As a flavone, acacetin is found naturally in up to 92 plants, especially abundant in chrysanthemum, turnera diffusa, safflower, propolis, linaria, betula pendula, and calamintha (Singh et al., 2020). Acacetin has a chemical formula of C₁₆H₁₂O₅, and its relative molecular weight is 284.26 (Kim et al., 2014). It naturally exists in free or complex form (glycosylated compounds) in nature (Yang et al., 2014). The log P and log D_7.4 values of acacetin exceed 3, suggesting that it is a highly lipophilic compound (Kiani and Jabeen, 2020; Hughes et al., 2008). Flavonoids generally exhibit poor water solubility, which may be a primary factor contributing to their limited oral bioavailability. For example, the double bonds between the C2 and C3 positions of flavones and flavonols make the molecular arrangement so compact that it is difficult for solvents to penetrate, thus leading to their poor solubility (Zhao et al., 2019). Previous studies showed that the oral bioavailability of the flavonol myricetin in rats was only 9.62%, which may be due to its limited water solubility of 16.60 μg/mL (Dang et al., 2014; Yao et al., 2014). Like other flavonoids, acacetin has a very low water solubility of 64.4 ± 10.9 ng/mL, and its solubility in ethanol is also limited to 0.712 ± 0.002 mg/mL (Wang et al., 2023a). Furthermore, acacetin was found to be stable under basic conditions but unstable under acidic and neutral conditions (Han et al., 2021).

Because acacetin exists in many plants, traditional plant isolation was the main method of obtaining it in the past. The conventional method for the synthesis of acacetin was mainly based on the Baker-Venkataraman rearrangement (Pandurangan, 2014). In another method, Zhao et al. synthesized acacetin using 4-dimethylaminopyridine as a catalyst (Zhao et al., 2016). In addition, acacetin is also synthesized from naringenin chalcone, which requires chalcone isomerase, flavone synthase, and apigenin 4′-O-methyltransferase as catalysts (Liu, 2023). However, due to the low growth rates of plants and the time-consuming and complex process of plant extraction, researchers wanted to perform the heterologous biosynthesis of acacetin. Microbial co-culture technology made the idea a reality. In comparison to traditional plant extraction, microbial production has the advantages of low cost, high yield, sustainability, and environmental friendliness (Dudnik et al., 2018). Recently, Wang et al. achieved the first de novo biosynthesis of acacetin in a heterologous microbial host by designing and using a two- or three-strain E. coli co-culture system, which could convert simple carbon substrate glucose to the final product acacetin (Wang et al., 2020). Importantly, they discovered that cultivating the three-strain co-culture in shake flasks resulted in the maximum production of acacetin at 20.3 mg/L after 48 h (Wang et al., 2020).

In previous studies, data showed that the bioavailability of acacetin in FVB mice was only 1.3% (Jiang et al., 2017), and the maximum plasma concentration (C _max) of acacetin in rats was 19.02 ± 1.29 ng/mL following oral administration of 6 mL/kg acacetin crude extract (Zhang et al., 2014). Meanwhile, the concentration of acacetin in rat plasma reached its peak 5 min after oral administration (Zhang et al., 2014). Another study suggested that after oral delivery of 100 mg/kg acacetin in rats, the unabsorbed dose of acacetin in the jejunal segments amounted to 97.1%, whereas the absorbed dose was only 2.34% (Han et al., 2021). In addition, Fan et al. conducted a pharmacokinetic study of acacetin in rats using a sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method, and the results indicated that after a single intravenous administration of acacetin at the dose of 5.0 mg/kg, the mean C _max of acacetin reached 1334.9 ± 211.6 ng/mL, succeeded by a rapid decrease in the blood concentration with a terminal half-life of 1.48 ± 0.53 h (Fan et al., 2015). Similarly, Kim and colleagues developed a highly selective LC-MS/MS method to perform the quantitative bio-analysis of acacetin in human plasma, and the results showed that the average recovery of acacetin in human plasma ranged from 91.5% to 95.6%, and the fraction of unbound acacetin in plasma was less than 1% (Kim et al., 2016). Acacetin is extensively metabolized by many tissues in the body, especially the liver. A systematic study on acacetin metabolism in rats revealed that the major phase I metabolic reaction of acacetin is an oxidation reaction principally catalyzed by cytochrome P450 enzymes, and about 10 phase I metabolites were identified, including luteolin, naringenin, and apigenin (Yin et al., 2019; Hodek et al., 2002). Furthermore, 21 metabolites of the phase II response of acacetin were recognized in rats, primarily comprising monosulfate and monoglucuronide produced mostly by UDP-glucuronosyltransferase 1A8 and sulfotransferase 1A1, respectively (Yin et al., 2019; Zhang et al., 2017; Dai et al., 2015).

