Advances in targeted treatment of ferroptosis in diabetic kidney disease with SGLT2 inhibitors

Abstract

Ferroptosis, an iron-dependent form of cell death, has recently gained attention in the file of diabetic kidney disease (DKD). It is characterized by the iron-catalyzed lipid peroxide accumulations, distinguishing it from the traditional forms of cell death, such as apoptosis and necrosis. Ferroptosis, which is closely associated with oxidative stress, may contribute to the progression of DKD. The discovery of ferroptosis provides new insights into DKD pathogenesis and may represent a novel therapeutic target. Recent research has shown that Sodium - glucose cotransporter 2 inhibitors (SGLT2i) may exert their kidney protecting effects by modulating ferroptosis-related pathways, thereby indirectly influencing the occurrence of ferroptosis. Therefore, this review systematically elucidates the molecular mechanisms by which SGLT2i target and inhibit ferroptosis in DKD. These mechanisms primarily involve: stabilizing the expression of SLC7A11 and SLC40A1 to restore glutathione synthesis and iron metabolic homeostasis; activating the AMPK/NRF2 axis to enhance antioxidant defense capacity; modulating the BHB-CaMKK2 axis to alleviate mitochondrial oxidative stress and lipid peroxidation via enhanced ketogenesis; down-regulating the HIF-1α/HO-1 pathway to mitigate oxidative injury associated with iron overload; and inhibiting the TGF-β/Smad signaling pathway to attenuate ferroptosis in renal tubular epithelial cells and renal fibrosis. Furthermore, SGLT2i may also indirectly modulate the ferroptosis via intervention in the MAPK and PKC-related pathway. In summary, SGLT2i inhibit ferroptosis through multiple pathways, thereby providing novel theoretical foundations and therapeutic dimensions for the early intervention of DKD. Further basic and clinical research is warranted to clarify the precise regulatory network and long-term clinical benefits in humans.

Status of diabetic kidney disease

Diabetes mellitus(DM) is a common chronic metabolic disease with a progressively increasing prevalence. According to the 2025 International Diabetes Federation (IDF) report, 589 million adults aged 20—79 years are projected to have diabetes, with China accounting for 148 million cases [1]. The incidence of diabetes in China continues to increasing annually, with a noticeable trend toward onset at younger ages. Prolonged hyperglycemia can damage various organs throughout the body, resulting in chronic complications, including microangiopathy, macroangiopathy, and neuropathy. Among these, diabetic kidney disease (DKD) is a major microangiopathy of diabetes. Under hyperglycemic conditions, the kidney exhibits varying degrees of injury, including glomerular basement membrane thickening, mesangial matrix expansion, nodular glomerulosclerosis (Kimmelstiel—Wilson nodules), and tubular damage leading to renal tubular dysfunction [2]. Patients with DKD often present with persistent proteinuria and progressive decline in renal function. DKD is a major cause of chronic kidney disease (CKD), and eventually leads to end-stage renal disease (ESRD) [3]. According to KDIGO 2024 data, CKD accounted for 41.5 million disability-adjusted life years(95%UI: 38.3–45.0), and 1.43 million deaths worldwide in 2019 [4]. DKD is one of the most important causes of CKD, and its incidence and mortality rates are increasing annually. Therefore, early prevention and management of DKD are urgent clinical priorities.

