Diabetic nephropathy (DN) is a leading cause of end-stage renal disease with limited therapeutic options. Ferroptosis contributes to renal tubular injury in DN. This study investigates whether mesenchymal stem cells (MSCs) ameliorate DN by inhibiting ferroptosis and elucidates the underlying mechanism. In a rat model of type 2 DN, MSCs transplantation improved renal function and histopathology, while reducing mitochondrial dysfunction, iron overload, and ROS-driven ferroptosis. In vitro, MSCs reversed high glucose-induced ferroptosis hallmarks in tubular epithelial cells. Mechanistically, RNA sequencing identified the MAPK/ERK pathway as key. MSCs suppressed the p-ERK/ERK-GPX4/ACSL4 axis, preventing glutathione depletion and lipid peroxidation. Activation of ERK abolished MSCs’ protection, whereas ERK inhibition mimicked it. These findings reveal that targeting ERK-mediated ferroptosis in renal tubules offers a novel therapeutic strategy, with MSCs acting through this specific mechanism. 1. Introduction Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes mellitus and is the leading cause of chronic kidney disease and end-stage renal disease globally [ 1, 2, 3]. Traditional perspectives considered DN a glomerulocentric disease. However, recent research has revealed that tubular injury may precede glomerulopathy and play a critical role in the early stages of DN [ 4, 5]. The pathogenesis of DN involves multifactorial mechanisms, including dysregulation of lipid metabolism, hemodynamic abnormalities, inflammation, oxidative stress, cellular damage, and ferroptosis [ 6]. Ferroptosis induces renal tubular epithelial cell death, triggering pathological cascades through damage-associated molecular pattern release, activating innate immunity, disrupting tubular reabsorption, causing proteinuria, and promoting renal fibrosis via epithelial-mesenchymal transition [ 5, 7]. Proximal tubular reabsorption critically demands iron for ATP production [ 8], and dysregulated iron metabolism secondary to diabetic renal injury heightens oxidative stress and inflammatory responses, thereby potentiating renal damage [ 9, 10, 11]. The vicious iron metabolism–oxidative stress cycle constitutes the core mechanism underlying ferroptosis in renal tubular epithelial cells during DN. The above reports suggested the importance of ferroptosis in the pathological progression of diabetic nephropathy. 3. Discussion In this study, we demonstrate the therapeutic efficacy of UMSCs in DN rats and elucidate the underlying molecular mechanisms. Under hyperglycemic conditions, pathological activation of the p-ERK/ERK signaling pathway in renal tubular epithelial cells drives ferroptosis by suppressing GPX4 and excessive ROS production, which results in oxidative damage to DNA, proteins, and lipids. UMSCs mitigate renal injury by inhibiting hyperglycemia-induced ERK phosphorylation, which in turn suppresses the ferroptosis-ROS feedback loop and attenuates oxidative stress ( Figure 7). Consistent with prior reports [ 13, 14, 15], UMSCs demonstrated renoprotective effects in high-fat diet/STZ-induced T2DN rats. Both low (2 × 10 6) and high-dose (5 × 10 6) groups showed reduced blood glucose, elevated insulin, and improved renal function, though without dose dependence. This absence of dose-dependence aligns with findings in T1DN mice [ 27] and a phase 1 systemic lupus erythematosus trial (2 × 10 6 ଗ୍ଧକ୍ଟ ୪ ୍ଠ ୧୦ 6 cells/kg) [ 28], whereas some spinal cord injury models report dose-dependent MSC effects (4 × 10 5 to 10 6 cells) [ 29], potentially due to lower doses used. Our lack of dose dependence may reflect supra-threshold dosing in this model. Pathological assessment confirmed early-stage DN, lacking advanced features like Kimmelstiel–Wilson nodules, consistent with evidence that tubular injury precedes glomerular damage in DN progression [ 4, 30]. Notably, UMSCs significantly reduced serum triglycerides and total cholesterol, along with glucose, suggesting multifaceted metabolic benefits and potential utility in lipid management. Our results demonstrate that DN rats exhibit renal tubular epithelial cell iron overload, mitochondrial dysfunction, and excessive oxidation affecting DNA, proteins, and lipids, culminating in ferroptosis. UMSCs ameliorated these abnormalities, indicating multi-target effects. Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation [ 31], with mitochondrial damage acting as both trigger and amplifier [ 32, 33]. In chronic hyperglycemia, mitochondrial injury promotes ROS overproduction, which, together with iron accumulation, PUFA-rich membranes, and GPX4 inactivation, facilitates mitochondrial ferroptosis [ 34, 35, 36]. UMSCs disrupted this “mitochondria-iron-ROS-ferroptosis” cascade, preserving mitochondrial integrity and limiting oxidative damage. We identify a novel role for the MAPK/ERK pathway in mediating ferroptosis in DN and its modulation by UMSCs. Ferroptosis is regulated via AMPK, Akt/mTOR, MAPK, and p53/NRF2/ATF4 axes [ 9, 32, 36, 37, 38, 39]. While MAPK typically promotes ferroptosis through JNK/p38-mediated ACSL4/LOX activation [ 9, 32, 38], ERK has been shown to promote ferroptosis in some cancers by inhibiting System Xc − [ 39]. In this study, RNA-seq analysis revealed that UMSCs suppress ferroptosis by inhibiting the MAPK/ERK pathway. Pharmacological intervention in HG-injured HK-2 cells using the ERK phosphorylation inhibitor GSK2606414 or the ERK activator MK-28 demonstrated that ERK inhibition effectively attenuated HG-induced ROS overproduction and ferroptosis. Conversely, ERK activation diminished the therapeutic efficacy of UMSCs against HG-induced oxidative stress and ferroptosis. These findings support ERK inhibition as a therapeutic strategy in DN. Although ERK inhibitors are extensively investigated in oncology, clinical translation is limited by feedback activation, toxicity, and resistance [ 40]. Combining ERK inhibitors with UMSCs may offer a novel therapeutic approach. Notably, hyperglycemia-activated p-ERK may enhance HIF 1α stability via ROS-mediated EGLN inactivation or direct phosphorylation, thereby upregulating iron uptake and exacerbating mitochondrial dysfunction [ 41, 42]. We hypothesize that UMSCs disrupt this ERK-HIF 1α-ferroptosis positive feedback loop by inhibiting ERK phosphorylation. Although HIF-1α/EGLNs were not directly examined here, they warrant further investigation as downstream effectors of the anti-ferroptotic effects of UMSCs. 4. Materials and Methods 4.1. Culture and Conditioned Medium Collection from UMSCs The primary human umbilical cord-derived MSCs (UMSCs) were provided by Cell Energy Life Sciences Group Co. Ltd., Qingdao, China (Initial ethical approval by the Ethics Committee of Liaocheng People’s Hospital, Approval No. 2021105, and the donors had signed informed consent). UMSCs were identified as described previously [ 45] ( Supplementary Figure S7). UMSCs of passage 4 or 5 were used in our experiments. Cells were cultured in a humidified incubator with 5% CO 2 at 37 °C and passaged with trypsin/EDTA after reaching confluence. Once the UMSCs reached 70–80% confluency, the medium was replaced with fresh full medium, and the cells were harvested after 24 h. Subsequently, UMSCs-CM were centrifuged at 3000 rpm for 20 min, followed by filtration through a 0.22 μm filter to remove detached MSCs and cell debris. 4.2. Animal Model and Treatment Protocols Subsequently, thirty of these T2DN rats were randomly selected and divided into 3 groups ( Supplementary Figure S2, n = 10 per group): the DN model group (DN), which received no cell therapy; the low-dose umbilical cord mesenchymal stem cell group (UMSCs-LD), administered 2 × 10 6 cells per rat; and the high-dose group (UMSCs-HD), administered 5 × 10 6 cells per rat. Cell suspensions were delivered via intravenous injection every 2 weeks for a total of 3 injections. Meanwhile, both the DN model group and a normal control group of SD rats (Ctrl, n = 9) received equal volumes of PBS via the same route and schedule. The timelines for model induction and treatment administration are presented in Figure 1A. In vivo, therapeutic efficacy was assessed by renal function parameters (glucose, HbA1c, insulin, creatinine, BUN, and 24-h urinary protein) and renal histopathological staining (HE, PAS, and Masson). 4.3. Biochemical Test The 24 h urine and blood samples were collected from rats at 4-week intervals up to week 20, and analyzed for urea nitrogen (BUN), 24 h urinary protein (PRO), creatinine (Cr), blood glucose, insulin, glycosylated hemoglobin (HbA1c), triglycerides (TG), and total cholesterol (CHOL) levels according to the manufacturer’s instructions. 