Farrerol and the miR-29b-3p/sirtuin 1 pathway: A mechanistic breakthrough in protecting the diabetic heart

Abstract

Diabetic cardiomyopathy (DCM) is a cardiac muscle disorder that causes heart failure independently of coronary artery disease. This condition remains a major clinical challenge, as current therapies primarily address traditional risk factors rather than the underlying molecular pathology. In this regard, endothelial dysfunction in the cardiac microvasculature is a key factor in DCM, linking metabolic alterations to impaired myocardial perfusion and fibrosis. Ferroptosis is a unique form of iron-dependent, regulated cell death characterized by lipid peroxidation. This mechanism has been linked to various diabetic complications, although its role in chronic diabetic heart disease remains unclear. In this editorial, we discuss new evidence highlighting endothelial cell ferroptosis as a key mechanism in DCM and a promising therapeutic target. Specifically, we discuss the recent study by Guo et al, demonstrating that farrerol, a natural flavonoid, improves DCM in mice by inhibiting endothelial ferroptosis through the microRNA-29b-3p/sirtuin 1 signaling axis. The findings of Guo et al reveal that downregulation of microRNA-29b-3p by farrerol is able to restore sirtuin 1 levels in cardiac endothelial cells, activating antioxidant defenses and preventing ferroptotic injury. Importantly, the endothelial protection generated by Farrerol translated into improvements in cardiac function and a reduction in fibrosis in diabetic mice. These results open a new therapeutic opportunity for the treatment of DCM by targeting the cardiac microvascular endothelium. Future studies should build on this mechanistic knowledge, addressing the challenges of converting Farrerol, a natural compound with antioxidant and antiferroptotic properties, or other ferroptosis inhibitors into targeted therapies that safely benefit patients with diabetic heart disease.

Key Words: Diabetic cardiomyopathy; Endothelial dysfunction; Ferroptosis; MicroRNA-29b-3p; Sirtuin 1; Farrerol

Core Tip: Diabetic cardiomyopathy (DCM) is a diabetes-related form of heart failure that lacks targeted therapies. Recent evidence identifies endothelial ferroptosis, an iron-dependent form of cell death, as a central driver of cardiac microvascular injury in DCM. Guo et al demonstrate that Farrerol, a natural flavonoid, inhibits ferroptosis by downregulating microRNA-29b-3p and restoring sirtuin 1 signaling in endothelial cells, thereby improving cardiac function and reducing fibrosis in diabetic mice. Targeting endothelial ferroptosis through the microRNA-29b-3p/sirtuin 1 pathway represents a novel disease-modifying strategy for DCM.

INTRODUCTION

Diabetes mellitus affects approximately 9% of the world's population, and its prevalence is projected to exceed 10% by 2045[1]. Among diabetes-related complications, diabetic cardiomyopathy (DCM) has emerged as a leading cause of heart failure in this population[2]. This condition is a type of heart failure that develops independently of hypertension or coronary artery disease, characterized by the development of diastolic dysfunction, myocardial fibrosis, and eventually systolic deterioration. There is increasing evidence indicating that cardiac microvascular dysfunction plays a central role in the pathogenesis of dilated cardiomyopathy; thus, chronic hyperglycemia and dyslipidemia are thought to induce progressive injury to cardiac microvascular endothelial cells, leading to reduced capillary perfusion, myocardial ischemia, and interstitial fibrosis[3]. Indeed, the loss of normal endothelial function, including decreased nitric oxide bioavailability and increased oxidative stress, is a key trigger linking metabolic disorders to cardiac remodeling in diabetes[3,4]. Despite advances in glycemic control and standard therapies for heart failure, a considerable residual risk of cardiac deterioration remains in patients with diabetes, underscoring the need for novel interventions targeting these mechanisms.