Ferroptosis and DKD

The pathogenesis of DKD is complex and may involve glomerular hyperfiltration, glucose and lipid metabolism disorders, oxidative stress, inflammatory factors activation, and abnormal cellular autophagy [5–7]. Cell death plays a critical role in its development and progression. Currently, cell death is classified as either regulatory(RCD) or accidental cell death (ACD). RCD is regulated by various signaling pathways, including apoptosis, pyroptosis, autophagy and ferroptosis, whereas.ACD is unregulated and mainly involves cell necrosis [8].Ferroptosis is a recently identified form of iron-dependent programmed cell death, characterized by iron accumulation and lipid peroxidation. High levels of membrane lipid peroxidation are a characteristic of the ferroptosis mechanism [9]. Excessive iron accumulation can easily induce the Fenton reaction, resulting in a large amount of reactive oxygen species (ROS), along with membrane lipid peroxidation, and further inducing ferroptosis [10]. During ferroptosis, the main morphological features are membrane shrinkage with increased membrane density and a reduced number of or loss of mitochondrial cristae [11]. Erastin, a small-molecule ferroptosis inducer, can deplete glutathione and inactivate phospholipid peroxidase (glutathione peroxidase 4, GPX4), ultimately leading to oxidative stress and cell death [12]. Studies have also demonstrated that an abnormal inflammatory response is vital to iron metabolism disorder and redox system imbalance [13]. A lot of research has shown that the regulatory pathway of Ferroptosis includes the system Xc⁻(cystine/glutamate antiporter system)- GSH(glutathione) - GPX4 axis, non - GPX4 dependent pathways, and the nuclear factor erythroid 2-related factor2(Nrf2) - heme oxygenase-1(HO−1) signaling pathway. Meanwhile, mounting evidence indicates that various endogenous molecules participate in the regulation of ferroptosis, including Fe²⁺, GPX4, GSH, transferrin receptor protein1(TfR1), system Xc^-, solute carrier family 7 member 11 (SLC7A11), solute carrier family3 member 2(SLC3A2), ROS, adenosine 5’-monophosphate-activated protein kinase (AMPK).Besides, lipid hydroperoxides can react with Fe²⁺ to generate toxic lipid free radicals through the Fenton reaction. Lipid free radicals can attack major components of cells and cause cell damage, leading to ferroptosis. Assessing these ferroptosis-related molecules offers approachs to detect ferroptosis process both in vitro and in vivo [13–15]. Increasing evidence links ferroptosis with CKD. Patients with CKD exhibit varying degrees of iron deposition in the proximal and distal renal tubules. Increased HO-1 expression in their kidneys, suggests that iron deposition contributes to renal injury via oxidative stress [16] (Fig. 1). Bruni et al. reported that the ferroptosis inducer, erastin, impairs islet function and secretion, resulting in abnormal glucose metabolism, whereas ferroptosis inhibitors can ameliorate this effect [17]. In the early stages of diabetes, elevated blood glucose levels, advanced glycation end products (AGEs), and lipid accumulation exacerbate oxidative stress, endoplasmic reticulum stress, inflammatory responses, and renin-angiotensin-aldosterone system (RAAS) activation. These factors lead to proliferation, hypertrophy, epithelial - mesenchymal transition (EMT), autophagy, and programmed cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis) in proximal renal tubules, ultimately resulting in tubulointerstitial fibrosis and accelerating the progression of DKD to ESRD [18, 19]. Gao et al. [20] demonstrated that iron accumulation in the kidneys aggravates DKD damage by increasing oxidative stress and reducing antioxidant capacity, indicating that ferroptosis contributed to the progression of diabetes through oxidative stress. Nuclear factor kappa-B (NF-κB) signaling pathway plays an essential role in inflammation and innate immunity [21]. Akria’s study reports that obesity - activated NF-κB is correlated with inflammation and oxidative stress in the glomerulus [22]. Zou et al. [23] found that oral administration of the ferroptosis inhibitor deferiprone alleviates renal oxidative stress, inflammatory infiltration, and collagen fibrosis in DKD rats by suppressing the expression of NF-κB, monocyte chemoattractant protein-1(MCP-1), and cyclooxygenase-2(COX-2). These studies suggest that targeting ferroptosis may be an effective strategy for treating diabetes and its complications. Recent studies indicated that the molecular mechanisms of ferroptosis in DKD involve GPX4, Nrf2, HO-1, and AMPK [24]. Given the role of ferroptosis in DKD, research on drugs targeting ferroptosis in has emerged rapidly. Wang et al. [25] established db/db mouse model of DKD and induced ferroptosis in renal tubular cells in vitro ferroptosis inducers. Treatment with the hypoglycemic agent rosiglitazone, a thiazolidinedione insulin sensitizer, was shown to alleviate ferroptosis and reduce peroxidation products, thereby improving renal function and mitigating DKD. Liraglutide, a GLP-1 receptor agonist, reduces oxidative stress and iron overload during cognitive impairment in T2DM mice by increasing the expression of GPX4 and SLC7A11, thereby inhibiting ferroptosis [26]. Additionally, various traditional Chinese medicines can inhibit ferroptosis in DKD via various molecular mechanisms. For example, quercetin reduces pancreatic iron deposition and affects insulin secretion, thereby improving diabetes [27]. These findings suggest that multiple drugs may target ferroptosis in DKD by ameliorating oxidative stress in the kidney.