As mentioned above, like many natural flavonoids, acacetin has several disadvantages, such as poor water solubility, rapid metabolism, and low bioavailability, which greatly limit its therapeutic potential. To address these issues, many promising strategies, like nanoparticle formulations, chemical modifications, microemulsions, and absorption enhancers, have been employed to increase the water solubility and gastrointestinal tract absorption of acacetin. For example, Wang et al. developed a novel acacetin-loaded microemulsion formulation that could significantly improve the solubility and percutaneous absorption efficiency of acacetin when combined with appropriate penetration enhancers (Wang et al., 2023a). Liu et al. successfully synthesized an acacetin prodrug through the structural modification of acacetin, namely, acacetin phosphate sodium, which could increase the water solubility of acacetin by over 1.9 million times and is suitable for intravenous administration (Liu et al., 2016a).

Although studies on the toxicity of acacetin are limited, current research indicates that its consumption does not result in significant adverse effects and may be considered safe for medical use. The results of toxicity studies on acacetin are summarized in Table 2. The acute toxicity of acacetin was not observed in mice orally administered a maximum dose of acacetin (900 mg/kg, administered in three doses of 300 mg/kg each within 3 h), and no mortality or abnormal activity was observed in any animal during 2 weeks of observation (Li et al., 2008; Wang S. Y. et al., 2024). To evaluate acacetin prodrug’s acute toxicity, researchers administered a single dose of acacetin prodrug to mice via tail vein injection and found that the median lethal dose (LD₅₀) was 721.7 mg/kg (Liu et al., 2016a). After converting the drug dosage based on body surface area (Blanchard and Smoliga, 2015), the LD₅₀ of the acacetin prodrug in dogs was 108.3 mg/kg, which was far more than the median effective dose in dogs with AF (Liu et al., 2016a). In addition, no subacute toxicity was observed in mice intraperitoneally administered 400 mg/kg of the acacetin prodrug daily for a total of 14 days (Wang S. Y. et al., 2024). Previous studies showed that acacetin did not exhibit significant toxicity in normal lung fibroblasts (WI-38 cells) treated with a high concentration of 50 μM (Chien et al., 2011) or in bone marrow-derived macrophages treated with the concentration range of 0–20 μM (Lin et al., 2022). Also, acacetin was found to have no adverse effects on seminiferous tubules of male Balb/c mice in any dose tested (Ghanbari et al., 2022). Additionally, it showed no insecticidal activity against Aedes atropalpus mosquito larvae (Pereda-Miranda et al., 1997). Acacetin (<50 mg/kg) was demonstrated to have no obvious toxic side effects on the liver and kidney in prostate tumor-bearing nude mice at the doses tested (Kim et al., 2014). Even with prolonged use or at a high dose (50 mg/kg), acacetin exerted no detrimental impact on the urinary as well as reproductive systems in mice (Shokri et al., 2020).

In previous reports, acacetin is known to be a potent molecule possessing extensive pharmacological potential, such as the most common anti-apoptotic, anti-inflammatory, antioxidant, and anti-tumor actions. Due to these pharmacological properties, acacetin shows protective and therapeutic effects on various diseases, including cancer, liver diseases, neurological disorders, and CVDs. The underlying mechanisms of acacetin protecting against these diseases may involve the regulation of diverse signaling pathways, including mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), nuclear factor-kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR), and cyclooxygenase-2 (COX-2) signaling (Singh et al., 2020).