4.4. Pathological Staining Renal tissues were fixed in 4% paraformaldehyde, paraffin-embedded, and sectioned at 5 μm. After hydration through graded ethanol (100%, 95%, 70%, and 30%) and distilled water (2 min each), sections were subjected to hematoxylin and eosin (HE), periodic acid–Schiff (PAS), and Masson’s trichrome staining to assess glomerular structure, mesangial matrix expansion, basement membrane changes, and interstitial fibrosis. All stained sections were evaluated by a blinded pathologist. For each slide, three random fields were quantitatively analyzed using ImageJ v1.54g. 4.5. Immunohistochemistry Kidney sections were deparaffinized, rehydrated, and subjected to antigen retrieval in 10 mM sodium citrate buffer for 20 min. After blocking with 5% BSA for 1 h at room temperature, slides were incubated overnight at 4 °C with primary antibodies (see Supplementary Methods). Following incubation with secondary antibodies, signals were developed using DAB and counterstained with hematoxylin. Staining intensity was semi-quantitatively analyzed using ImageJ software in at least three random 20× fields per section selected by an independent pathologist ( n = 5). 4.6. Cell Culture and Intervention The human renal tubular epithelial cell line HK-2 (CCTCC No. GDC0152, Wuhan, China) was cultured in MEM (C11095500BT, Gibco, Waltham, MA, USA) and divided into four groups: normal glucose (5 mM, NG), high glucose (30 mM, HG), HG plus UMSCs-CM (HG+CM), and osmotic control (5 mM glucose + 24.5 mM mannitol, Man). To investigate the role of the p-ERK pathway, HG-cultured cells were treated with 10 nM GSK2606414 (HY-18072, MCE, Princeton, NJ, USA) for 72 h. To determine whether UMSCs-CM inhibits ferroptosis via p-ERK/ERK, HG cells were co-treated with UMSCs-CM and 10 μM MK-28 (HY-137207, MCE) for 72 h. In vitro, efficacy was evaluated in HK-2 cells under high glucose by measuring oxidative stress markers (ROS, MDA, GSH, PCO, and 8-OHdG) and mitochondrial function (mitochondrial membrane potential, ATP levels); MAPK/ERK involvement was confirmed using pathway inhibitors/activators with total ROS as the readout. 4.7. ELISA Detection of 8-OHdG The levels of 8-OHdG in kidney tissues and HK-2 cells were determined using ELISA kits (MM-0331H1, Meimian, Yancheng, China) according to the manufacturer’s instructions. 4.8. Malondialdehyde (MDA) Assay According to the MDA Assay Kit (S0131S, Beyotime, Shanghai, China), MDA levels in kidney tissues or HK-2 cells were measured after lysis and incubation using a microplate reader. 4.9. Glutathione (GSH) Assay Total GSH content in tissues or HK-2 cells was assessed using the Reduced Glutathione Content Assay Kit (BC1175, Solarbio, Beijing, China) following the manufacturer’s instructions. 4.10. Protein Carbonyl Content (PCO) Test The levels of PCO in kidney tissues and HK-2 cells were determined by Protein Carbonyl Content Assay Kit (BC1275, Solarbio) following the manufacturer’s instructions. 4.11. Prussian Blue Staining (Enhance with DAB) Kidney sections were deparaffinized, rehydrated, and stained with Prussian blue, followed by DAB incubation for 2 min. After hematoxylin counterstaining, three random non-overlapping fields per slide were selected by a blinded pathologist and quantified using ImageJ ( n = 5). 4.12. Iron Array Total iron levels in tissues were assessed using a tissue iron assay kit (BC4355, Solarbio, China) following the manufacturer’s instructions. 4.13. Western Blotting Western blotting was performed as previously described [ 46]. Primary antibodies (See Supplementary Methods) were incubated overnight at 4 °C. Secondary antibodies were incubated for 1 h at room temperature. Chemiluminescent detection was performed to visualize the protein bands. Band intensities were quantified using ImageJ software (NIH, Bethesda, MD, USA). The relative changes in protein expression in treated groups compared to control cells or tissues were statistically analyzed. 4.14. ATP Level Following the procedure of the ATP Assay Kit (S0026, Beyotime), the ATP level of kidney tissues and HK-2 cells was detected by chemiluminescence. 4.15. Mitochondrial Membrane Potential (MMP) Assay HK-2 cells were harvested and incubated with the JC-1 probe according to the manufacturer’s protocol for the mitochondrial membrane potential assay kit (M8650, Solarbio). Subsequently, mitochondrial membrane potential was assessed via flow cytometry. 4.16. MtDNA Copy Number Genomic DNA was isolated from kidney tissues or total cells pursuant to the instructions of the DNA extraction kit (DP304, TianGen, Beijing, China). Subsequently, cycle threshold (Ct) values were acquired via quantitative real-time PCR (qPCR) performed with a standard system and procedure. Primer sequences are available in the Supplementary Methods. 4.17. ROS Level HK-2 cells were loaded with DCFH probe (S0033S, Beyotime) in situ according to the instructions and then incubated at 37 °C for 15 min for staining, and photographed by laser confocal microscopy under microscopic observation or assessed via flow cytometry. 