Fig. 1.

The relationship between diabetic kidney disease and ferroptosis. (By Figdraw. https://www.figdraw.com)

Sodium-glucose cotransporter inhibitor and DKD

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent a novel class of glucose-lowering agents, that provide not only glycemic control, but also renal and cardiac protection. They act by inhibiting sodium-glucose cotransporter 2 in the renal tubules, thereby reducing accelerated glucose reabsorption and promoting urinary glucose excretion. The 2024 American Diabetes Association Standards of Care in Diabetes [28] recommends the use of SGLT2i for patients with T2DM and CKD to slow kidney disease progression, reduce cardiovascular events, and decrease heart failure hospitalization rates. Similarly, the 2024 KDIGO guidelines [4]recommend SGLT2i use in patients with T2DM, CKD, and a eGFR ≥ 20 mL/min/1.73 m². Both authoritative guidelines further affirm the important role of SGLT2i in DKD treatment.

SGLT2i improves insulin resistance and restores pancreatic β-cell functions. The protective effects on the kidney include reversing renal hypertrophy, reducing intraglomerular pressure, inhibiting tubuloglomerular feedback, and reducing proteinuria [29]. Meanwhile, SGLT2 inhibitors can also delay the progression of DKD [30].Given these multifaceted renal benefits, the question arises whether SGLT2i confer protection by influencing ferroptosis. Multiple studies have shown that SGLT2i protect the organs by suppressing ferroptosis. Quagliariello et al. [31] reported that empagliflozin reduced doxorubicin-induced oxidative stress and ferroptosis in mouse cardiomyocytes through NLRP3 and MyD88-related pathways, thereby significantly improving cardiac function. Additionally, Chen et al. [32] demonstrated that SGLT2i can inhibit ferroptosis. In an obesity-related heart failure model, dapagliflozin increased GSH levels and upregulated GPX4 and SLC7A11, thereby alleviating obesity-related myocardial remodeling by inhibiting ferroptosis.

Based on this evidence, this review explores the role of SGLT2i in ferroptosis within DKD.

1. Stabilizing of SLC7A11 and SLC40A1 expression

GPX4 plays a pivotal role in regulating ferroptosis. Ferroptosis is initiated when GPX4 and GSH synthesis are inhibited. Extracellular cystine is exchanged for intracellular glutamate at a ratio of 1:1 by the system Xc⁻ and subsequently converted to cysteine, which is required for GSH production [33]. Intracellular depletion of GSH or inactivation of GPX4 triggers ferroptosis [34]. System Xc⁻ consists of the light chain SLC7A11 and the heavy chain SLC3A2 [35]. SLC7A11 is a cystine/glutamate antiporter andthe main functional subunit. In cells, cysteine is reduced to cysteine by GSH or thioredoxin reductase 1 (TXNRD1). During ferroptosis, inhibition of System Xc⁻ reduces active GSH levels and SLC7A11 expression, resulting in diminished GPX4 activity and compromised cellular antioxidant capacity [36]. Solute carrier family 40 member 1 (SLC40A1) is a critical molecule involved in iron metabolism. Dysregulated SLC40A1 expression disrupts cellular iron homeostasis, leading to intracellular iron overload and ferroptosis [37]. Huang et al. [38] established a T2DM mouse model, performed in vitro experiments using human renal cortical proximal tubular epithelial cells (HK-2 cells), and measured ferroptosis-related molecules after treatment with dapagliflozin. Transmission electron microscopy revealed ruptured mitochondrial membranes and the disappearance of mitochondrial cristae in the kidney cells of mice in the T2DM groups, which are the characteristic alterations of ferroptosis. Dapagliflozin administration significantly reduced GSH and iron ion levels in the kidney tissues of mice, and the mitochondrial changes were also significantly ameliorated. Simultaneously, the GPX4 and SLC7A11 in the T2DM group were significantly reduced, the changes were significantly ameliorated by treatment with dapagliflozin. These changes were attenuated by dapagliflozin treatment, and similar alterations were observed in the cellular model. In a renal tubular cell model, high-glucose conditions downregulated SLC40A1 expression in a high-glucose environment, which was ameliorated by dapagliflozin administration. These findings suggest that SLC40A1 contributes to ferroptosis in renal tubules of DKD, and dapagliflozin restores the expression of SLC40A1 and SLC7A11. While GPX4, SLC7A11 and GSH are core components of the ferroptosis defense network, they are also central players in general cellular redox homeostasis. Therefore, their restoration alone does not constitute definitive proof of ferroptosis inhibition. However, their coordinated improvement together with the reduction in iron overload and mitochondrial damage strongly supports a role for SGLT2i in counteracting ferroptosis in renal tubules.