Ischemic cardiomyopathy (ICM) such as acute MI is one of the leading causes of death and disability worldwide. After the onset of ischemia, cardiac reperfusion to restore coronary and myocardial blood supply is usually considered as the most critical measure to save ischemic myocardium (Lejay et al., 2016). Clinically, thrombolysis, percutaneous coronary intervention, and coronary artery bypass grafting are the most commonly used revascularization techniques for ICM. However, reperfusion can cause more severe cardiac injury than ischemia alone, called myocardial I/R injury. Studies have indicated that various mechanisms, including oxidative stress, mitochondrial dysfunction, inflammation, autophagy, and cell apoptosis, are involved in cardiac I/R injury (Xiao et al., 2022; Liu et al., 2023). I/R injury is able to cause infarct expansion, arrhythmias, cardiac dysfunction, and even death (Rassaf et al., 2014). Therefore, developing novel therapies to reduce I/R injury is of particular importance.

In a H/R injury model of cardiomyocytes, which is often used to simulate cardiac I/R injury in vitro, acacetin significantly decreased lipid peroxidation and enhanced antioxidant activity in neonatal rat cardiomyocytes, thereby attenuating cellular H/R injury (Yang et al., 2014). Similarly, Wu et al. demonstrated that the protective effect of acacetin (0.3–3 μM) against H/R injury in cardiomyocytes was associated with the activation of AMPK/Nrf2 signaling, thereby reducing cell apoptosis and reactive oxygen species (ROS) production, restoring the levels of SOD1 and SOD2, preventing the secretion of TLR-4 and IL-6, and increasing the production of IL-10 (Wu et al., 2018). Furthermore, in H9C2 cardiomyocytes exposed to H/R insult, acacetin (12.5–50 μg/mL) protected against H/R-induced damage by enhancing autophagy through the activation of the PI3K/Akt/mTOR cascade (Liu C. et al., 2021). In an in vivo study, an acacetin prodrug (10 mg/kg) showed notable cardioprotective effects on I/R injury in rats (Liu et al., 2016b). Mechanistically, acacetin markedly inhibited the reduction of antioxidant levels and the expression of pro-inflammatory mediators, while preventing cardiomyocyte apoptosis, thereby exerting obvious cardioprotection against I/R injury. In another study on rat cardiac I/R injury, acacetin (10 mg/kg) attenuated cardiac I/R injury mainly by activating the Nrf2/heme oxygenase-1 (HO-1) signaling pathway to reduce inflammation, oxidative stress, and cardiomyocyte apoptosis (Wu et al., 2022c). The potential mechanisms of acacetin in reducing cardiac I/R injury are summarized in Figure 2.

Atherosclerosis emerges as a chronic progressive disease of the arteries, which is attributed to inflammatory reaction, oxidative stress, lipid dysregulation, and epigenetic disorders (Agrawal et al., 2020; Khosravi et al., 2019). It starts with endothelial injury, followed by oxidized low-density lipoprotein (ox-LDL) aggregation in the intima and vascular smooth muscle cell activation, ultimately leading to plaque instability and rupture, which can have fatal consequences (Wu et al., 2022c; Grootaert and Bennett, 2021; Koenig and Khuseyinova, 2007). Stroke, ICM, and peripheral arterial disease are the main clinical manifestations of atherosclerosis and collectively represent the leading cause of cardiovascular mortality (Libby and Theroux, 2005). Despite the good effects of current treatments, many patients still encounter serious coronary events (Libby, 2005). Therefore, the development of new therapeutic approaches for treating atherosclerosis is essential.

