Cardiovascular diseases (CVD) persist to be a major public health challenge, contributing significantly to global morbidity and mortality [1]. In 2019, CVD was responsible for 9.6 million deaths in men and 8.9 million deaths in women, totaling 17.9 million deaths, or approximately one-third of all deaths globally [2]. Heart attacks and strokes were responsible for 85% of these fatalities [1,2]. CVD risk factors are rising globally, driven by lifestyle changes, aging populations, and the increased prevalence of conditions like obesity and diabetes [2,3]. For instance, the global prevalence of hypertension, a major risk factor for CVD, has doubled over the past 30 years, currently affecting around 1.28 billion individuals [4]. Similarly, the diabetes prevalence has increased significantly, from 108 million in 1980 to 529 million in 2021 [5].

Other medical conditions, such as neuromuscular diseases (NMDs), can also induce or exacerbate heart disease. Many NMDs, particularly those affecting skeletal muscles, lead to significant cardiac complications, such as rhythm disturbances, cardiomyopathy, or heart failure [6]. For instance, although survival in Duchenne muscular dystrophy (DMD) has improved due to glucocorticoid use and respiratory support, cardiac complications continue to be the primary cause of death in end-stage DMD patients [6]. This comorbidity further complicates patient care, as each condition can exacerbate the severity of heart disease and vice versa, necessitating an integrated and comprehensive approach to treatment.

Therefore, the economic impact of heart disease, which includes both direct healthcare expenses and indirect costs associated with decreased productivity and other factors, is profound and contributes to the social burden [3,7]. These highlight the critical need for novel therapies.

Maltol is a naturally occurring organic compound known for its pleasant, caramel-like odor, commonly found in the bark of larch trees (Larix decidua), fine trees, and roasted malt [8]. It has been extensively used as a flavor enhancer (INS number 636 in the US and E number E636 food additive in the European Union) in the food industry due to its capacity to enhance food products’ flavor and fragrance. During red ginseng production, maltol is formed as a Maillard reaction product through heat-induced changes such as deacetylation, deglycosylation, and dehydration of the chemical constituents of fresh ginseng, with significant contributions from amino acids and saccharides [9,10]. Hence, maltol is employed as a critical indicator for the quality control of various ginseng products.

Chemically, maltol is a pyrone derivative (3-hydroxy-2-methyl-4-pyrone), which binds to hard metal centers such as ferric iron (Fe³⁺), thereby significantly enhancing the oral bioavailability of iron in the body [11]. Ferrous maltol, a complex of iron and maltol, is used clinically to treat iron deficiency anemia, inflammatory bowel disease, and chronic kidney disease [12,13]. Due to its antioxidant and anti-inflammatory properties, maltol has exhibited additional pharmacological activities, such as antitumor properties [14,15] and protection against liver and kidney damage [16-19]. However, research on the impact of maltol on the heart is limited, and no studies have examined its effects in various pathological conditions, including NMDs.

This study evaluates the cardioprotective effects of maltol by assessing its cardiac cytotoxicity, anti-cardiopathologic effects, and cardiac physiological impacts utilizing experimental models in both in vitro and in vivo settings. The aim is to evaluate maltol’s therapeutic potential for enhancing cardiac health in the presence of comorbid conditions.

Animal

All animal procedure was approved by the Animal Experimental Committee of Pusan National University (protocol number: 2024-0439) and were carried out according to the Guide for the Care and Use of Laboratory Animals (US National Institutes of Health Publications, eighth edition, 2011). Male mdx (C57BL/10ScSn-Dmdmdx/J) and control (C57BL/10ScSn) mice were purchased from The Jackson Laboratory and housed at specific pathogen-free level.

Cells and biochemical analysis

H9c2 rat embryonic cardiomyocytes (ATCC) and AC16 human ventricular cardiomyocytes (Merck) were cultured in Dulbecco’s Modified Eagle Medium supplemented with 10% fetal bovine serum. Cytotoxicity was evaluated using the WST-1 Assay Kit (Donginbio) following the manufacturer’s instructions, with measurements performed in triplicate.

Total RNA was isolated using the TRIzol reagent (Life Technologies) according to the manufacturer’s protocol. cDNA was synthesized with the iScript cDNA Synthesis Kit (Bio-Rad). Quantitative real-time PCR was performed in duplicates using SYBR green on Real-Time PCR systems (Qiagen). Relative gene expressions were determined using the ΔΔCt method and presented as RQ values (RQ = 2−ΔΔCt), with the 18S rRNA gene used for normalization.