One emerging culprit in diabetes-related tissue damage is ferroptosis, a distinct form of regulated cell death driven by iron-catalyzed lipid peroxidation. Unlike apoptosis or necroptosis, ferroptosis is uniquely iron-dependent and marked by the accumulation of toxic lipid peroxides in cell membranes[5]. This non-apoptotic cell death mechanism has been implicated in acute cardiovascular injuries such as myocardial infarction and ischemia-reperfusion injury, as well as in heart failure models[6,7]. In the context of diabetes, recent studies suggest that ferroptosis may also contribute to cardiometabolic disorders and complications[7,8]. Therefore, the excess of reactive oxygen species and iron overload in diabetes can create a permissive environment for ferroptotic cell death, compounding organ damage. However, the involvement of ferroptosis in chronic diabetic heart disease had not been fully elucidated until now.

Importantly, endothelial cells appear especially vulnerable to ferroptosis in diabetic conditions. Endothelial ferroptosis has been linked to atherosclerotic plaque instability in diabetes and to impaired angiogenic wound healing in diabetic ulcers[8,9]. These observations raised the question of whether ferroptosis might also drive the microvascular endothelial injury underlying DCM. Guo et al[10] have addressed this question in a recent study by investigating the role of endothelial ferroptosis in a mouse model of DCM and testing a novel therapeutic strategy to counter it. Their work identifies a microRNA (miR)-mediated ferroptotic pathway in diabetic cardiac endothelial cells and demonstrate that its modulation can ameliorate cardiomyopathy. In particular, Guo et al[10] show that farrerol, a natural compound with known antioxidant properties, protects the diabetic heart by inhibiting endothelial ferroptosis via the miR-29b-3p/sirtuin 1 (SIRT1) signaling pathway. This editorial will discuss the mechanistic insights from that study, the therapeutic implications of targeting endothelial ferroptosis, and the future challenges in translating these findings into clinical practice.

MECHANISTIC INSIGHT: ENDOTHELIAL FERROPTOSIS AND THE MIR-29B-3P/SIRT1 AXIS

A key novelty of the study by Guo et al[10] is the identification of endothelial ferroptosis as a triggering factor in DCM and the elucidation of the miR-29b-3p/SIRT1 pathway as its regulatory mechanism. MiRs are small non-coding RNAs that post-transcriptionally regulate gene expression, often optimizing cell survival and stress responses. Guo et al[10] focused on miR-29b-3p based on preliminary RNA sequencing data and bioinformatics predictions, and discovered a crucial link between this miR and ferroptosis in diabetic cardiac microvascular endothelial cells.

In diabetic mice, cardiac endothelial cells exhibited evidence of ferroptosis, including lipid peroxidation and ultrastructural mitochondrial changes, contributing to capillary rarefaction and myocardial damage. Farrerol treatment potently suppressed these ferroptotic changes in the endothelium, which was associated with preservation of microvascular density and improved cardiac function[10]. At the molecular level, farrerol was found to downregulate miR-29b-3p in cardiac endothelial cells. This is significant because miR-29b-3p directly targets SIRT1, a deacetylase enzyme that plays a well-established role in cellular stress resistance and metabolism. In the untreated diabetic hearts, elevated miR-29b-3p correlated with depressed SIRT1 protein levels, suggesting that diabetes-induced miR-29b-3p may silence a key endothelial survival factor. Guo et al[10] confirmed the direct interaction between miR-29b-3p and the 3′UTR of SIRT1 mRNA through a luciferase reporter assay, firmly establishing SIRT1 as a target of miR-29b-3p in these cells (Figure 1).

Figure 1 Proposed mechanism by which farrerol protects cardiac endothelial cells from ferroptosis in diabetic cardiomyopathy. In diabetic conditions, hyperglycemia-induced oxidative stress increases miR-29b-3p expression in cardiac endothelial cells. Elevated miR-29b-3p binds to the sirtuin 1 (SIRT1) mRNA, promoting translational repression and mRNA degradation. The resulting decrease in SIRT1 impairs antioxidant defenses and enhances susceptibility to ferroptosis, contributing to endothelial dysfunction and progression of diabetic cardiomyopathy. Treatment with farrerol downregulates miR-29b-3p expression, restoring SIRT1 protein levels and thereby inhibiting ferroptosis. SIRT1: Sirtuin 1.