Hyperlipidemia can promote atherosclerosis development through accelerating the formation and accumulation of ox-LDL in the subendothelial space. Obesity is an important cause leading to hyperlipidemia. A previous study demonstrated that the adipogenesis in adipocytes and lipid deposition in high-fat diet-evoked obese mice were notably reduced by acacetin, indicating acacetin’s potential anti-obesity effects (Liou et al., 2017). Endothelial dysfunction is recognized as a feature of many different human panvascular diseases, comprising diabetes, atherosclerosis, and hypertension (Xu et al., 2021). In this context, endothelial cells can serve as a potential interventional target for acacetin to improve endothelial function and prevent atherosclerosis. In an in vitro study, acacetin (30 μM) prevented TNF-α-induced E-selectin expression and monocyte-endothelial interaction in HUVECs partly through inhibiting the activation of p38 MAPK and NF-κB pathways, thus exerting its potential therapeutic value in vascular inflammation (Tanigawa et al., 2013). Wei et al. confirmed that acacetin (25–50 mg/kg) attenuated endothelial dysfunction and aortic fibrosis in spontaneous hypertension rats (SHR) with insulin resistance by suppressing inflammatory responses and improving vasodilatory function through the activation of estrogen receptors (Wei et al., 2020). Besides, Han et al. showed that acacetin (0.3–3 μM in vitro; 20 mg/kg in vivo) attenuated hyperglycemia-induced endothelial injury by restoring mitochondrial function through regulation of the Sirt1/AMPK/PGC-1α pathway, thus ameliorating diabetes-stimulated atherosclerosis in ApoE^−/− mice (Han et al., 2020). This study revealed that acacetin was expected to become a novel therapy for improving atherosclerosis in patients. Recently, another report revealed that acacetin (0.3–3 μM in vitro; 15 mg/kg in vivo) not only reduced ox-LDL-caused endothelial cell apoptosis by enhancing cellular antioxidant capacity through the methionine sulfoxide reductase A (MsrA)-Nrf2/Kelch-like ECH-associated protein 1 (Keap1) signaling axis in vitro but also markedly alleviated atherosclerosis by inhibiting oxidative stress and inflammation while promoting lipid metabolism in Western diet-fed ApoE^−/− mice, which also suggested a potential therapeutic effect of acacetin on atherosclerosis-related CVD (Wu et al., 2021). The major signaling cascades mediating the protection of acacetin against atherosclerosis are presented in Figure 3.

MF refers to the accumulation of extracellular matrix proteins (mainly collagen types I and III) in the myocardial interstitium, which can ultimately result in cardiac dysfunction and even heart failure (Kong et al., 2014). During fibrosis, activated myofibroblasts derived from resident cardiac fibroblasts are the central drivers. They not only overexpress α-smooth muscle actin but also secrete matrix proteins massively (Liu M. et al., 2021). Despite great progress in pharmacotherapy, there are still no effective therapeutic strategies for preventing MF. One previous report found that water-soluble acacetin prodrug (15 mg/kg) could remarkably improve doxorubicin (DOX)-induced MF in mice, although the underlying mechanism was not elucidated (Wu et al., 2020). In a recent report, the authors identified that acacetin (10–20 mg/kg) could significantly reduce hypertension-induced ventricular fibrosis in SHR and inhibit angiotensin II (Ang II)-stimulated proliferation, migration, and myofibroblast transformation in human cardiac fibroblasts, implying that acacetin could serve as a promising therapeutic agent for MF (Li et al., 2023). Further mechanistic analysis indicated that, as shown in Figure 4A, the inhibitory effect of acacetin on hypertension-induced MF may involve regulating the TGF-β1/Smad3 and Akt/mTOR cascades. In addition, Chang et al. showed that acacetin (10 mg/kg) could alleviate MI-induced cardiac fibrosis in mice probably by blocking the MAPK signaling pathway (Figure 4A) (Chang et al., 2017).

Cardiac hypertrophy is initially a compensatory response of the myocardium to diverse pathological stresses such as pressure or volume overload, but prolonged or sustained stimuli induce pathological hypertrophy and can result in cardiac remodeling, heart failure, and even sudden cardiac death (Ba et al., 2019; Oka et al., 2014). Cardiac hypertrophy is commonly defined as cardiomyocyte enlargement, enhanced protein synthesis, cytoskeletal remodeling, and fibrosis development (Zhang et al., 2021). Although multiple molecular mechanisms have been identified to mediate the process of cardiac hypertrophy, effective treatment for improving cardiac hypertrophy is still lacking.

In an in vivo study, acacetin (10 mg/kg) was shown to alleviate post-MI cardiac hypertrophy in mice by inhibiting the PI3K/Akt signaling pathway, implying that acacetin may produce a protective effect against cardiac hypertrophy (Chang et al., 2017). The important role of cardiomyocyte apoptosis in the transition from cardiac hypertrophy to heart failure cannot be overemphasized. In this study, the authors also suggested that acacetin significantly reduced post-MI cardiomyocyte apoptosis by inhibiting p-p65, Bax, and cleaved caspase-3 expression, thereby preventing cardiac hypertrophy progression to heart failure (Chang et al., 2017). Both in vivo and in vitro studies have further elucidated the effects and mechanisms of acacetin on cardiac hypertrophy (Cui et al., 2022). The results indicated that acacetin (0.3–3 μM in vitro; 10 mg/kg in vivo) effectively attenuated Ang II-induced cardiomyocyte hypertrophy in vitro and abdominal aortic constriction-induced cardiac hypertrophy in vivo through activating the Sirt1/AMPK/PGC-1α pathway, indicating its potential for the prevention and treatment of cardiac hypertrophy. The effects and mechanisms of acacetin in protecting against cardiac hypertrophy are shown in Figure 4B.

