolic effects but are devoid of clinical trial data (99). As a result, ALA presents the most robust translational evidence, followed by UA, while ET emerges as a potential candidate.

A more coherent view of the translational landscape emerges when these compounds are classified by their mechanistic roles within mitochondrial redox regulation rather than by the sheer volume of clinical studies available. Among the three agents discussed, ALA currently shows the greatest degree of clinical preparedness. This is largely attributable to its established biochemical function as a mitochondrial cofactor and facilitator of glutathione recycling, which enables relatively predictable modulation of systemic oxidative stress and endothelial dysfunction across diverse cardiometabolic populations. Reported clinical improvements in inflammatory biomarkers, vascular responsiveness, and insulin sensitivity align with experimental findings demonstrating ALA’s capacity to preserve mitochondrial bioenergetics and attenuate lipid peroxidation–related injury pathways linked to ferroptotic vulnerability.

UA, by comparison, occupies a transitional translational stage. Although preclinical cardiometabolic models provide robust mechanistic evidence supporting its effects, controlled human data remain comparatively limited. Experimental studies consistently show that UA enhances mitophagic flux, restores mitochondrial membrane potential, and improves oxidative phosphorylation efficiency following ischemic or metabolic stress. However, because UA is generated through gut microbiota–mediated metabolism of dietary ellagitannins, variability in microbial composition across individuals may significantly influence systemic exposure and therapeutic response. This microbiome-dependent activation introduces an important translational variable when considering reproducibility in heterogeneous cardiometabolic populations.

EGT represents an earlier-stage translational candidate with strong mechanistic rationale but limited large-scale clinical validation. Its therapeutic promise stems from distinctive intracellular transport characteristics and mitochondria-targeted antioxidant properties. Uptake via the OCTN1 transporter facilitates selective tissue accumulation in environments characterized by elevated oxidative stress, such as vascular endothelium and cardiomyocytes. Within these settings, EGT contributes to stabilization of iron–sulfur cluster–containing enzymes and buffering of redox-active transition metals implicated in ferroptotic lipid peroxidation cascades. Although observational and experimental findings suggest a cardiometabolic protective role, rigorously controlled intervention trials examining mitochondrial functional outcomes and ferroptosis-associated lipid peroxidation biomarkers remain sparse.

Importantly, differences in translational maturity likely reflect not only disparities in clinical trial volume but also variation in the availability of measurable pharmacodynamic markers that directly link mitochondrial redox modulation to cardiometabolic outcomes. For ALA, systemic oxidative stress indices and endothelial function assessments provide accessible clinical endpoints. In contrast, effective translation of UA-driven mitophagy enhancement and EGT-mediated iron buffering will require integration of emerging mitochondrial biomarkers, such as lipid peroxidation signatures, mitophagy-related protein expression patterns, and iron-handling pathway indicators. Incorporating these mechanistically aligned measures into future trials could substantially enhance interpretability of nutritional modulation of the ferroptosis–mitophagy axis in cardiometabolic disease.

Overall, current evidence positions ALA as the most immediately actionable mitochondrial redox modulator among the compounds reviewed, while UA and EGT remain compelling candidates for further translational development within precision nutrition frameworks targeting mitochondrial dysfunction in cardiometabolic pathology. A clinically informed, mechanism-based evaluation strategy incorporating mitochondrial quality-control metrics and ferroptosis-relevant lipid biomarkers may help clarify their therapeutic roles and guide future combination approaches.