Restoring SIRT1 is likely pivotal for inhibiting ferroptosis. SIRT1 is known to enhance antioxidant defenses and mitochondrial function, for example by activating the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and modulating glutathione metabolism, thereby countering the lipid peroxidation that drives ferroptosis[11]. In line with this, the study found that the downregulation of miR-29b-3p elicited by farrerol led to upregulation of SIRT1 in endothelial cells, which would be expected to increase the resistance to ferroptotic cell death. The causal role of the miR-29b-3p/SIRT1 axis was demonstrated by administrating a miR-29b-3p inhibitor (antagomir) in diabetic mice which mimicked the protective effects of farrerol on the cardiac microvasculature and function, whereas overexpression of miR-29b-3p abolished the benefits of farrerol[10]. Thus, endothelial ferroptosis in DCM is regulated by a miR-gene circuit, where miR-29b-3p promotes ferroptotic injury by repressing the SIRT1-mediated anti-oxidative program. Farrerol, by tipping the balance of this circuit (lowering miR-29b-3p and increasing SIRT1), emerges as a ferroptosis suppressor.

It is worth noting that miR-29b-3p has been implicated in vascular cell injury in other diabetic complications as well. For example, in models of diabetic retinopathy, miR-29b-3p upregulation was shown to trigger retinal microvascular endothelial cell apoptosis by suppressing SIRT1[12]. The results of Guo et al[10] extend this concept to ferroptosis and the heart, highlighting the concept that diabetes-induced miRs can inactivate endothelial protective pathways (such as SIRT1), leading to cell death and organ damage. By rescuing SIRT1, farrerol may restore the endothelial defenses. This mechanistic insight into endothelial ferroptosis adds a new dimension to our understanding of DCM. It shifts some focus from cardiomyocytes to the often-overlooked microvascular endothelial cells, and identifies a the miR-29b-3p/SIRT1 axis as a novel molecular target that can be modulated to protect the diabetic heart.

THERAPEUTIC IMPLICATIONS: FARREROL AS A NOVEL ENDOTHELIAL PROTECTIVE AGENT

The findings by Guo et al[10] have potential therapeutic implications, pointing toward endothelial protection and ferroptosis inhibition as a strategy to combat DCM. Farrerol, in particular, emerges as a promising lead compound. Farrerol is a bioactive flavanone isolated from the medicinal plant Rhododendron dauricum, traditionally used in Chinese medicine (“Man-shan-hong”) for its antitussive and anti-inflammatory effects[13]. As a natural product, farrerol is notable for its broad pharmacological profile and low toxicity in preclinical studies. Prior research has demonstrated several beneficial activities of farrerol that complement its newly discovered anti-ferroptotic role. For instance, farrerol can attenuate inflammatory responses by modulating Toll-like receptor 4 signaling in microglial cells[14], and it suppresses pyroptosis (inflammatory cell death) in models of chronic cerebral ischemia[15]. These actions suggest an overall cytoprotective and anti-inflammatory tendency, which is highly desirable in the context of diabetic organ damage.

With respect to cardiovascular and metabolic diseases, farrerol has already shown therapeutic potential. A recent experimental study in type 2 diabetic rats demonstrated that farrerol alleviates DCM by activating AMP-activated protein kinase (AMPK) and improving cardiac lipid metabolism[16]. That study indicated that farrerol can reduce myocardial triglyceride accumulation and ameliorate cardiac dysfunction in diabetes, albeit via a mechanism distinct from ferroptosis. The work by Guo et al[10] complements and extends these findings by showing that farrerol also preserves the cardiac microvasculature and prevents cell death. The dual action on the cardiomyocyte and microvascular aspects of the disease, by improving myocardial energy metabolism and preventing endothelial ferroptotic injury, makes farrerol especially attractive as a multifaceted therapy for dilated cardiomyopathy. Moreover, the antiferroptotic ability of farrerol has been previously observed; thus it was reported to protect against collagenase-induced tendinopathy by blocking ferroptosis in tendon cells[15], and to reduce hypoxic-ischemic brain injury in neonatal rats via activating Nrf2 (an upstream regulator of anti-ferroptotic defenses)[17]. These convergent findings underscore that farrerol is a potent inhibitor of pathological cell death across different tissues, likely through its enhancement of anti-oxidant pathways.

