Potential Mechanisms of Sodium-Glucose Cotransporter 2 Inhibitors in Regulating Cardiac and Renal Fibrosis

Abstract

Background

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of agents initially developed for glycemic control in type 2 diabetes mellitus. Beyond their glucose-lowering effects, accumulating clinical evidence has demonstrated significant cardiorenal protective benefits in patients with chronic kidney disease (CKD), irrespective of diabetic status. Cardiac and renal fibrosis are central pathological processes contributing to CKD progression and cardiovascular dysfunction. However, the mechanisms underlying the anti-fibrotic effects of SGLT2 inhibitors remain incompletely understood.

Summary

This review summarizes current experimental and clinical evidence regarding the role of SGLT2 inhibitors in modulating cardiac and renal fibrosis. We discuss their potential mechanisms, including hemodynamic regulation, metabolic reprogramming, attenuation of oxidative stress and inflammation, inhibition of pro-fibrotic signaling pathways, and modulation of cellular crosstalk within the cardiorenal axis. Emerging insights from molecular and translational studies are integrated to clarify how SGLT2 inhibitors may exert anti-fibrotic effects beyond glycemic control.

Key Messages

SGLT2 inhibitors confer cardiorenal protection that extends beyond glucose lowering and involves multifaceted anti-fibrotic mechanisms. Understanding these molecular and cellular pathways may provide new therapeutic perspectives for targeting fibrosis in CKD and cardiovascular disease.

Introduction

Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels primarily by reducing renal glucose reabsorption and have become widely used for glycemic control for patients with diabetes [1]. In recent years, large-scale randomized controlled trials have demonstrated that SGLT2 inhibitors not only slow the progression of diabetic nephropathy but also provide renal benefits in nondiabetic kidney disease. Additionally, they reduce the risk of cardiovascular events in chronic kidney disease (CKD) patients and are increasingly applied in the clinical management of CKD and heart failure [2–4]. Cardiac and renal fibrosis are hallmark pathological changes in the progression of heart failure and CKD. Cardiac fibrosis contributes to ventricular remodeling and functional decline in patients with heart failure, while renal fibrosis is a critical factor driving CKD toward end-stage renal disease. Therefore, interventions that effectively attenuate cardiac and renal fibrosis are crucial for improving outcomes in patients with CKD and heart failure [5, 6]. Emerging studies indicate that SGLT2 inhibitors may suppress fibrosis in the heart and kidneys by regulating multiple pathways such as inflammation, oxidative stress, endoplasmic reticulum stress, autophagy, mitochondrial dynamics, and transforming growth factor-beta (TGF-β) signaling [7–9]. However, the existing evidence remains largely fragmented. Most studies focus on isolated pathways within a single organ, failing to provide a holistic view of the interconnected mechanisms that may operate across cardiorenal systems. Furthermore, apparent contradictions exist, for instance, whether SGLT2 inhibitors inhibit or activate certain pathways like signal transducer and activator of transcription 3 (STAT3) appears to be context-dependent, a nuance that has not been critically evaluated. A systematic synthesis that comprehensively integrates these multifaceted mechanisms and elucidates their crosstalk is currently lacking. In this review, we summarize current evidence on the potential molecular and cellular mechanisms of SGLT2 inhibitors in preventing cardiac and renal fibrosis, aiming to provide a foundation for understanding their cardiorenal protective effects.

Regulatory Effects of SGLT2 Inhibitors on Cardiac Fibrosis

Cardiac fibrosis is a common pathological feature underlying a variety of cardiovascular diseases, including heart failure, myocardial infarction, coronary artery disease, and cardiomyopathy. It plays a central role in myocardial hypertrophy, ventricular enlargement, and adverse ventricular remodeling [10–12]. Increasing evidence indicates that SGLT2 inhibitors can mitigate cardiac fibrosis by regulating multiple molecular and cellular pathways, including inflammation, oxidative stress, endoplasmic reticulum stress, mitochondrial dynamics, autophagy, TGF-β/Smad, and intercellular communication pathways (Fig. 1).

Fig. 1.

Possible mechanism of SGLT2 inhibitors regulating cardiac fibrosis.

Regulation of Cardiac Fibrosis via Inflammatory Pathways

Inflammation contributes to cardiac fibrosis through several mechanisms. It promotes the proliferation and differentiation of cardiac fibroblasts, induces the expression of inflammatory mediators and pro-fibrotic factors, as well as upregulates the expression of extracellular matrix (ECM) [13, 14]. SGLT2 inhibitors have been shown to attenuate cardiac fibrosis by targeting multiple aspects of the inflammatory response [15].

Targeting Core Inflammatory Signaling Axes

A pivotal mechanism is the suppression of the Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) pathway. For instance, Zhan et al. [16] demonstrated that dapagliflozin could alleviate atrial remodeling and myocardial fibrosis in diabetic rats by inhibiting the TLR4/interleukin receptor-associated kinase 1/tumor necrosis factor receptor-associated factor 6/NF-κB signaling pathway. Inhibition of the downstream NF-κB pathway reduces phosphorylation of P65 and IκB, suppresses macrophage polarization, and decreases the production of fibrosis markers, including TGF-β, α-smooth muscle actin (α-SMA), collagen I, and collagen III, indicating that dapagliflozin can mitigate diabetic cardiomyopathy-related structural remodeling independently of its glucose-lowering effects [17]. Additionally, dapagliflozin inhibits activation of the NLRP3 inflammasome in cardiac fibroblasts of diabetic mice, thereby regulating downstream cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α), which leads to reduced myocardial fibrosis [18]. Similarly, Trang et al. [19] reported that empagliflozin significantly downregulates NLRP3 inflammasome components, IL-1β, and TNF-α, improving myocardial fibrosis in diabetic cardiomyopathy models. Empagliflozin also reduces cardiac fibrosis and the expression of pro-inflammatory cytokines (IL-1β, IL-8, and IL-6) through modulation of NLRP3 and myeloid differentiation factor 88 (MyD88)/NF-kB pathways, ameliorating myocardial injury in nondiabetic mice [20]. Moreover, empagliflozin can downregulate the expression of cardiac high mobility group box 1 and neutrophil extracellular traps, thereby inhibiting NLRP3 inflammasome activation in macrophages and improving ventricular diastolic function and fibrosis in heart failure with preserved ejection fraction mice [21]. Given that neutrophil extracellular traps interact with multiple inflammatory pathways, their suppression reduces the production of inflammatory mediators and chemotactic factors, thereby preventing adverse cardiac remodeling [22].