2. Activation of the AMPK/NRF2 axis

AMPK is a serine/threonine kinase that is ubiquitously expressed in eukaryotes. It serves as a crucial energy sensor that monitors the cellular energy status and plays an important role in regulating systemic cellular energy homeostasis. Under energy stress conditions, such as glucose deprivation, hypoxia, or ischemia, AMPK is phosphorylated and activated in response to an increased intracellular AMP/ADP ratio, promoting ATP synthesis and inhibiting ATP catabolism to maintain the balance of cellular and systemic energy metabolism. Ferroptosis is characterized by iron-dependent ROS generation and lipid peroxidation and is regulated by energy stress-mediated AMPK activation [39]. NRF2 is the main regulator of antioxidant responses. NRF2 protects cells from ferroptosis by increasing GSH production, promoting glutathione synthesis by upregulating genes directly involved in the glutathione biosynthesis pathway. Simultaneously, NRF2 facilitates the expression of SLC7A11, increasing intracellular cysteine and intracellular glutathione levels, thereby inhibiting ferroptosis [40]. Upon stimulation by ROS, NRF2 alters its molecular conformation and translocates from the cytoplasm to the nucleus, and then promotes the transcription of downstream HO-1, SLC7A11, and GPX4, which play an important role in anti-oxidation and inhibition of ferroptosis. The activation of AMPK can enhance the nuclear translocation of NRF2, further amplifying its effects [41–43]. Empagliflozin ameliorates oxidative stress in rats with bleomycin-induced pulmonary fibrosis by regulating the AMPK/NRF2 signaling pathway to inhibit ferroptosis, indicating that empagliflozin improves ferroptosis by regulating AMPK/NRF2 [44]. Lu et al. investigated whether empagliflozin improves ferroptosis in DKD [45]. Their preliminary clinical research demonstrated a significant decrease in GPX4 and SLC7A11 expression at the tubular level in DKD patients. Meanwhile, lipid ROS were increased in the proximal tubules. These results all suggest that ferroptosis may be involved in the pathogenesis of DKD. Then used a DKD mouse model and in vitro culture of HK-2 cells to validate the mechanism.A higher iron content and an increased expression of the TfR-1 were observed in the DKD mouse model. After treatment with empagliflozin, the expression of GPX4 and SLC7A11 was upregulated. Additionally, empagliflozin upregulated the expression of phosphorylated AMPKα1 at threonine 172(pThr172-AMPKα1) and NRF2 in HK-2 cells treated with HG(high-glucose). Intervention with AICAR(an AMPK agonist) enhanced the protective effect of empagliflozin and promoted NRF2 from nuclear translocation. It is important to note that NRF2 orchestrates a broad antioxidant and cytoprotective program, and the upregulation of SLC7A11 and GPX4 may partly reflect an overall enhancement of cellular redox capacity rather than an exclusively ferroptosis-targeted effect. Nevertheless, the concomitant suppression of lipid ROS and iron accumulation indicates that AMPK/NRF2 axis activation by SGLT2i converges on ferroptosis inhibition within the broader antioxidant response.