From a translational perspective, using a natural compound like farrerol to target a novel pathway in DCM is compelling. Patients with diabetes often have multiple comorbidities, so a therapy that is broadly protective (anti-oxidative, anti-inflammatory, and anti-fibrotic) could provide holistic benefits. Importantly, the study of Guo et al[10] highlights endothelial cells as a therapeutic target in DCM. Most current interventions for diabetic heart disease (apart from glycemic control) do not specifically address the microcirculation. The success of Farrerol in preserving endothelial function hints that protecting the microvasculature could fundamentally alter the course of DCM, potentially slowing or preventing the transition to heart failure. This aligns with a paradigm shift also being considered in other diabetic complications (e.g., diabetic kidney disease) where therapies aim to directly fortify endothelial or tubular cell health. By inhibiting ferroptosis, farrerol essentially prevents irreversible cell loss in the capillaries, thereby maintaining capillary density and myocardial perfusion. In theory, such an approach could preserve cardiac reserve in diabetic patients and reduce fibrosis and stiffness of the heart.

Another implication is the potential to target miR-29b-3p itself as a therapy. While farrerol indirectly modulates this miR, one could envision developing oligonucleotide therapeutics (such as antagomirs) to specifically inhibit miR-29b-3p in cardiac endothelium. Indeed, miRs are being explored as drug targets in cardiovascular disease[18]. However, delivering such molecules to the heart in a cell-specific manner remains challenging. Conversely, farrerol is a small molecule that can be orally administered and reach the heart, as demonstrated in the animal studies. It effectively acts as a chemical miR-29b suppressor and SIRT1 activator. Natural polyphenols and flavonoids (e.g., resveratrol, quercetin) have a precedent of modulating SIRT1 and related pathways, but farrerol appears unique in its ability to impact the miR/SIRT1/ferroptosis axis. Altogether, the therapeutic implication is that farrerol or its derivatives could be developed as a novel class of therapy for DCM, one that targets the root cause of microvascular injury and thereby interrupts the vicious cycle of ischemia, oxidative stress, and myocardial fibrosis in the diabetic heart. Given the growing success of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in reducing diabetic heart failure, it is conceivable that farrerol’s endothelial and anti-ferroptotic actions could complement these agents. Exploring such combinatorial strategies might yield additive or synergistic protection by concurrently addressing metabolic stress, oxidative injury, and microvascular dysfunction.

CHALLENGES AND FUTURE DIRECTIONS

While the protective effects of Farrerol in DCM are promising, several challenges must be addressed before these insights can translate into clinical therapy. First, the evidence so far is from preclinical models (mice with streptozotocin-induced diabetes and high-fat diet). It will be important to validate the role of endothelial ferroptosis in human DCM. For example, analyzing myocardial biopsies or autopsy samples from diabetic patients for markers of ferroptosis (such as 4-hydroxynonenal or glutathione peroxidase 4 expression) could confirm whether this cell death process is indeed active in human DCM. Similarly, assessing circulating or cardiac tissue levels of miR-29b-3p in patients could indicate whether the miR-29b-3p/SIRT1 pathway is dysregulated in clinical disease. If human data corroborate the animal findings, it would strengthen the rationale for moving farrerol toward clinical trials.