4.18. RNA-Seq and Analysis Total RNA was isolated from rat kidney tissues using Trizol (Invitrogen, Carlsbad, CA, USA) and RNeasy Mini Kit (Qiagen, Valencia, CA, USA). rRNA-depleted libraries were prepared with NEBNext Directional RNA Library Prep Kit (NEB, Ipswich, MA, USA) and sequenced on Illumina NovaSeq (Illumina, San Diego, CA, USA). Gene expression was quantified as FPKM, and differential expression analysis was performed using DESeq2 R package (1.30.0) with FDR correction. 4.19. Statistical Analysis All results were analyzed using GraphPad Prism software (version 10.1.2) and expressed as means ± standard deviation (Mean ± SD). Statistical analysis was performed as indicated in the figure legends. For the two-group comparison, a Student’s t-test was performed. For the multiple-group comparison, a one-way ANOVA was performed. 5. Conclusions In conclusion, this study elucidates the molecular mechanisms underlying UMSC efficacy, moving beyond descriptive accounts. We demonstrate that UMSCs protect renal parenchymal cells by inhibiting MAPK/ERK phosphorylation, which disrupts the ferroptosis-ROS feedback loop. This mechanistic insight not only validates UMSC-based therapy for DN but also highlights the ERK/ferroptosis axis as a promising target. Targeting this pathway, whether through cell therapy or paracrine mediators, thus holds substantial translational potential. Supplementary Materials The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms27115101/s1. Author Contributions Conceptualization, Q.H., X.B. and R.C.Z.; methodology, Q.H., X.B. and R.C.Z.; validation, S.M., J.L. and H.W.; formal analysis, Y.W.; data curation, S.M. and J.L.; writing—original draft preparation, S.M.; writing—review and editing, Q.H., X.B. and R.C.Z.; visualization, S.M.; supervision, J.L.; project administration, Q.H. and X.B.; funding acquisition, R.C.Z. All authors have read and agreed to the published version of the manuscript. Funding This research was funded by the State Key Laboratory of Common Mechanism Research of Major Diseases Platform. Institutional Review Board Statement UMSCs used in this study were provided by the Cell Energy Life Sciences Group Co. Ltd. Cell Energy Life Sciences Group Co. Ltd. obtained the initial ethical approval for human umbilical cord tissue collection according to procedures from the Ethics Committee of Liaocheng People’s Hospital (Title of the approved project: Establishment of a Clinical-Grade Stem Cell Product Preparation, Quality Control, and Standardization System Integrated with a Biobank. Approval No. 2021105. Date of approval: 20 July 2021; donors had signed informed consent. All animal experiments were approved by the Experimental Animal Ethics Committee of Kangtai Medical Laboratory Service Hebei Co., Ltd. (Title of the approved project: Human Umbilical Cord Mesenchymal Stem Cell Injection for the Treatment of Diabetic Nephropathy in Rats. Approval No. MDL2021-11-18-02. Date of approval: 18 November 2021, and conducted in compliance with the relevant laws and institutional guidelines. Informed Consent Statement Written informed consent was obtained from all participants, and measures were taken to ensure the privacy and confidentiality of the subjects. No identifying information of human subjects will be published as part of this manuscript. Data Availability Statement The original contributions presented in this study are included in the article/ Supplementary Materials. Further inquiries can be directed to the corresponding authors. Acknowledgments The primary UMSCs were provided by Shuang Peng. Conflicts of Interest The authors declare no conflict of interest. Abbreviations The following abbreviations are used in this manuscript: MAPK Mitogen-activated protein kinase ERK Extracellular signal-regulated kinase DN Diabetic nephropathy MSCs Mesenchymal stem cells UMSCs Human umbilical cord-derived MSCs UMSCs-CM UMSCs-conditioned medium MDA Malondialdehyde GSH Glutathione 8-OHdG 8-Hydroxy-2′-deoxyguanosine PCO Protein carbonyl ROS Reactive oxygen species PRO 24 h urinary protein excretion MMP Mitochondrial membrane potential ATP Adenosine Triphosphate References International Diabetes Federation. IDF Diabetes Atlas, 11th ed.; International Diabetes Federation: Brussels, Belgium, 2025; Available online: https://www.diabetesatlas.org (accessed on 19 February 2026). Genitsaridi, I.; Salpea, P.; Salim, A.; Sajjadi, S.F.; Tomic, D.; James, S.; Thirunavukkarasu, S.; Issaka, A.; Chen, L.; Basit, A.; et al. 11th edition of the IDF Diabetes Atlas: Global, regional, and national diabetes prevalence estimates for 2024 and projections for 2050. 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