Modulation of the Renin-Angiotensin System and Sympathetic Activity

SGLT2 inhibitors also exert anti-inflammatory effects by modulating the renin-angiotensin system. Canagliflozin upregulates apelin, activating the protective ACE2/Ang-(1–7)/MasR axis, which counteracts the pro-fibrotic and pro-inflammatory ACE-Ang II-AT1R axis. This shift reduces the production of TGF-β, TNF-α, and IL-6, thereby attenuating ECM deposition and myocardial fibrosis [23, 24]. Castoldi et al. [25] reported that empagliflozin could attenuate Ang II-mediated inflammation and myocardial sympathetic nerve activity, thereby preventing Ang II-induced myocardial hypertrophy and fibrosis.

Context-Dependent Regulation of Inflammatory Mediators and STAT3

Additionally, activation of cardiac STAT3 can mediate synergistic effects of inflammation and oxidative stress, promoting myocardial hypertrophy and fibrosis in Ang II-treated mice. In a chronic corticosterone-induced cardiomyopathy mouse model, empagliflozin treatment downregulated phosphorylated STAT3 and TLR4 in cardiomyocytes, inhibited macrophage infiltration, and improved left ventricular hypertrophy and cardiac fibrosis [26]. The underlying mechanism may involve reduction of IL-6 expression, which inhibits STAT3 phosphorylation and consequently decreases fibrotic factor expression. However, Chang et al. [27] found that dapagliflozin could restore STAT3 activity to prevent doxorubicin-induced cardiac toxicity and significantly reduce myocardial fibrosis in rats. Similarly, Lee et al. [28] demonstrated that dapagliflozin significantly increased STAT3 activity and nuclear translocation in a rat model of myocardial infarction, elevated myocardial IL-10 levels, enhanced M2 macrophage infiltration through the STAT3 pathway, effectively attenuating fibroblast activation. These findings indicate that STAT3-mediated regulation of myocardial fibrosis is complex, and the effects of SGLT2 inhibitors on STAT3 activity may vary depending on the specific cardiac disease model.

SGLT2 inhibitors can modulate the expression of key inflammatory mediators, including IL-6, TNF-α, monocyte chemoattractant protein-1 (MCP-1), and high-sensitivity C-reactive protein (hs-CRP), thereby alleviating myocardial fibrosis. Wang et al. [29] reported that dapagliflozin significantly reduced inflammation, as evidenced by decreased MCP-1 and hs-CRP levels, and attenuated myocardial fibrosis, reflected by reduced ST2 concentrations, in patients with heart failure. The growth stimulation expressed gene 2 protein (ST2) exists in two forms: the transmembrane receptor ST2L and soluble ST2 (sST2). sST2 competitively inhibits the IL-33/ST2L pathway, promoting myocardial fibroblast activation and mediating fibrosis [30]. However, Ibrahim et al. [31] observed that dapagliflozin treatment in heart failure patients did not alter sST2 and galectin-3 concentrations, although levels of fibronectin (FN) 1, IL-6, matrix metalloproteinase-7 (MMP-7), and TNF-α decreased. This suggests that the regulatory effects of SGLT2 inhibitors on the ST2 pathway are complex, and further studies are needed to clarify their precise role in myocardial fibrosis. In preclinical models, dapagliflozin reduced myocardial fibrosis in both heart failure with preserved ejection fraction pig models and type 2 diabetic cardiomyopathy rat models by suppressing inflammatory factors such as IL-6 and TNF-α [32, 33]. Similarly, Lee et al. [34] demonstrated that empagliflozin decreased the expression of peroxisome proliferator-activated receptor α, exosomal medium-chain acyl-CoA dehydrogenase, brain natriuretic peptide, and TNF-α in atrial and ventricular tissue of rats with heart failure, thereby reducing myocardial fibrosis. Inflammatory mediators, such as IL-6 and TNF-α, can activate cardiac fibroblasts or stimulate the NF-κB signaling pathway, leading to increased TGF-β expression or inhibition of matrix metalloproteinases (MMPs), which promotes ECM deposition and myocardial fibrosis.

ECM Remodeling via MAPK Pathways

Furthermore, SGLT2 inhibitors can attenuate myocardial fibrosis by upregulating the expression of MMPs through modulation of inflammatory pathways. Madonna et al. [35] demonstrated that empagliflozin reversed cardiac stem cell senescence in diabetic mice by reducing pro-inflammatory markers, such as phosphorylated p38 (p-p38), and increasing pro-survival marker phosphorylated Akt, thus ameliorating cardiac fibrosis. p38, which is activated during myocardial ischemia and hypoxia, is a key signaling protein involved in cardiomyocyte remodeling. Pharmacological or genetic inhibition of p38 suppresses the secretion of senescence-associated secretory phenotype factors, maintaining the balance between MMPs and tissue inhibitors of metalloproteinases [27, 36]. Shi et al. [37] evaluated dapagliflozin in a mouse model of aortic constriction-induced cardiac remodeling and observed that it reduced myocardial hypertrophy, interstitial fibrosis, and cardiomyocyte apoptosis. These effects were associated with inhibition of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation. Inhibition of the p38/JNK pathway promotes MMP2 and MMP9 expression, contributing to the attenuation of cardiac fibrosis. In addition, Habibi et al. [38] reported that empagliflozin inhibited the serum- and glucocorticoid-inducible kinase 1 (SGK1)/epithelial sodium channel (ENaC) signaling pathway, thereby alleviating SGK1-mediated inflammatory injury and restoring MMPs/tissue inhibitors of metalloproteinases balance. This modulation improved myocardial fibrosis and mitigated cardiac damage in mouse models of cardiovascular disease.