Another challenge lies in drug delivery and pharmacokinetics. Like many flavonoids, farrerol displays rapid hepatic metabolism, low aqueous solubility, and limited tissue penetration, which may reduce its bioavailability in the heart. Several strategies could enhance its translational feasibility: (1) Nanoparticle encapsulation (e.g., lipid or polymeric nanocarriers) to prolong systemic circulation and facilitate endothelial uptake; (2) PEGylation or liposomal formulations to improve solubility and protect against first-pass metabolism; and (3) Pro-drug or structural analog design to optimize cardiac distribution. Combining these approaches with endothelial-specific targeting ligands may maximize microvascular exposure while minimizing systemic off-target effects.

The pleiotropic nature of farrerol, while generally beneficial, also warrants careful evaluation of off-target effects. By influencing pathways like AMPK, Toll-like receptor 4, Nrf2, and others, farrerol could theoretically have unintended consequences in certain contexts. For example, systemic SIRT1 activation might affect metabolic processes in the liver or adipose tissue. Although such effects might be positive (e.g., improving insulin sensitivity), they should be thoroughly studied. Long-term safety data will be needed, especially since natural compounds can sometimes have subtle toxicities or interact with other medications. Available preclinical evidence indicates a favorable safety profile. In rodent studies, repeated oral administration of farrerol at doses up to 200 mg/kg/day for four weeks produced no hepatic, renal, or hematologic toxicity, while improving metabolic indices. Nonetheless, systematic toxicokinetic and chronic exposure studies remain mandatory before initiating first-in-human evaluation. Encouragingly, the historical use of Rhododendron dauricum in traditional medicine implies a favorable safety margin, but rigorous toxicological studies in multiple animal species and eventually humans are required.

An additional consideration is the specificity of targeting miR-29b-3p. MiR-29 family members (which include miR-29a, b, and c) have diverse roles in different tissues. Notably, miR-29 is known to regulate extracellular matrix production, limiting the development of fibrosis by suppressing collagen synthesis in fibroblasts. There is some concern that broad inhibition of miR-29 might remove a brake on fibrosis in certain organs. However, and in the context of DCM, Guo et al[10] observed that inhibiting miR-29b-3p actually reduced cardiac fibrosis, likely because the dominant effect was via improving microvascular perfusion and reducing endothelial-to-mesenchymal activation. This highlights the complexity of miR therapeutics, where the outcome can depend on which cell type is targeted. Going forward, strategies to target miR-29b-3p or SIRT1 specifically in endothelial cells (for example, using endothelial-specific promoters in gene therapy, or targeted lipid nanoparticles delivering antisense oligonucleotides) would be valuable to avoid unwanted effects in other cell types. Notably, miR-29a, b, and c share partial seed sequence overlap yet differ in tissue distribution and target selectivity. Off-target inhibition of miR-29a/c could disrupt antifibrotic programs in non-cardiac organs such as liver or kidney. To mitigate this, future research should employ isoform-specific antagomirs and cell-restricted delivery systems, for example, endothelial-targeted nanoparticles, to ensure selective modulation of miR-29b-3p within the cardiac microvasculature.

From a drug development and regulatory standpoint, translating a natural compound like farrerol into a clinically approved medication will require navigating the same rigorous pathway as any new drug. Key steps include standardizing the compound (ensuring purity and consistent bioavailability), scaling up production, and performing well-controlled trials. Regulatory agencies will require clear demonstrations of efficacy in animal models (which this study provides a strong basis for) and safety in toxicity studies. Given that farrerol is not yet widely studied in humans, early-phase clinical trials would likely start by assessing its pharmacokinetics, tolerability, and optimal dosing in healthy volunteers, followed by proof-of-concept studies in patients with diabetes. It is worth noting that some natural compounds have reached clinical trial stages for diabetic complications (for instance, berberine and others in Chinese herbal medicine have been tested for diabetic nephropathy), so there is precedent. However, farrerol will need to compete with other emerging therapies. Any move into clinical application would benefit from demonstrating that farrerol can add value on top of existing standard-of-care (such as renin-angiotensin-aldosterone system blockers, sodium-glucose cotransporter 2 inhibitors, or glucagon-like peptide-1 receptor agonists that have cardiovascular benefits in diabetes). Perhaps farrerol could be eventually used in combination with these agents, providing microvascular protection in parallel with the hemodynamic and metabolic improvements offered by current drugs.