Aging is deemed to be a primary independent risk factor for CVD (Ren and Zhang, 2018). During aging, deterioration in heart structure and function makes the heart more vulnerable to stress (Boyle et al., 2011; Shimizu and Minamino, 2019). Several molecular mechanisms, including mitochondrial dysfunction, reduced autophagy, telomere attrition, increased oxidative stress, protein acetylation, and aberrant mTOR signaling, have been demonstrated to mediate cardiac aging (Shirakabe et al., 2016; Obas and Vasan, 2018). Nevertheless, there are currently no effective therapeutic methods for reversing or slowing cardiac aging. Acacetin (1–3 μM in vitro; 20–50 mg/kg in vivo) was found to activate the Sirt1/Sirt6/AMPK signaling cascade in H9C2 cells and senescent mice induced by D-galactose, thus leading to decreases in the levels of senescence-related proteins (p53 and p21) and an enhancement of mitochondrial autophagy (as indicated by increases in the levels of autophagy-related proteins PTEN-induced kinase 1 (PINK1) and Parkin E3 ubiquitin ligase). These effects ultimately attenuated cardiac senescence (Figure 5) (Hong et al., 2021). These findings reveal that acacetin is likely to become a promising agent for improving aging-related CVD. Nevertheless, the effects of acacetin in protecting against cardiac senescence and its potential mechanisms require further investigation.

Diabetes mellitus, a serious metabolic disorder with an increasing prevalence, can lead to a wide range of complications. Diabetes induce abnormalities of cardiac structure and function independent of other conventional pathological conditions, like hypertension, valvular heart disease, and coronary artery disease, known as DCM (Jin et al., 2022). DCM is defined by adverse cardiac remodeling, dysregulation in diastolic and systolic function, and eventual progression to heart failure (Gollmer et al., 2020). Despite extensive research on DCM, there is still no specific therapy for DCM.

In a preclinical study, it was found that acacetin (3 and 31.6 mg/kg), as a major compound extracted from the edible plant Anoda cristata, exerted a significant hypoglycemic effect in nicotinamide-streptozotocin (STZ)-induced hyperglycemic mice (Juárez-Reyes et al., 2015), which might be in association with acacetin’s antioxidant properties and PPAR-activating activities (Matin et al., 2009). Using computational chemistry approaches, researchers found that acacetin could inhibit the catalytic activity of aldose reductase by stably binding to its catalytic site and forming hydrogen bonds with the tyrosine residue at position 48, thus likely developing into a novel anti-diabetic agent (Manivannan et al., 2015). In an in vitro study, acacetin (20–40 μM) promoted glucose uptake in cultured L6 muscle cells by enhancing glucose transporter type 4 translocation through activation of the cytosolic free Ca²⁺-calcium/calmodulin-dependent protein kinase II (CaMKII)-AMPK and atypical protein kinase C (PKC) λ/ζ pathways, as well as promotion of intracellular ROS production, indicating that an insulin-independent mechanism may be involved in acacetin’s anti-diabetic property (Figure 6) (Kwon et al., 2020). Additionally, the study also found that acacetin (10–40 μM) inhibited oleic acid-evoked lipid deposition and increased glucose uptake in HepG2 cells, both of which were mediated by activating the AMPK signaling pathway. The above studies indicate that acacetin may be used as a novel anti-diabetic agent. To further explore the role played by acacetin in DCM and the underlying mechanism, Song et al. used high glucose-treated cardiomyocytes and STZ-induced DCM rats as an in vitro and in vivo model, respectively, and demonstrated a new pharmacological application of acacetin for the treatment of DCM (Song et al., 2022). They found that, in vitro, acacetin (3 μM) markedly prevented the elevation of Bax protein and the decrease of antioxidant proteins SODs induced by high glucose. In vivo, acacetin prodrug (10 mg/kg) obviously ameliorated cardiac dysfunction and ventricular fibrosis and inhibited the elevation of serum MDA, IL-6, and Ang II levels, as well as cardiac IL-6 and Bax expression, while preventing the reduction of serum SOD activity. These results implied that the protective effects of acacetin on DCM may be associated with its antioxidant, anti-inflammatory, and anti-apoptotic activities. Besides, they also revealed that the major mechanism by which acacetin improves DCM might be due to activating the PPAR-α/AMPK signaling pathway (Figure 6).