Regulation of Cardiac Fibrosis through Oxidative Stress and Endoplasmic Reticulum Stress

Extensive evidence indicates that both oxidative stress and endoplasmic reticulum (ER) stress play critical roles in the pathogenesis of cardiac fibrosis [39, 40]. Excessive production of reactive oxygen species (ROS) during oxidative stress can directly promote cardiac fibroblast proliferation or indirectly contribute to fibrosis by activating the NF-κB signaling pathway and modulating the expression of MMPs [41]. ER stress also plays a central role in n myocardial injury and fibrosis, both directly by inducing cardiomyocyte apoptosis and indirectly by interacting with oxidative stress pathways. Oxidative stress, inflammation, and dysregulated mitochondrial autophagy can accelerate ER stress, leading to ER membrane damage and calcium imbalance [40]. Furthermore, protein-folding enzymes within the ER, such as protein disulfide isomerase, ER oxidoreductin, and NADPH oxidase 4, can drive excessive ROS generation, creating a vicious cycle of ER stress and oxidative stress that exacerbates myocardial injury [42]. Experimental studies demonstrate that SGLT2 inhibitors can suppress ER stress and thus reduce myocardial fibrosis.

Attenuation of Oxidative Stress and Activation of Antioxidant Defenses

Emerging studies suggest that SGLT2 inhibitors attenuate oxidative stress and thereby slow the progression of cardiac fibrosis. For instance, Wang et al. [43] demonstrated in a rat model of myocardial infarction that empagliflozin reduced NT-proBNP and hs-CRP levels, suppressed intracellular ROS and inducible nitric oxide synthase (iNOS) expression, and subsequently improved myocardial fibrosis by limiting fibroblast activation. Similarly, in an isoproterenol (ISO)-induced myocardial injury model, Wang et al. [44] reported that dapagliflozin attenuated plasma Ang II levels and AT1R expression by reducing oxidative stress, thus alleviating myocardial fibrosis. Beyond these effects, SGLT2 inhibitors can modulate oxidative stress-related signaling pathways and transcription factors, thereby regulating the expression of fibrotic mediators. Li et al. [45] demonstrated that empagliflozin activated the nuclear factor erythroid 2-related factor (Nrf2)/antioxidant response element (ARE) signaling pathway and inhibited TGF-β expression, improving oxidative stress-induced myocardial injury and fibrosis in diabetic mice. Activation of the Nrf2/ARE pathway enhances the synthesis of downstream antioxidant proteins and enzymes while suppressing TGF-β -driven fibrotic signaling.

SGLT2 inhibitors can also attenuate myocardial fibrosis by regulating oxidative stress-related factors. Hussein et al. [33]demonstrated that dapagliflozin improved oxidative stress markers, including reduced malondialdehyde and increased glutathione, in rats with type 2 diabetic cardiomyopathy, while simultaneously downregulating TGF-β expression. Moreover, dapagliflozin protected cardiomyocytes from high glucose-induced damage by inhibiting NADPH oxidase-mediated oxidative stress, thereby ameliorating cardiac dysfunction and myocardial fibrosis [46]. Similarly, dapagliflozin reduced oxidative stress and myocardial fibrosis by decreasing oxygen free radical production and inhibiting calcium transport-related membrane channel proteins, such as voltage-gated L-type calcium channels (CACNA1C), sodium-calcium exchanger (NCX), and sodium-hydrogen exchanger 1 (NHE) [47].

Modulation of Hypoxia-Inducible Factor-1α Signaling

Yang et al. [17] reported that dapagliflozin inhibited the hypoxia-inducible factor-1α (HIF-1α) pathway in cardiac tissue of diabetic mice, leading to reduced expression of TGF-β, α-SMA, collagen I, and collagen III. In Ang II-stimulated hypertrophic myocardium, dapagliflozin also restored SIRT1 expression and attenuated HIF-1α upregulation, thereby mitigating myocardial hypertrophy [48]. However, Janbandhu et al. [49] provided evidence that HIF-1α may exert protective effects after myocardial infarction by limiting ROS production, suppressing fibroblast over-proliferation, and reducing fibrosis. These findings suggest that the regulation of HIF-1α by SGLT2 inhibitors is context-dependent and not solely mediated through oxidative stress pathways. Further mechanistic studies are warranted to clarify the precise role of HIF-1α in SGLT2 inhibitor-mediated cardioprotection.

Suppression of Endoplasmic Reticulum Stress

By mitigating oxidative stress, SGLT2 inhibitors indirectly alleviate ER stress. Moreover, they directly target the ER stress response. Shih et al. [50] reported that dapagliflozin inhibited ER stress, reduced myocardial fibrosis, and improved overall cardiac function in diabetic rats. Similarly, dapagliflozin improved hemodynamics and myocardial remodeling in mitral regurgitation-induced heart failure by attenuating ER stress [51] and also protected against doxorubicin-induced cardiotoxicity [52]. Mechanistically, dapagliflozin significantly downregulated the expression levels of ER stress-related proteins, including glucose-regulated protein 78 (GRP78), protein kinase (PKR)-like ER kinase (PERK), eukaryotic translation initiation factor 2α (eIF-2α), activating transcription factor 4 (ATF-4), and C/EBP homologous protein (CHOP), thereby limiting cardiomyocyte apoptosis and myocardial fibrosis. Additional studies further support these effects. In β-adrenergic receptor-overactivated cardiomyopathic rats, dapagliflozin inhibited ER stress-related myocardial cell apoptosis and fibrosis by upregulating sarcoplasmic reticulum Ca(2+)-ATPase protein and ryanodine receptor 2 (RyR2), while suppressing calmodulin-dependent protein kinase II (CaMKII) [53]. Chung et al. [54] demonstrated that empagliflozin reduced atrial fibroblast activity by inhibiting Na+/H+ exchanger (NHE), suppressing phospholipase C phosphorylation, and decreasing IP3 expression, thereby reducing ER Ca2+ release. Moreover, empagliflozin alleviated left ventricular fibrosis and cardiomyocyte apoptosis in hypertrophic rat hearts through activation of the adenosine monophosphate-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling pathway, attenuating unfolded protein response activation under ER stress [55].