Although the current evidence relies on murine models combining streptozotocin and a high-fat diet, validating these mechanisms in human DCM is essential. Future work should evaluate endothelial ferroptosis markers such as 4-hydroxynonenal accumulation, glutathione peroxidase 4 depletion, and miR-29b-3p/SIRT1 dysregulation in myocardial biopsies or autopsy samples from diabetic patients. In vitro, human induced pluripotent stem cell-derived endothelial cells represent a valuable translational platform to test farrerol’s endothelial and anti-ferroptotic effects in a human context. Integrating such humanized models would bridge the current preclinical-clinical gap and validate farrerol’s therapeutic potential.

It should also be noted that species-specific compensatory mechanisms may attenuate disease severity in mice. Unlike humans, murine models often maintain cardiac output despite microvascular injury and lack the chronic comorbidities, such as hypertension, renal impairment, and dyslipidemia, that accelerate DCM progression in patients. Consequently, future studies combining diabetic and hypertensive models or using aged animals could provide a more faithful representation of human disease complexity.

LIMITATIONS

Although the present findings provide a compelling mechanistic framework, several limitations must be acknowledged. First, the streptozotocin-induced diabetic model primarily reflects type 1 diabetes and carries inherent β-cell toxicity, limiting extrapolation to the more prevalent type 2 diabetes context. Validation in genetic (db/db, ob/ob) and diet-induced models will be essential to confirm mechanistic generality. Second, the pleiotropic nature of farrerol, acting on AMPK, lipid metabolism, and inflammatory signaling, complicates attribution of its cardioprotective effects solely to the miR-29b-3p/SIRT1/ferroptosis pathway. Targeted inhibition experiments (e.g., with SIRT1 or AMPK blockers) are required to delineate causality. Third, the context-dependent roles of miR-29 family members pose potential safety concerns: Systemic suppression may inadvertently promote fibrosis in other organs. Endothelial-targeted delivery approaches are therefore indispensable for therapeutic development. Lastly, the absence of human validation data underscores the need for translational studies using patient-derived endothelial cells or myocardial tissues.

CONCLUSION

The study by Guo et al[10] represents an important milestone in our understanding of DCM and its potential treatment. It shines a spotlight on cardiac microvascular endothelial ferroptosis as a previously under-recognized mechanism driving diabetic heart disease, and importantly, it offers a solution to counteract this mechanism through the natural compound Farrerol. These findings deepen the paradigm that diabetic complications can be alleviated by targeting fundamental cell death and stress pathways. By inhibiting ferroptosis via the miR-29b-3p/SIRT1 axis, farrerol preserved the microvasculature and function of heart in diabetic mice, essentially demonstrating that DCM is modifiable when the right molecular lever is pulled. This not only provides hope that to slow the progression of DCM, but also establishes a new therapeutic avenue centered on endothelial health.

Looking ahead, further exploration of endothelial-targeted therapies could pave the way for disease-modifying treatments for DCM. The concept of “ferroptosis inhibition” may join the armamentarium alongside metabolic control and neurohormonal blockade in combating diabetic heart failure. Nonetheless, translating these promising results into the clinical scenario will require multidisciplinary efforts that will include: Validating biomarkers of ferroptosis in patients, designing targeted delivery systems, and conducting carefully phased clinical trials. If successful, such efforts could substantially reduce the burden of diabetes-related cardiac failure. In summary, targeting endothelial ferroptosis emerges as an exciting strategy to change the trajectory of DCM, improving both the quality and longevity of life for millions of patients worldwide.