Tissue and cell lysates were prepared using RIPA buffer containing protease inhibitor cocktails and separated on precast 4%–20% SDS-PAGE gels (Bio-Rad). The separated proteins were transferred to nitrocellulose membranes (Bio-Rad). Membranes were incubated overnight with specific primary antibodies. Following a wash step, the membranes were incubated with HRP-conjugated secondary antibodies for 1 h. The bands were then visualized using the ECL detection system (GE Healthcare). The intensity of the bands was analyzed using Image J software (National Institutes of Health).

Chemicals and antibodies

Maltol was purchased from MedChemEexpress (CAT no. HY-W012788), and isoproterenol (ISO) and dimethyl sulfoxide were purchased from Sigma-Aldrich Co. The following primary antibodies were used for immunoblot analysis: anti-BNP (Santa Cruz Biotechnology), anti-phospho-PLN (Badrilla LTD), anti-PLN (Badrilla LTD), anti-NCX1 (Cell Signaling Technology), SERCA2a (home-made), and anti-GAPDH (Sigma-Aldrich).

Echocardiography

Echocardiography was performed using a LOGIQ P9 echocardiography system (GE Healthcare). M-mode (2-D guided) images and recordings were acquired from the long-axis view of the left ventricle (LV) at the level of the papillary muscles. The thickness of the LV posterior and interventricular septum was measured from the images. Ejection fraction (EF) and fractional shortening (FS) are calculated using the following formulas: EF (%) = 100 × [(LVIDd3 – LVIDs) 3/LIVDd3], FS (%) = 100 × [(LVIDd-LVIDs)/LVIDd].

Statistical analysis

Data are presented as mean ± standard deviation. Statistical analysis was performed using GraphPad Prism software. Statistical significance among the groups was assessed using ANOVA. A p-value less than 0.05 was considered statistically significant.

Maltol exhibits low cardiac cytotoxicity in H9c2 and AC16 cell lines compared to dapagliflozin

We evaluated he cardiac cytotoxicity of maltol in rodent-derived H9c2 and human-derived AC16 cardiac cell lines. The cells were subjected to a WST-1 assay after being treated with various concentrations of maltol (1–100 μM) for 24 h. Maltol’s cytotoxicity was compared with that of dapagliflozin, an antidiabetic drug recognized for its encouraging cardiovascular effects [20].

When the H9c2 cardiomyocytes were treated with maltol, no significant cytotoxicity was observed up to a concentration of 30 μM of maltol. The cell viability decreased to about 86% at a concentration of 100 μM of maltol, comparable to the level observed with 30 μM of dapagliflozin (Fig. 1A, B). Dapagliflozin exhibited H9c2 cell survival rates of 92% at 10 μM, 80% at 30 μM, and 62% at 100 μM.

Figure 1. Maltol exhibits low cardiac cytotoxicity and mitigates ISO-induced stress in cardiomyocytes. Viability of H9c2 and AC16 cells treated with various concentrations of maltol for 24 h. (A) Information of maltol. (B) Comparison of cell viability between maltol and dapagliflozin treatments in H9c2 cells. (C) Comparison of cell viability between maltol and dapagliflozin treatments in AC16 cells. (D) mRNA expression levels of NPPA, NPPB, and MYH7 in ISO-treated H9c2 cells with and without maltol treatment. (E) Protein levels of BNP in ISO-treated H9c2 cells with and without maltol treatment. (F) Changes in the surface area of ISO-induced AC16 cardiomyocytes with and without maltol treatment. The cell size was measured by immunofluorescence staining with alpha-actinin, using DAPI for nuclear staining, and images were captured at 40× magnification. (G) mRNA expression levels of IL1B, IL10, LC3, SIRT1, and HO1 in ISO-treated AC16 cells with and without maltol treatment. Data are means ± SD. ISO, isoproterenol; MAL, maltol; DAPA, dapagliflozin; NT, no treatment. *p < 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001.

The survival rate of AC16 cells was approximately 79% at 100 μM, which was comparable to that of H9c2 cells in response to maltol (Fig. 1C). When treated with 100 μM dapagliflozin, the AC-16 cell survival rate was 34%. In subsequent cell line experiments, 10 μM maltol was used, considering the cytotoxic concentration range.