Regulation of Cardiac Fibrosis through Mitochondrial Dynamics and Autophagy

Mitochondrial dynamics and autophagy are critical determinants of cardiomyocyte homeostasis and fibrosis. Disruption of the balance between mitochondrial fusion and fission leads to impaired energy metabolism, excessive oxidative stress, calcium dysregulation, and aberrant mitochondrial autophagy, ultimately driving cardiomyocyte hypertrophy and fibrotic remodeling [56]. Under physiological conditions, mitochondrial autophagy (mitophagy) eliminates damaged or dysfunctional mitochondria to preserve mitochondrial quality, thereby limiting oxidative and inflammatory injury to cardiomyocytes [57]. However, disturbances in mitochondrial dynamics and autophagy flux have been observed in diabetic and nondiabetic cardiomyopathy, heart failure, and myocardial infarction, where they contribute to cardiomyocyte apoptosis and fibrosis [58, 59].

Restoration of Mitochondrial Dynamics and Function

Emerging evidence indicates that SGLT2 inhibitors restore mitochondrial homeostasis and regulate autophagy, thereby alleviating cardiac fibrosis. Xi et al. [60] reported that diabetic cardiomyopathy in rats was characterized by mitochondrial pleomorphism, impaired lipid metabolism, myocardial dysfunction, and fibrosis. Empagliflozin treatment attenuated lipid accumulation, improved mitochondrial structure, and reduced myocardial fibrosis. Sustained hyperglycemia in type 2 diabetes disrupts mitochondrial dynamics by inhibiting fusion and promoting fission, which contributes to fibrotic remodeling [61]. Bugga et al. [62] demonstrated that empagliflozin counteracted these effects by promoting mitochondrial fusion, thereby improving insulin sensitivity, reducing oxidative stress, and mitigating myocardial fibrosis. In vitro experiments further revealed that empagliflozin reduced insulin resistance, total ROS, and mitochondrial ROS induced by palmitic acid in H9c2 cardiomyoblasts, supporting its role in protecting against diabetic cardiomyopathy by restoring mitochondrial dynamics and suppressing oxidative injury. In heart failure models, empagliflozin also suppressed mitochondrial fission in cardiomyocytes by modulating the expression of mitochondrial dynamics-related proteins, which reduced lactate accumulation from anaerobic metabolism and improved myocardial fibrosis [63, 64].

Context-Dependent Modulation of Autophagy Flux

The regulatory mechanisms of mitochondrial autophagy in cardiovascular diseases are highly complex. Both insufficient and excessive autophagy flux can aggravate cardiomyocyte apoptosis and fibrosis. Autophagy flux in cardiomyocytes is tightly controlled by enzymes and transcription factors that are highly responsive to environmental cues, particularly nutritional and energetic states [65]. For example, SIRT1 and AMPK promote autophagy under nutrient deprivation, facilitating the clearance of dysfunctional organelles and metabolic intermediates to maintain cellular homeostasis and survival. Conversely, Akt and mechanistic target of rapamycin complex 1 (mTORC1) inhibit autophagy during nutrient abundance, thereby promoting glucose and lipid storage, oxidative metabolism, mitochondrial oxygen consumption, and ultimately cardiomyocyte hypertrophy [66, 67]. Evidence suggests that SGLT2 inhibitors can modulate cellular stress pathways and autophagy-related transcription factors, thereby influencing the progression of myocardial fibrosis [68].

In a murine model of pressure overload-induced heart failure, Li et al. [69] demonstrated that empagliflozin could interact with cardiac glucose transporters to reduce glycolytic flux, restore AMPK activation, and suppress mTORC1 pathway activation. This intervention alleviated left ventricular remodeling and cardiac fibrosis, even in nondiabetic mice, suggesting that empagliflozin enhances autophagy, rebalances glycolysis and mitochondrial oxidative phosphorylation, and suppresses oxidative and inflammatory drivers of fibrosis. Similarly, in a myocardial infarction model, Wang et al. [70] reported that dapagliflozin restored cardiomyocyte autophagy, inhibited the PI3K/Akt/mTOR pathway, and reduced myocardial inflammation and fibrosis, thereby improving both structural and functional outcomes. However, not all effects are strictly pro-autophagic. Jiang et al. [71] found that empagliflozin inhibited Na(+)/H(+) exchanger 1 (NHE1) activity in myocardial cells, thereby preventing excessive autophagy, which significantly reduced infarct size and fibrosis. These findings highlight the context-dependent nature of autophagic regulation. Notably, ischemic and hypoxic conditions promote excessive ROS generation and mitochondrial dysfunction, and the imbalance between AMPK (a positive regulator of autophagy) and mTOR (a negative regulator) exacerbates hypertrophy and fibrosis. The precise role of NHE1 in autophagy remains incompletely understood, as NHE1 activity in pathological cardiac states is influenced by multiple signaling pathways. Supporting this, Lee et al. [72] demonstrated that dapagliflozin inhibited the SGK1/NHE1 pathway in myocardial tissue and H9C2 cells, which improved mitochondrial integrity and attenuated myocardial fibrosis. Inhibition of NHE1 activity may reduce mitochondrial damage, thereby decreasing the burden on mitophagy. This hypothesis, however, requires further validation in mechanistic studies.

Regulation of Cardiac Fibrosis by TGF-β/Smad and Pericyte Signaling Pathways

TGF-β is a key pro-fibrotic cytokine that promotes the differentiation of fibroblasts into myofibroblasts and drives ECM deposition through signaling cascades such as the TGF-β/Smad and pericyte-related signaling pathways [73, 74]. Among its isoforms, TGF-β1 is considered the principal mediator of myocardial fibrosis. Aberrant activation of the TGF-β/Smad axis and pericyte-related signaling pathways has been reported across multiple cardiovascular diseases [75]. Emerging evidence indicates that SGLT2 inhibitors can attenuate myocardial fibrosis by suppressing TGF-β expression and modulating these downstream pro-fibrotic signaling pathways.