3. Regulation of the BHB-CaMKK2 axis

Fatty acid oxidation produces ketone bodies, including acetoacetate, β-hydroxybutyric acid (BHB), and acetone. Recent studies have indicated that ketone bodies can reduce mitochondrial oxidative stress and improve energy metabolism imbalance [46]. BHB is converted to ATP in the mitochondria of energy-demanding cells, playing a key role in inhibiting mitochondrial oxidative stress and lipid peroxidation [47]. The levels of ketone bodies in patients treated with SGLT2i are also increased [48]. SGLT2i can alleviate proteinuria and podocyte injury in DKD mice by increasing ketone bodies [49]. Calcium/calmodulin-dependent protein kinase 2 (CaMKK2) is a serine/threonine kinase that undergoes Ca²⁺ signal transduction, thereby activating AMPK to participate in energy metabolism. Additionally, it inhibits ferroptosis by suppressing lipid peroxidation [50]. Tian et al. [51] showed that dapagliflozin inhibits ferroptosis by modulating the BHB-CaMKK2 axis. In a DKD mouse model, dapagliflozin was applied, and HK-2 cells were used in vitro to verify its effect. They observed that the iron content of renal tissue increased significantly in the DKD group, and the number of mitochondria and the surface area in the renal tissue decreased. After treatment with dapagliflozin, these changes were significantly improved. Meanwhile, dapagliflozin restored the antioxidant capacity of the kidney in mice with DKD. The results also showed increased CaMKK2 protein expression in HK-2 cells under high-glucose conditions. After dapagliflozin administration, GPX4 and SLC7A11 expression were upregulated, whereas CaMKK2 expression was suppressed. Additionally, dapagliflozin enhanced BHB expression, indicating that it promotes ketone body production via lipolysis, restores mitochondrial function, and reduces lipid peroxidation. The specific intersection of BHB-CAMKK2 axis with ferroptosis is reflected by the normalized lipid peroxidation and the restoration of iron-handling proteins. Thus, dapagliflozin may influences ferroptosis in DKD by regulating the BHB-CAMKK2 axis.

4. Down-regulation of HIF-1α/HO-1 expression

Heme is the primary source of iron. HO-1 is a stress-responsive enzyme that catabolizes free heme into carbon monoxide, iron, and biliverdin. Its main biological function is to prevent the accumulation of highly deleterious free heme; however, free iron produced by HO-1 catabolism can promote free radical production [52]. HO-1 overexpression has a pro-oxidant effect [53]. Cells overexpressing HO-1exhibit a two-fold increase in intracellular iron content compared to other cells [54]. Excessive intracellular iron accumulation induces ferroptosis. Hypoxia-inducible factor-1 (HIF-1), consisting of a constitutively expressed HIF-1β and an oxygen-regulated HIF-1α subunit, is key in mitigating hypoxia-induced injury [55]. However, sustained HIF-1α overactivation could lead to tissue damage; in the hypoxic diabetic kidney, elevated HIF activity in glomerular cells promotes glomerulosclerosis and proteinuria [56]. HIF-1α is a pivotal node upstream of HO-1. HIF-1α modulates mitochondrial dynamics via HO-1 in renal tubular cell injury in DKD [57]. In DKD mice, HIF-1α and HO-1 expression in the kidneys is elevated, accompanied by increased iron content in the renal tubules. Treatment with the ferroptosis inhibitor, Ferrostatin-1, significantly reduces the expression of HIF-1α/ HO-1, indicating that the HIF-1α/HO-1 pathway is involved in ferroptosis in renal tubules in DKD [58]. The SGLT2i, empagliflozin, downregulates HO-1 expression in neuronal cells, reducing lipid peroxidation and regulating ferroptosis. This finding indicates that SGLT2i ameliorate ferroptosis by regulating HO-1 [59], as confirmed by Wang et al. [60]. Ferroptosis-related molecules were detected by establishing a DKD model in db/db mice and culturing HK-2 cells with high glucose in vitro, followed by dapagliflozin treatment. The results showed that dapagliflozin improved mitochondrial ferroptosis in kidney tubular epithelial cells, upregulated GPX4 expression. Under HG condition, the overexpression of HIF-1α decreased mitochondrial activity, accompanied by enhanced lipid peroxidation and iron overload in HK-2 cells. In addition, HIF-1α enhanced the expression of HO-1. Dapagliflozin treatment attenuated HG-induced ferroptosis by reducing HIF-1α accumulation, and its significantly decreased both HIF-1α and HO-1 levels in vivo and in vitro. Yet, in this context, the observed decline in HIF-1α/HO-1 is closely paralleled by a reduction in labile iron and lipid peroxidation which are key driving events of ferroptosis. This distinct correlation underscores that SGLT2i-mediated suppression of HIF-1α/HO-1 extends beyond general redox improvement to specifically target the iron - driven peroxidation cascade.