Maltol mitigates ISO-induced cardiac hypertrophy and inflammation in cardiomyocytes

Cardiac hypertrophy is a significant risk factor for cardiovascular morbidity and mortality. To evaluate the cardioprotective effects of maltol, hyperstimulation with ISO was used to mimic cardiac stress and pathology conditions, especially those related to cardiac hypertrophy and heart failure [21]. The mRNA expression of NPPA, NPPB, and MYH7 in H9c2 cardiomyocytes was markedly increased by the ISO treatment (10 μM for 24 h). Conversely, the administration of 10 μM maltol significantly inhibited the expression of these genes (Fig. 1D). The protein levels of natriuretic peptides B (BNP) were substantially increased in H9c2 cardiomyocytes treated with ISO, as confirmed by immunoblot analysis. In contrast, maltol cotreatment resulted in lower BNP protein levels compared to ISO-treated cells (Fig. 1E).

The surface area size of ISO-induced H9c2 cardiomyocytes was reduced when cotreated with maltol compared to untreated conditions (Supplementary Fig. 1). Consistent with the H9c2 cardiomyocyte results, maltol effectively reduced the ISO-induced enhancement in AC16 cardiomyocyte size (Fig. 1F). Maltol treatment downregulated NPPB mRNA expression, a marker of cardiac hypertrophy. Quantitative RT-PCR results demonstrated that maltol exhibited an additional cardioprotective effect under ISO-induced cardiac hypertrophy conditions.

In AC16 cardiomyocytes, ISO treatment significantly increased the mRNA expression of the proinflammatory factor IL1B and decreased the anti-inflammatory mediator IL10. This effect was mitigated by maltol treatment (Fig. 1G). ISO treatment of AC16 cardiomyocytes resulted in the upregulation of LC3 expression, an autophagy marker gene, which was inhibited by maltol. Furthermore, maltol elevated the expression of SIRT1 and HO1, genes that are recognized for their antioxidant and anti-inflammatory effects in ISO-induced pathological conditions (Fig. 1G).

Maltol treatment improves cardiac function in mice with DMD

The mdx mice are a representative model of DMD characterized by myocyte loss, leading to skeletal muscle wasting and progressive dilated cardiomyopathy [22]. To investigate the in vivo effect of maltol treatment on cardiac physiology, heart function was analyzed after maltol treatment in mdx mice. Five-month-old mdx mice (C57BL/10ScSn-Dmdmdx/J) were administered saline (vehicle, VEH) or maltol (20 and 50 mg/kg) daily via oral gavage for two months (Fig. 2A). Controls were age-matched WT (C57BL/10ScSn) mice that were administered saline. There were no differences in body weight changes between the groups during the study (Fig. 2B).

Figure 2. Maltol treatment improves cardiac function in mdx mice with Duchenne muscular dystrophy. (A) Experimental design and treatment regimen for mdx and WT mice with maltol. (B) Body weight (BW) changes in WT and mdx mice treated with vehicle or maltol. (C) Representative M-mode echocardiography images of WT and mdx mice. Quantitative analysis of (D) systolic left ventricular internal diameter (LVIDs), (E) fractional shortening (FS), (F) ejection fraction (EF), (G) left ventricular posterior wall thickness (LVPWd), (H) interventricular septal thickness (IVSd), (I) heart rate (HR) in WT and mdx mice treated with vehicle or maltol. Each dot represents an individual animal. Data are means ± SD. PO, per os; WT, wild-type; VEH, vehicle; MAL, maltol; ns, not significant. *p < 0.05.

Noninvasive echocardiography was employed to quantify myocardial wall thickness and cavity dimensions. The representative images are illustrated in Fig. 2C. M-mode echocardiography revealed that the systolic left ventricular internal diameter (LVIDs) was smaller in mdx mice treated with maltol compared to vehicle-treated mdx controls (LVIDs: MDX + MAL 50 mpk = 0.25 ± 0.03 cm; MDX + MAL 20 mpk = 0.27 ± 0.04 cm; MDX + VEH = 0.30 ± 0.04 cm, p < 0.05 MDX + MAL 50 mpk vs. MDX + VEH, Fig. 2D). At 50 mpk, maltol significantly increased FS, an index of the LV systolic function (FS: MDX + MAL 50 mpk = 34.62 ± 1.66%; MDX + MAL 20 mpk = 31.45 ± 3.56%; MDX + VEH = 26.91 ± 5.44%, p < 0.05 MDX + MAL 50 mpk vs. MDX + VEH, Fig. 2E). Additionally, maltol treated mdx mouse hearts also exhibited an increase in EF compared to vehicle controls (EF: MDX + MAL 50 mpk = 70.29 ± 2.06%; MDX + MAL 20 mpk = 65.97 ± 5.50%; MDX + VEH = 58.65 ± 9.33%, p < 0.05 MDX + MAL 50 mpk vs. MDX + VEH, Fig. 2F). Maltol administration did not influence LV posterior wall thickness (Fig. 2G) or interventricular septal thickness (Fig. 2H). The study groups exhibited comparable heart rates (Fig. 2I). Table 1 provides a comprehensive summary of all values.