Inhibition of the Canonical TGF-β/Smad Signaling Pathway

SGLT2 inhibitors directly target the core components of the pro-fibrotic TGF-β1 cascade. In a rabbit model of congestive heart failure induced by aortic stenosis, Chen et al. [76] showed that 12 weeks of dapagliflozin treatment significantly reduced myocardial fibrosis. Mechanistically, dapagliflozin inhibited the TGF-β1/Smad signaling pathway. Upon activation, TGF-β1 binds to TGF-β receptor II (TGFR-II), which recruits and activates TGF-β receptor I (TGFR-I). Activated TGFR-I phosphorylates Smad2 and Smad3, which subsequently form a heteromeric complex with Smad4. This complex translocates to the nucleus and initiates transcription of fibrosis-related genes, driving fibroblast-to-myofibroblast differentiation and ECM accumulation [74]. Consistent findings have been reported in rodent models. Tian et al. [77] demonstrated that dapagliflozin suppressed the TGF-β/Smad pathway in type 2 diabetic rats while simultaneously activating AMPKα, thereby inhibiting endothelial-to-mesenchymal transition and fibroblast activation. Similarly, in a nondiabetic rat model of myocardial infarction, Daud et al. [78] found that empagliflozin reduced collagen deposition in infarcted myocardium by suppressing TGF-β1/Smad3 signaling. Furthermore, in diabetic cardiomyopathy, empagliflozin alleviated oxidative stress and myocardial fibrosis by activating the Nrf2/ARE pathway and concurrently inhibiting the TGF-β/Smad pathway [44]. Activation of the Nrf2/ARE signaling pathway enhances antioxidant defenses, limits ROS accumulation, and indirectly suppresses TGF-β/Smad activation, collectively mitigating fibrotic remodeling.

Stabilization of Pericytes and the Microvasculature

Beyond direct signaling inhibition, SGLT2 inhibitors mitigate fibrosis by preserving coronary microvascular integrity through pericyte stabilization. Tu et al. [79] reported in a diabetic cardiomyopathy mouse model that reduced numbers of cardiac pericytes, diminished microvascular coverage, elevated TGF-β1 expression, and subsequent coronary microvascular rarefaction were accompanied by cardiac fibrosis. Treatment with empagliflozin restored pericyte density and microvascular coverage while attenuating fibrosis, suggesting that empagliflozin mitigates TGF-β1-mediated pericyte loss and protects against microvascular dysfunction and fibrotic remodeling. Pericytes, located along the basal membrane of endothelial cells in the microvasculature, play a critical role in regulating vascular tone, permeability, and angiogenesis through dynamic interactions with endothelial cells [80]. In diabetic cardiomyopathy, aberrant TGF-β1 activation disrupts pericyte-endothelial cell homeostasis, promoting pericyte activation, migration, and transdifferentiating into myofibroblasts, thereby enhancing ECM synthesis. Conversely, detachment of pericytes from coronary capillaries reduces microvascular density and increases vascular permeability, leading to microvascular destabilization and rarefaction [81]. Importantly, pericytes exhibit context-dependent signaling, activating distinct receptors and pathways across tissues, organs, and disease states. Thus, while current evidence suggests that SGLT2 inhibitors can alleviate myocardial fibrosis at least in part by stabilizing pericyte-endothelial interactions, further research is needed to elucidate the precise mechanisms underlying pericyte-mediated microvascular protection.

Regulation of Renal Fibrosis by SGLT2 Inhibitors

Renal fibrosis is the principal pathological hallmark underlying the progression of CKD. Emerging evidence suggests that SGLT2 inhibitors exert anti-fibrotic effects through multiple mechanisms, including modulation of TGF-β1 signaling, suppression of inflammation and oxidative stress, regulation of autophagy, and mitigation of hypoxia. For example, based on transcriptomic and network pharmacology analysis, Liu et al. [82] demonstrated that the therapeutic effect of dapagliflozin on renal fibrosis is mediated through the multiple signaling pathways. Using molecular biology techniques, they further confirmed that dapagliflozin treatment markedly attenuated inflammation, apoptosis, oxidative stress, and mitochondrial injury in the kidneys of mice with unilateral ureteral obstruction (UUO). Similarly, in a streptozotocin-induced diabetic nephropathy rat model, Oraby et al. [83] observed pronounced oxidative, inflammatory, fibrotic, and apoptotic responses, all of which were significantly alleviated by dapagliflozin. Treatment reduced early markers of diabetic kidney disease, including kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, vanin-1, and urinary β-N-acetyl glucosaminidase, while restoring nephrin expression in glomeruli and reversing renal histopathological alterations. Collectively, these findings indicate that dapagliflozin mitigates oxidative stress, inflammation, and fibrosis in diabetic and obstructive kidney injury (Fig. 2).

Fig. 2.

Possible mechanism of SGLT2 inhibitors mediating renal fibrosis.

Regulation of Renal Fibrosis via the TGF-β1 Signaling Pathway

TGF-β is a multifunctional cytokine that regulates cellular proliferation, differentiation, apoptosis, adhesion, and migration across diverse cell types, including macrophages, activated T and B lymphocytes, immature hematopoietic cells, neutrophils, and dendritic cells. Importantly, TGF-β is a central mediator of tissue fibrosis [84]. Among its isoforms, TGF-β1 plays a particularly critical role in the development of renal fibrosis [85]. Tian et al. [86] reported that SGLT2 inhibitors reduce renin depletion in patients with diabetic kidney disease and enhance urinary TGF-β1 excretion. These effects were associated with reduced podocyte apoptosis, improved albuminuria, and attenuation of renal fibrosis. In a diabetic kidney disease mouse model, Gallo et al. [87] showed that empagliflozin suppressed the upregulation of FN and TGF-β, thereby ameliorating renal fibrosis.