5. Down-regulation of the TGF-β/Smad signaling pathway

Transforming growth factor-β (TGF-β), a cytokine family of three isoforms, is essential for cell growth, differentiation, and apoptosis. In mammals, three separate genes encode the three closely linked isoforms, TGF-β-1, -2, and − 3 [61, 62]. TGF-β1 plays a role in the pathogenesis of type 2 DKD [63]. It is produced by renal tubular epithelial and mesenchymal cells, and upon activation and release, it initiates cellular immune responses, differentiation, and other processes [64]. Hyperglycemia activates the TGF-β-dependent Smad signaling pathway to stimulate collagen synthesis in renal and vascular cells. TGF-β1 induces mesangial cell hypertrophy and proliferation, accelerates glomerulosclerosis [65], and plays a pivotal role in DKD [66]The study by Akria et al. demonstrated a significant correlation between urinary Smad protein levels in the early stages of diabetes and glomerular mesangial matrix expansion as well as glomerulosclerosis [67]. Furthermore, they found that the activation of the Ang II - Src/Smad1 pathway can induce mesangial matrix expansion, leading to DKD [68]. Meanwhile, the Bone Morphogenetic protein4 (BMP4) / TGF-β / Smad1 /type 4 collagen signaling pathway is involved in the proliferation process of the mesangial cells’ extracellular matrix [30].The TGF-β1 signaling pathway is activated in DKD, and its inhibition reduces renal fibrosis in diabetic animal models [69]. Exposure to TGF-β1 significantly reduces SLC7A11 and GPX4 expression in renal tubular epithelial cells, while increasing cellular lipid peroxidation, indicating that elevated TGF-β1 levels induce ferroptosis in these cells. Ferroptosis inhibitors can enhance this effect [70]. Zhang et al. [71] established DKD mouse models and treated them with dapagliflozin for 8 weeks. The expression of TGF-β1, Smad2, Smad3, p-Smad2, and p-Smad3 was significantly up-regulated in the model group and significantly decreased after dapagliflozin administration, the iron deposition in renal tissue was also improved. The increased expression of GPX4 and GSH indicates alleviation of oxidative stress. TGF-β/Smad signaling is a master regulator of fibrosis and inflammation, and its inhibition leads to broad cytoprotective effects, including restoration of cellular antioxidant defenses. The concurrent reduction in lipid peroxidation and iron accumulation provides the necessary ferroptosis-specific dimension, suggesting that dapagliflozin’s interruption of the TGF-β/Smad cascade mitigates both fibrotic and ferroptotic drivers in DKD.

6. Potential mechanism

SGLT2i can affect ferroptosis in DKD through the above molecular mechanisms, with additional potential molecular mechanisms still under investigation. The mitogen-activated protein kinase (MAPK) signaling pathway is a crucial pathway regulating multiple cellular processes. It includes four major branches: extracellular signal-regulated kinase(ERK), c-Jun N-terminal kinase(JNK), p38 MAPK, and extracellular signal-regulated kinase 5(ERK5) [72]. Extensive studies have shown [73–77] that in the context of DKD, persistent activation of the MAPK pathway—including the ERK, JNK, and p38 MAPK signaling cascades—by hyperglycemia, oxidative stress, and inflammatory factors further leads to dysfunction of renal tubular cells and glomerular cells, thereby exacerbating DKD. Activation of the MAPK pathway has also been demonstrated in multiple studies to be involved in ferroptosis [78, 79]. Activating the MAPK signaling pathway can influence the expression levels of ferroptosis-related molecules, such as SLC7A11, by modulating ERK activity [80]. Meanwhile, activation of the JNK/p38 MAPK signaling pathway can stimulate the expression of transferrin receptor 1 (TfR1) [81], leading to intracellular iron accumulation and further aggravating cellular ferroptosis. From the above research, it is evident that MAPK participates in ferroptosis through different mechanisms, suggesting that the MAPK pathway may serve as a key bridge linking renal cell ferroptosis in DKD. However, studies on the role of the SGLT2 inhibitors and MAPK pathway in ferroptosis in DKD relatively limited.

Chen’s study [82] has shown that SGLT2i can inhibit MAPK pathway conduction to reduce ferroptosis, thereby reducing myocardial ischemia/reperfusion injury; however, whether they can improve ferroptosis in DKD through the MAPK pathway remains to be studied.