Table 1 . Echocardiographic parameters in control and mdx mice.

Parameter	WT	MDX + VEH	MDX + MAL 20 mpk	MDX + MAL 50 mpk
N	4	9	5	5
FS (%)	35.18 ± 1.05	26.91 ± 5.44#	31.45 ± 3.56	34.62 ± 1.66*
EF (%)	71.07 ± 1.50	58.65 ± 9.33#	65.97 ± 5.50	70.29 ± 2.06*
LVIDd (cm)	0.40 ± 0.03	0.42 ± 0.02	0.39 ± 0.04	0.39 ± 0.04
LVIDs (cm)	0.26 ± 0.01	0.30 ± 0.03	0.27 ± 0.04	0.25 ± 0.03*
IVSd (cm)	0.09 ± 0.01	0.12 ± 0.02	0.12 ± 0.03	0.12 ± 0.02
IVSs (cm)	0.13 ± 0.01	0.15 ± 0.02	0.16 ± 0.03	0.17 ± 0.01
LVPWd (cm)	0.09 ± 0.01	0.10 ± 0.01	0.09 ± 0.01	0.09 ± 0.01
LVPWs (cm)	0.13 ± 0.01	0.13 ± 0.02	0.12 ± 0.01	0.13 ± 0.01
HR (bpm)	363.56 ± 7.41	358.65 ± 7.04	361.48 ± 4.02	364.60 ± 8.44

Data are means ± SD. WT, wild-type; VEH, vehicle; MAL, maltol; FS, fractional shortening; EF, ejection fraction; LVIDd, left ventricular internal dimension in diastole; LVIDs, left ventricular internal dimension in systole; IVSd, interventricular septal thickness at end-diastole; IVSs, interventricular septal thickness at end-systole; LVPWd, left ventricular posterior wall thickness at end-diastole; LVPWs, left ventricular posterior wall thickness at end-systole; HR, heart rate. *p < 0.05 vs. MDX + VEH. ^#p < 0.05 vs. WT.

Maltol treatment enhances phospholamban (PLN) phosphorylation and modulates calcium handling in mdx mouse hearts

The regulation of calcium ions (Ca²⁺) is essential for the contraction and relaxation of heart muscles, which in turn significantly influences cardiac function [23]. Immunoblot analysis was conducted to assess the status of key Ca²⁺ handling proteins in the mdx rodents. No significant differences were observed in the expression of sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA2a), responsible for pumping Ca²⁺ from the cytoplasm back into the SR during cardiac muscle relaxation, between the wildtype littermates (WT) and mdx groups.

However, the primary inhibitory mechanism of SERCA2a was activated in the mdx mouse heart. In the mdx heart, the proportion of phosphorylated PLN in total PLN was significantly lower than that of the WT mouse heart. This suggests that a greater amount of PLN, the endogenous regulator of SERCA2a, was in its inhibitory state. Additionally, there was a trend toward increased PLN expression. The expression level of sodium-calcium exchanger (NCX1), the primary Ca²⁺ extrusion mechanism in cardiomyocytes, remained unaltered (Supplementary Fig. 2).

In the cardiac tissue of mdx mice, PLN phosphorylation levels increased (215%) with the dose of maltol treated compared with the vehicle group (58%) (Fig. 3A, B). SERCA2a expression showed an increasing trend, while NCX1 expression exhibited a decreasing trend, although these changes did not reach statistical significance (Fig. 3C, D).

Figure 3. Maltol treatment enhances phospholamban (PLN) phosphorylation and modulates Ca2+ handling signaling proteins in mdx hearts. (A) Representative immunoblots showing phosphorylation levels of PLN and PLN in WT and mdx mice hearts treated with vehicle or maltol. GAPDH was used as a loading control. (B) Quantitative analysis of phosphorylated PLN and total PLN in WT and mdx mice hearts. (C) Immunoblots showing expression levels of SERCA2a and NCX1 in WT and mdx mice hearts treated with vehicle or maltol. (D) Quantitative analysis of SERCA2a and NCX1 in WT and mdx mice hearts treated with vehicle or maltol. Data are means ± SD. WT, wild-type; VEH, vehicle; MAL, maltol; ns, not significant. *p < 0.05.