Dysregulation of the TGF-β1/Smad pathway is widely recognized as a major pathogenic mechanism in renal fibrosis [88]. Smad2 and Smad3 are key downstream effectors that promote TGF-β1-driven fibrogenesis, whereas Smad7 acts as a negative regulator by inhibiting this pathway. Under pathological conditions, Smad2/3 expression is upregulated, while Smad7 expression is downregulated, resulting in unchecked fibrotic signaling [89]. SGLT2 inhibitors appear to restore this balance. For instance, Zhai et al. [90] demonstrated that canagliflozin attenuated renal fibrosis and downregulated expression of TGF-β1/Smad2/3 signaling proteins in rats fed a high-salt diet, which was otherwise associated with elevated systolic blood pressure, fibrosis, and increased fibrotic protein expression.

Further mechanistic insights were provided by Zeng et al. [91], who showed that dapagliflozin reduced the expression of FN and α-SMA, while improving mitochondrial respiratory chain complex activity in human renal proximal tubular epithelial cells exposed to TGF-β1. These protective effects were mediated, at least in part, through inhibition of the TGF-β1/MAPK pathway. Likewise, Huang et al. [92] found that dapagliflozin significantly reduced blood glucose levels, renal signal transducer and activator of transcription 1 (STAT1) expression, and TGF-β1 signaling in diabetic mice. This was accompanied by improved renal function and attenuation of diabetes-induced tubulointerstitial fibrosis. In vitro, dapagliflozin also suppressed aberrant STAT1 expression in human kidney-2 (HK-2) cells, restoring E-cadherin expression and reducing α-SMA induction under high glucose conditions, thereby slowing the progression of glucose-mediated tubulointerstitial fibrosis.

Beyond these molecular interactions, SGLT2 inhibition attenuates the TGF-β1/Smad signaling cascade, producing direct benefits for glomerular hemodynamics and structure. Reduced glomerulosclerosis lowers mechanical stress on the glomerular capillary wall and helps preserve the effective filtration surface. At the same time, decreased peritubular fibrosis attenuates microvascular compression and tissue hypoxia, thereby lowering post-glomerular vascular resistance that can compromise glomerular function. Together, these anti-fibrotic effects plausibly account for the clinically observed slowing of glomerular filtration rate (eGFR) decline and the reduction in albuminuria, both key markers of improved glomerular health.

Regulation of Renal Fibrosis via Inflammation and Oxidative Stress Pathways

The progression of CKD is closely associated with the activation of inflammatory cytokines, inflammatory mediators, and excessive production of ROS, all of which contribute to the exacerbation of renal fibrosis [93, 94]. The anti-fibrotic effects of SGLT2 inhibitors are thought to be partly mediated by their ability to suppress local renal inflammation and attenuate oxidative stress [8].

Targeting Key Regulatory Proteins and Pathways

Evidence indicates that SGLT2 inhibitors mediate renal fibrosis by targeting multiple aspects of inflammation and oxidative stress. Wang et al. [95] reported that epithelial-mesenchymal transition (EMT) promotes renal fibrosis in CKD, and that canagliflozin inhibits EMT by modulating the sirtuin 3 (SIRT3)-forkhead box O3a (FOXO3a) signaling pathway, thereby suppressing renal fibrosis. Li et al. [96] corroborated these findings in a diabetic nephropathy mouse model, showing that both empagliflozin and canagliflozin ameliorated EMT induced by SIRT3 inhibition and aberrant glycolysis, thus mitigating renal fibrosis.

SGLT2 inhibitors also modulate fibrosis by interacting with specific proteins or altering protein activity, thereby improving inflammation and oxidative stress. In a study of mice with UUO, Liu et al. [97] demonstrated through transcriptomic and bioinformatics analyses that dapagliflozin attenuated renal interstitial fibrosis (RIF) by regulating inflammatory and oxidative stress-related pathways. Target prediction suggested that glutamate ionotropic receptor NMDA type subunit 1 (GRIN1), which is upregulated in the kidneys of CKD and RIF patients, is closely related to inflammatory and oxidative stress signaling. Molecular docking analysis revealed that dapagliflozin binds stably to GRIN1, altering its spatial conformation. Additional studies further highlight diverse anti-fibrotic mechanisms. Feng et al. [98] showed that dapagliflozin delayed tubulointerstitial fibrosis by inhibiting the activation of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling axis in renal proximal tubule epithelial cells (RPTCs). In a diabetic kidney disease rat model, dapagliflozin demonstrated stronger anti-inflammatory, antioxidant, and anti-fibrotic effects than verteporfin. Likewise, Chang et al. [99] reported that dapagliflozin reduced doxorubicin-induced ROS production and apoptosis-related protein activity, restored endothelial nitric oxide synthase signaling, and alleviated tubular atrophy and fibrosis in a rat model of doxorubicin nephrotoxicity. Moreover, dapagliflozin suppressed the receptor interacting protein 1 (RIP1)-RIP3-mixed lineage kinase domain-like protein (MLKL) necroptosis axis via inhibition of the Wnt3α/β-catenin/glycogen synthase kinase-3β (GSK-3β) pathway, thereby ameliorating inflammation and oxidative stress in UUO rats [100, 101].

Amelioration of Metabolic Dysregulation and Hypoxia

In diabetic nephropathy (DN), SGLT2 inhibitors also exert anti-fibrotic effects by reducing oxidative stress and inflammation. Al-Tantawy et al. [92] reported that dapagliflozin activated autophagy, decreased oxidative stress, inhibited apoptosis, and prevented renal fibrosis in DN rats, possibly through downregulation of miR-192 and miR-21. Tang et al. [102] demonstrated that dapagliflozin lowered renal expression of NF-kB p65, MCP-1, Nox4, Nox2, and p47phox, as well as urinary thiobarbituric acid reactive substances, suggesting improvement in glucose-induced inflammation and oxidative stress and attenuation of diabetic glomerulosclerosis. Wu et al. [103] further found that combination therapy with ursolic acid and empagliflozin synergistically reduced oxidative stress and inflammation, thereby alleviating fibrosis in DN rats. Additionally, Shirakawa et al. [104] observed that canagliflozin improved renal fibrosis in DN mice by suppressing glycolytic dysregulation and mitochondrial ROS generation in proximal tubule epithelial cells under hyperglycemic conditions.