Since its clinical introduction, DOX has become one of the most effective chemotherapeutic agents for the management of various cancers, including lung cancer, breast cancer, Hodgkin’s lymphoma, acute leukemia, and others (Carvalho et al., 2009). Nevertheless, the clinical application of DOX has been limited due to its serious cardiotoxic side effects, which can contribute to chronic, progressive, and potentially life-threatening cardiomyopathy (Nebigil and Désaubry, 2018; Mitry and Edwards, 2016). Studies have shown that multiple mechanisms, including oxidative stress, mitochondrial dysfunction, calcium overload, and apoptosis in cardiomyocytes, play an instrumental role in DOX-stimulated cardiotoxicity (Ghigo et al., 2016; Wu B. B. et al., 2022). Despite this, there is still a lack of effective treatments to attenuate DOX-induced cardiomyopathy.

At present, there are very few reports available on the effects of acacetin on drug-induced cardiotoxicity. However, in a recent study, acacetin (0.3–3 μM in vitro; 15 mg/kg in vivo) notably improved DOX-evoked cardiac dysfunction and MF in mice and relieved DOX-induced cardiotoxicity in H9C2 cells through preventing oxidative stress and cardiomyocyte apoptosis via the activation of Sirt1/AMPK/Nrf2 signaling. These findings provide a basis for the future use of acacetin for the management of DOX-induced cardiomyopathy in clinical practice (Figure 6) (Wu et al., 2020).

Hypertension is a primary risk factor for CVDs. It induces vascular endothelial dysfunction, leading to diminished vascular compliance, compromised blood flow, and impaired vasodilation (Versari et al., 2009; Panza et al., 1995). The potential application of therapies focused on improving endothelial dysfunction in the prevention and treatment of hypertension should not be overlooked.

Several studies have demonstrated that acacetin has vasorelaxant effects in an ex vivo rat aortic ring model, although the underlying mechanisms remain unclear and require further investigation. For instance, one study reported that acacetin exhibited a tetraethylammonium chloride-insensitive vasorelaxant effect on ex vivo rat aortic rings (Calderone et al., 2004). In another study, acacetin, identified as one of the bioactive components of Ziziphora clinopodioides Lam., was also found to present vasodilatory activity in isolated rat aortic rings (Senejoux et al., 2012). In addition, it was indicated that acacetin, a main active compound separated from the dichloromethane-soluble extract of Agastache mexicana, had a notable vasorelaxant effect in endothelium-denuded rat aortic rings (Flores-Flores et al., 2016).

Estrogen acts as a vasodilator and binds to its receptors to activate downstream signaling pathways, including ERK1/2, p38 MAPK, and PI3K/Akt, thereby exerting its cardiovascular protective effects (Scott et al., 2007; Freay et al., 1997; Fardoun et al., 2020; Madak-Erdogan et al., 2008). One previous study confirmed that acacetin (25–50 mg/kg) could distinctly reduce the systolic blood pressure of insulin-resistant SHR, which might be related to the estrogen-like effect of acacetin to hamper inflammation-related cytokine expression and improve vasodilatory function in SHR with insulin resistance (Figure 7) (Wei et al., 2020). Recently, Li et al. have discovered that intraperitoneal administration of acacetin (20 mg/kg) remarkably lowered the mean arterial pressure only in SHR but not in Wistar-Kyoto (WKY) rats with normal arterial blood pressure. This effect was likely mediated by acacetin’s ability to induce endothelium-dependent vasorelaxation in rat mesenteric arteries via activation of the Akt/eNOS cascade and restoration of mitochondrial function (Figure 7) (Li et al., 2022).