Maltol treatment reduces the expression of fibrosis-related and inflammatory genes in mdx mouse hearts

The qPCR results revealed that transcript levels of stiffness-related genes, such as COL1A1 and POSTN (Fig. 4A, B), and proinflammatory genes, such as IL1B, were significantly upregulated in the mdx mouse hearts; maltol administration significantly inhibited this upregulation (Fig. 4C) (Relative values of COL1A1: WT = 1.00 ± 0.18; MDX + VEH = 29.80 ± 10.77; MDX + MAL 50 mpk = 11.00 ± 13.12. p = 0.04 MDX + MAL 50 mpk vs. MDX + VEH. Relative values of POSTN: WT = 1.00 ± 0.20; MDX + VEH = 49.97 ± 19.69; MDX + MAL 50 mpk = 8.77 ± 3.62. p = 0.0017 MAL + MAL 50 mpk vs. MAL + VEH. Relative values of IL1B: WT = 1.00 ± 0.06; MDX + VEH = 9.34 ± 3.78; MDX + MAL 50 mpk = 3.82 ± 1.28. p = 0.03 MAL + MAL 50 mpk vs. MAL + VEH). These findings are consistent with the results observed in the ISO-induced stress model, underscoring the potential of maltol to mitigate pathological cardiac remodeling both in vitro and in vivo settings.

Figure 4. Maltol treatment attenuates the upregulation of fibrosis and inflammatory genes in mdx mouse hearts. mRNA expression levels of (A) COL1A1, (B) POSTN, and (C) IL1B in wild-type (WT) and mdx mouse hearts treated with vehicle (MDX + VEH) or 50 mpk maltol (MDX + MAL 50 mpk), as determined by qPCR analysis. Data represent 3 to 5 animals per group and are presented as means ± SD. *p < 0.05; **p ≤ 0.01; ***p ≤ 0.001.

This study revealed the cardiovascular benefits of maltol under diverse pathogenic conditions. For the first time, the cardiac cytotoxicity of maltol was assessed in rodent (H9c2) and human (AC16) cells and compared with dapagliflozin, a sodium-glucose cotransporter 2 inhibitor that is recognized for its antidiabetic and potential cardiovascular effects. The results emphasize the relative cardiac safety of maltol compared to dapagliflozin, as maltol treatment led to increased cell viability in both cell lines. H9c2 cells demonstrated superior survival rates than AC16 cells throughout the concentration range that was examined when contrasted with the effects of maltol treatment alone. These differences in responses are likely due to species-specific variations and intrinsic cellular characteristics, with H9c2 cells (derived from rat cardiac myoblasts) generally exhibiting greater resilience than AC16 cells (derived from human ventricular cardiomyocytes). There is no overlapping chemical core between the two compounds. Instead, dapagliflozin is a standard reference point, enabling a meaningful comparison of toxicity profiles. This approach allows us to determine whether the toxicity profile of maltol is within acceptable limits compared to standard treatments.

The study findings underscore the multifaceted cardioprotective effects of maltol in ISO-induced cardiac stress, which resembles pathological cardiac hypertrophy and inflammation. Cardiac hypertrophy is both a complication and a major risk factor for cardiovascular morbidity and mortality. It becomes maladaptive when it encompasses cell death, fibrosis, Ca²⁺ handling dysregulation, mitochondrial dysfunction, metabolic reprogramming, fetal gene reactivation, impaired protein and mitochondrial quality control, altered sarcomere structure, and insufficient angiogenesis [24]. Maltol exhibits the potential to serve as a therapeutic agent for preventing and treating pathological cardiac hypertrophy and related conditions by inhibiting gene expression that is responsible for hypertrophic growth and fibrosis, reducing cell size, preventing inflammatory responses, and modulating autophagy and antioxidant pathways.