In a hypertensive rat model, Castoldi et al. [105] demonstrated that empagliflozin reduced inflammatory cell infiltration in angiotensin II (Ang II)-dependent hypertension and decreased the expression of collagen types I and IV, independent of its blood pressure-lowering effects. In a related study, the same group [106] showed that empagliflozin attenuated cyclosporine A-induced nephropathy in rats, not only reducing hypertension but also lowering renal collagen I and IV deposition, macrophage infiltration, and tyrosine hydroxylase expression. These findings suggest that empagliflozin confers renoprotective benefits even in nondiabetic nephropathy. Furthermore, Chen et al. [107] reported that empagliflozin increased the urinary excretion of uric adenosine in a dose-dependent manner, which negatively correlated with RIF. His effect may be attributable to its ability to suppress the upregulation of complement component 1Q subcomponent A chain (C1QA) and C chain (C1QC) gene expression in CKD mice.

Excessive activation or inhibition of specific inflammatory pathways and oxidative factors can enhance the expression of pro-fibrotic mediators. SGLT2 inhibitors also mitigate renal fibrosis by modulating these signaling cascades. For instance, contrast-induced acute kidney injury, a common cause of acquired renal disease, is characterized by hypoxic injury to proximal tubular epithelial cells. Hypoxia activates the HIF-1α/HE4/NF-κB pathway, thereby exacerbating renal fibrosis. Huang et al. [108] showed that dapagliflozin attenuated contrast-induced acute kidney injury both in vitro and in vivo by suppressing this pathway. Consistent with these findings, Hodrea et al. [109] demonstrated in a DN rat model that dapagliflozin inhibited high glucose-induced protein O-GlcNAcylation and improved tubular responses to hypoxia via regulation of the HIF pathway, thereby reducing renal tubular injury markers such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Cai et al. [110] further revealed that in diabetic kidney disease, renal fibrosis is associated with a metabolic shift in proximal tubules from fatty acid oxidation toward glycolysis and lipid accumulation, a process in which HIF-1α plays a central role. Dapagliflozin effectively inhibited the upregulation of HIF-1α in proximal tubules, thereby limiting fibrotic progression. Similarly, Zhang et al. [111] found that empagliflozin improved peritubular capillary hypoxia in mice with renal injury, upregulated the expression of vascular endothelial growth factor-A, and significantly inhibited renal fibrosis following ischemia/reperfusion injury.

Regulation of Renal Fibrosis through Autophagy

Autophagy dysregulation is strongly implicated in the pathogenesis of renal fibrosis [112]. N6-methyladenosine RNA modification plays a crucial role in autophagy regulation. Downregulation of N6-methyladenosine demethylase stabilizes sequestosome 1 (SQSTM1) mRNA, thereby promoting the formation of autophagosomes. Yang et al. [113] demonstrated that canagliflozin alleviated renal fibrosis by modulating SQSTM1 mRNA stability through the STAT6/peroxisome proliferator-activated receptor α/fatty acid oxidation signaling axis in renal tubular cells. mTOR, a central protein kinase regulating cell growth, survival, metabolism, and immunity, is also critically involved in renal fibrosis [114]. Lu et al. [115] reported that empagliflozin attenuated RIF and glomerulosclerosis in a CKD rat model, partly by inhibiting CD206(+)CD68(+) M2 macrophage polarization and reducing inflammatory signaling from CD8(+) effector T cells via mTOR and mitochondrial autophagy pathways. Consistently, Kogot-Levin et al. [116] showed that activation of mTORC1 in RPTCs triggers fibrogenic programs within the renal cortex. By suppressing RPTC-mTORC1 activity, SGLT2 inhibitors exert significant renoprotective effects.

Discussion and Future Perspectives

Distinct yet Interconnected Cardiorenal Protection

The ability of SGLT2 inhibitors to modulate fibrosis in both the heart and the kidney highlights the presence of a tightly linked cardiorenal axis in disease progression. Their protective effects in these two organs are not simply parallel but profoundly synergistic. Improvements in kidney function, driven by reductions in tubulointerstitial fibrosis and glomerulosclerosis, directly benefit the heart by limiting fluid overload, correcting electrolyte imbalances, and reducing the systemic pro-inflammatory and pro-fibrotic milieu associated with uremic toxins [117]. These renal benefits help dampen neurohormonal activation, a major contributor to adverse cardiac remodeling and fibrosis.

Conversely, attenuation of cardiac fibrosis and the resulting improvement in ventricular compliance and output help preserve renal perfusion. In heart failure, impaired cardiac function leads to renal hypoperfusion and venous congestion, activating intra-renal inflammatory and fibrotic pathways [118]. By interrupting this vicious cycle at both ends, SGLT2 inhibitors achieve a holistic anti-fibrotic effect that exceeds the impact expected from either organ alone. This interconnected physiology offers a compelling explanation for the pronounced benefits observed in patients with coexisting heart and kidney disease.

Combination Therapy

This review has summarized the diverse mechanisms through which SGLT2 inhibitors mitigate cardiac and renal fibrosis, including anti-inflammatory, antioxidant, anti-autophagic, and direct anti-fibrotic effects, particularly suppression of the TGF-β/Smad pathway. Nonetheless, the progressive nature of cardiorenal disease frequently requires therapeutic approaches that target multiple pathological pathways simultaneously. Finerenone, a novel nonsteroidal mineralocorticoid receptor (MR) antagonist, has greater selectivity and a lower risk of adverse effects than traditional steroidal agents [119]. Combination therapy with SGLT2 inhibitors and finerenone has emerged as a particularly promising strategy. Both drug classes have independently demonstrated significant cardiorenal benefits in large randomized trials [120, 121], and their mechanisms of action, while distinct, are strongly complementary.