Protein kinase C (PKC) is a family of multifunctional isoenzymes that has various subtypes, including PKC-α, PKC-β, and PKC-δ, etc [83]. Akria et al.’s research [84] found that hyperglycemia activated several PKC isoforms, including β, which led to endothelial dysfunction. Meanwhile, they also denmostrate that the elevation of glucose levels induced PKCδ and p38 MAPK to increase Src homology-2 domain-containing phosphatase-1 expression, increased podocyte apoptosis [85]. Zhang et al. further confirmed that PKCβ amplifies lipid peroxidation linked to ferroptosis through the phosphorylation and activation of Acyl - CoA Synthetase Long chain family member 4 (ACSL4) [86]. The study by Maki et al. found that SGLT2 inhibitors can inhibit the high - glucose - induced activation of the PKC - NAD(P)H oxidase pathway and the increase in reactive oxygen species (ROS) production, thereby improving DKD [87]. While PKC inhibition thus reduces general oxidative stress, its modulation of ACSL4 provides a mechanistic link directly relevant to ferroptosis. Further studies must dissect whether SGLT2i can specifically target PKCβ-mediated ACSL4 activation to inhibit ferroptosis in DKD.

Discussion

This review has focused on the impact of SGLT2i on ferroptosis in DKD, yet limitations remain. Ferroptosis exhibits cross-talk with apoptosis and autophagy. Therefore, multiple specific indicators—beyond redox-sensitive markers—are required to confirm ferroptosis and its improvement after treatment. Throughout the literature, the regulatory effects of SGLT2 inhibitors in DKD are predominantly attributed to the modulation of oxidative stress-related molecules. These effects create a favorable cellular context, but direct, specific regulation of the ferroptotic death machinery remains to be fully demonstrated. Future research must move beyond relying solely on general redox markers and incorporate definitive ferroptosis endpoints to more precisely delineate the anti-ferroptotic mechanisms of SGLT2i. Meanwhile, further exploration of whether SGLT2i can regulate ferroptosis through MAPK, PKC, or other unexplored pathways in DKD is warranted, as is investigation into their effect on ferroptosis in other diabetic complications (Table 1).

Table 1.

Mechanisms and models

Mechanism/Intervention Target	Model/Cell
Stabilization of SLC7A11/SLC40A1 expression	DKD mouse model, HK−2 cells
Activation of the AMPK/NRF2 axis	Rat pulmonary fibrosis model, HK−2 cells
Regulation of the BHB-CaMKK2 axis	DKD mouse model, HK−2 cells
Down-regulation of HIF-1α/HO1 expression	Neuronal cell model, DKD mouse model, HK−2 cells
Down-regulation TGF-β/Smad signaling pathway	DKD mouse model
Inhibition of the MAPK signaling pathway	Myocardial hypoxia/reperfusion injury rat model
Inhibition of PKC	DKD mouse model

Outlook

DKD, as one of the major microvascular complications of diabetes, has become a significant cause of CKD and ESRD worldwide. Therefore, early intervention in DKD carries substantial clinical importance. Ferroptosis, an iron-dependent form of cell death, is closely associated with oxidative stress, inflammatory responses, and cellular damage. Its unique regulatory mechanisms may play a key role in driving the progression of DKD. This review summarizes recent studies indicating that SGLT2i can inhibit ferroptosis through multiple molecular pathways. Beyond general antioxidant effects, these pathways may involve ferroptosis - specific processes such as the modulation of iron metabolism and lipid peroxide accumulation, thereby alleviating ferroptosis-driven oxidative damage and inflammatory responses in renal tubular epithelial cells. This highlights the distinctive value of SGLT2i in multi-target intervention (Fig. 2).

Fig. 2.

Diabetic kidney disease involves ferroptosis-related signaling pathways. (By Figdraw. https://www.figdraw.com)

In summary, ferroptosis plays an important role in the pathogenesis of DKD, and SGLT2i influences ferroptosis through various pathways, including the attenuation of oxidative stress, which provides new dimensions and theoretical foundations for DKD treatment. Further basic and clinical research is needed to clarify the specific ferroptosis-regulatory network of SGLT2i and its long-term efficacy in humans. Such efforts will promote the precise application of SGLT2i in DKD therapy and improve patient prognosis.

Author contributions

All authors contributed to the article design.XC wrote the main manuscript text, and MW and ZY reviewed and revised the article.All authors read and approved the final manuscript.

Funding

Supported by the Natrual Science Foundation of Inner Mongolia Autonomous Region(2022SHZR2220),Science and Technology Plan Project of the Department of Science and Technology of Inner Mongolia Autonomous Region(2025YFSH0065).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

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Human/animal studies informed consent statement

This article does not contain any studies with human or animal subjects performed by any of the authors.

Competing interests

The authors declare no competing interests.