Previous studies have indicated that maltol possesses potent antioxidant properties, which contribute to the prevention of hepatic fibrosis by targeting the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway [16-18]. In mice, maltol treatment inhibits the brain aging process by activating the PI3K/Akt-mediated nuclear factor erythroid 2-related factor 2 (Nrf2)/heme-oxygenase 1 (HO-1) signaling pathway [25]. The maltol-induced upregulation of HO1 and sirtuin 1 (SIRT1) in ISO-treated cardiac cells is likely mediated by the PI3K/Akt signaling pathway. Studies have shown that PI3K/Akt signaling enhanced Nrf2 nuclear translocation, increasing the binding of Nrf2 to the antioxidant response element in the HO1 promoter, leading to increased HO-1 expression [26,27]. HO1 exhibits potent antioxidant and anti-inflammatory effects [28]. By degrading prooxidant hemes into biliverdin, carbon monoxide, and free iron, HO1 reduces oxidative stress and inflammation, potentially protecting cardiac cells from ISO-induced damage. Elevated SIRT1 activity can enhance cellular antioxidant capacity, reduce inflammation, and improve cell metabolism, all of which promote cardiac cell health under stress conditions [29]. Furthermore, additional phenolic compounds, including curcumin and caffeic acid, have been reported to transcriptionally regulate HO1 expression [30]. However, it cannot be excluded that other pathway may also contribute to the maltol-induced upregulation of HO1 and SIRT1.

This study provides substantial evidence regarding the cardioprotective effects of maltol in the context of DMD. A two-month oral treatment of maltol enhanced cardiac contractility and mitigated pathogenic remodeling in mdx mice. These beneficial cardiac effects were observed in the 20 mg/kg groups and were statistically significant in the 50 mg/kg dosing group when compared with the vehicle-treated mdx controls.

In previous studies, maltol has been administered at doses ranging from 12.5 to 100 mg/kg for 7 to 30 days [16-19,25,31]. Our research is particularly significant because it is the first to illustrate the cardiac effects of maltol in the context of DMD, and only one prior study has investigated these effects.

The enhancement of crucial indicators of left ventricular systolic function indicates that maltol effectively alleviates the progressive dilatation and systolic dysfunction characteristic of DMD cardiomyopathy [6]. Furthermore, the absence of substantial body weight changes, LV posterior wall thickness, interventricular septal thickness, and heart rate among the study groups suggests that the cardioprotective effects of maltol are specific and not due to systemic physiological changes.

The biochemical findings in this study corroborate the physiological improvements observed in mdx mice. More importantly, the elevated PLN phosphorylation following maltol treatment indicates critical cardiac benefits, especially in heart diseases where defective Ca²⁺ handling contributes to dysfunction [6,23]. PLN is an endogenous inhibitor of the SERCA2a Ca²⁺ pump, which is a key determinant of cardiac relaxation and contraction [23]. Upon phosphorylation, which is mediated through β-adrenergic stimulation, PLN’s inhibitory effect on SERCA2a is relieved, enhancing Ca²⁺ cycling and cardiac function [32].

Several groups, including ours, are targeting the SERCA2a pump as a novel therapeutic approach for heart diseases. These studies aim to increase SERCA2a activity to boost Ca²⁺ cycling and cardiac function, potentially benefiting patients with heart failure and other cardiac conditions [33]. For instance, a phase 1 clinical trial (NCT04179643) has been initiated to examine the potential of I-1c gene therapy for treating patients with New York Heart Association class III heart failure. This therapy is designed to enhance cardiac function by increasing the phosphorylated form of PLN through the inhibition of protein phosphatase.

In this study, although not statistically significant, the inclination toward increased SERCA2a expression and decreased NCX1 expression with maltol treatment further supports the potential of maltol to optimize Ca²⁺ dynamics in the mdx mouse heart.

Given the severe cardiac phenotypes observed in aged mdx mice, conducting further studies on these models or administering treatments over extended periods would be highly beneficial. This approach is crucial for assessing the therapeutic efficacy of maltol in such scenarios. Additionally, exploring the impact of maltol on the skeletal muscle function in DMD could provide valuable insights into its broader therapeutic potential.

In conclusion, maltol demonstrates substantial cardioprotective effects by enhancing cardiac contractility, optimizing Ca²⁺ handling, and reducing oxidative stress and inflammation. These properties, together with its low cytotoxicity, have made maltol a prospective therapeutic candidate for DMD and other cardiac conditions characterized by hypertrophy and inflammation.

Supplementary data including two figures can be found with this article online at https://doi.org/10.4196/kjpp.24.246

None.

The authors declare no conflicts of interest.

This research was supported by the National Research Foundation of Korea grant funded by the Korea government (RS-2024-00339639 and 2021R1A2C3004938) and partially supported by the 2023 Health Fellowship Foundation and Brain Korea 21 Plus Program.