SGLT2 inhibitors exert pleiotropic effects by improving metabolic status, lowering glomerular hypertension, and directly attenuating cellular stress, inflammation, and fibrotic signaling in cardiomyocytes and renal cells. Finerenone, in contrast, directly antagonizes MR activation, a key driver of fibrosis, inflammation, and oxidative stress in both organs [122]. MR overactivation promotes the transcription of multiple pro-fibrotic genes and plays a key role in the pathophysiology of cardiorenal continuum. Thus, while SGLT2 inhibitors create a more favorable metabolic and hemodynamic environment, finerenone directly blocks a parallel core pathway of fibrotic progression. This mechanistic complementarity supports the potential for additive, or even synergistic, cardiorenal protection.

Clinical evidence increasingly supports this concept. Both animal studies and early clinical data show that the combination of an SGLT2 inhibitor with finerenone produces substantially greater reductions in proteinuria than either agent alone. For instance, decreases in the urinary albumin-to-creatinine ratio (UACR) were consistently larger with combination therapy than with monotherapy [123, 124]. Notably, a recent study published in the New England Journal of Medicine provided the most compelling evidence to date [121]. In this study, combination therapy achieved a significantly greater reduction in UACR at 180 days, 52% with the combination vs. 29% with empagliflozin alone and 32% with finerenone alone. This profound synergistic effect strongly corroborates the mechanistic complementarity between the pleiotropic actions of SGLT2 inhibitors, which ameliorate metabolic, hemodynamic, inflammatory, oxidative, and autophagic stress, and the direct blockade of the pro-fibrotic MR by finerenone. The reduction in UACR, a well-established surrogate marker of glomerular injury and a predictor of long-term renal outcomes, is closely associated with preservation of eGFR and decreased risk of progressive kidney disease [125]. Therefore, the superior proteinuria-lowering effect observed with combination therapy suggests that concurrently targeting multiple fibrotic pathways yields more effective protection of the glomerular filtration barrier and a more pronounced attenuation of renal fibrosis. Although a small, reversible decline in eGFR and a mild increase in serum potassium were noted with the combined regimen, the overall safety profile remained acceptable and comparable to that of monotherapy. Taken together, these findings indicate that the empagliflozin-finerenone combination offers robust efficacy with manageable risks, marking a potential shift toward early multi-pathway therapeutic intervention for cardiorenal fibrosis.

Future research should focus on delineating the molecular crosstalk between SGLT2 inhibition and MR blockade in experimental models of fibrosis, including their interactions at the level of immune signaling, mitochondrial homeostasis, and ECM turnover. Furthermore, long-term outcomes from ongoing and future prospective clinical trials will be critical to fully establish the durability, safety, and clinical applicability of this dual pathway inhibition strategy. Overall, the combination of SGLT2 inhibitors with finerenone, built upon a solid and complementary mechanistic foundation, represents a promising paradigm shift toward multi-targeted therapy for the management of cardiorenal fibrosis.

Limitations and Safety Considerations

Despite the preclinical evidence summarized herein, a comprehensive assessment of SGLT2 inhibitors must also integrate their clinical safety profile and the unanswered questions surrounding their anti-fibrotic agents. It is well established that the glycosuric mechanism of SGLT2 inhibition predisposes patients to genital mycotic infections [126]. A more serious concern is the risk of euglycemic diabetic ketoacidosis, a form of ketoacidosis occurring despite only modest elevations in blood glucose levels [127]. This condition may be difficult to recognize in nondiabetic individuals and can progress rapidly if not detected early, highlighting the need for improved clinical vigilance.

The translation of SGLT2 inhibitors’ anti-fibrotic properties to nondiabetic populations also warrants careful consideration. Although trials such as DAPA-CKD have demonstrated renal benefits in nondiabetic CKD, the risk-benefit ratio may differ when the primary therapeutic goal is fibrosis attenuation rather than glycemic control [3]. In such scenarios, adverse effects, such as volume depletion, particularly relevant in elderly patients, individuals with autonomic dysfunction, or those receiving concomitant diuretics, may assume greater relative importance during clinical decision-making.

Furthermore, the long-term safety of SGLT2 inhibitors in nondiabetic individuals or patients with multiple comorbidities remains insufficiently characterized. Potential off-target or remote effects on other organ systems, including the gastrointestinal tract, liver, and central nervous system, remain incompletely understood [128]. Future research is needed to define their mechanistic effects and safety profile in nondiabetic models of fibrosis, where current evidence remains limited.

Conclusion

In summary, SGLT2 inhibitors modulate the progression of both cardiac and renal fibrosis through diverse and interconnected mechanisms. Recent in vivo evidence demonstrates that these agents alleviate cardiac fibrosis by targeting multiple protective pathways, including TLR4/NF-κB-mediated inflammation, Nrf2-driven antioxidant responses, and HIF-2α/SIRT1 signaling. In the kidney, their anti-fibrotic effects are supported by direct modulation of pro-fibrotic signaling cascades, such as inhibition of the TGF-β/Smad axis, suppression of the YAP/TAZ and HIF-1α pathways, and modulation of autophagy, thereby attenuating tubulointerstitial fibrosis in both obstructive and diabetic kidney disease models. By interfering with critical steps in fibrogenesis, such as fibroblast activation and ECM deposition, SGLT2 inhibitors offer substantial therapeutic promise across the cardiorenal spectrum. Nevertheless, further studies are warranted to elucidate their precise molecular targets, clarify inter-organ crosstalk, and determine the extent to which these mechanisms operate independently of glycemic modulation.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This work was supported by the National Natural Science Foundation of China (Grant No. 82260908) and Sanming Project of Medicine in Shenzhen (No. SZZYSM202406019).

Author Contributions

Yuanwu Cui was responsible for resources. Wei Huang and Tianxiang Guan contributed to writing – original draft preparation. Dongkai Yuan and Mingxia Wu contributed to writing – review and editing. Shanrong Bi supervised the study. Ziyou Yan acquired funding.

Funding Statement

This work was supported by the National Natural Science Foundation of China (Grant No. 82260908) and Sanming Project of Medicine in Shenzhen (No. SZZYSM202406019).