Mapping the future: bibliometric insights into ferroptosis and diabetic nephropathy

In our search period, publication numbers related to ferroptosis in DN showed a pronounced upward trend, particularly from 2020 to 2023. Notably, between 2018 and 2020, publication numbers remained minimal, with only a few studies contributing to the field. However, from 2020 to 2023, publication numbers surged exponentially, increasing by several orders of magnitude when compared to earlier years (Figure 2). This trend underscored ferroptosis as a critical research area in the broader academic landscape.

Globally, China emerged as a leading contributor to ferroptosis research in DN, accounting for over 60% of publications from 2018 to 2023. This dominance was exemplified by Zhengzhou University, which contributed five publications in this field. Key international collaborations primarily involved China, the United States of America, and Germany, forming the most substantial global research network (Figure 3). Institutional analysis revealed that Anhui Medical University, Central South University, and Nanjing Medical University had pivotal roles in advancing research on renal ferroptosis mechanisms (Figures 4, 5). Among academic journals, Frontiers in Endocrinology (nine articles) and Biomedicine and Pharmacotherapy (five articles) were primary platforms for disseminating ferroptosis research, while Free Radical Biology and Medicine and Cell Death and Disease ranked among the most frequently cited journals (Table 1). Thus, these patterns underscored China’s leadership in both research output and collaborative influence in this rapidly evolving field.

Our literature search included 551 authors, with Feng Qi and Chen Yan each contributing four publications. As shown (Figures 6, 7), some authors had close collaborations, whereas others appeared to work more independently. Given the emerging nature of this research field, individual’s publication outputs remained relatively modest. Although variations in publication numbers among authors were minimal, Wang Y, Li SW, Dixon SJ, Kim S, and Feng XM were the five most cited authors (Table 2), underscoring their significant contribution to the field. In terms of scholarly influence, Yang WS and Dixon SJ ranked among the top 10 most cited scholars, demonstrating notable centrality with scores of 0.15 and 0.12, respectively. These values indicated their pivotal roles within the academic community. Notably, José Pedro Friedmann Angeli↗, despite a relatively modest publication count, had the highest centrality score (0.66). This suggested that this author was the most influential researcher in the specific research block, reinforcing their prominence in the field despite a lower publication volume.

In total, 56 journals were included in analyses. As shown (Figure 8), Frontiers in Endocrinology had the highest number of publications, with nine articles on ferroptosis and DN (Table 3), followed by Biomedicine and Pharmacotherapy. Given that ferroptosis in DN is an emerging research field, the overall publication volume in each journal remained relatively low, with minimal differences between them. This made it challenging to determine which journals were authoritative and representative in the field. However, Frontiers in Endocrinology publications were nearly double that of the second-ranked journal, suggesting a possible leading role for this journal in ferroptosis and DN research in the future.

Among the 56 journals, nine were cited over 100 times. Co-citation analysis revealed that Free Radical Biology and Medicine, Cell Death and Disease, and Journal of the American Society of Nephrology ranked among the top three most cited journals. Cell Death and Disease demonstrated a steady increase in impact factor and high citation rates, while the Journal of the American Society of Nephrology had a significant position in nephrology research. Journal prominence is shown (Figure 9) while the top 10 most cited journals are listed (Table 4).

To demonstrate the citation relationships between journals, a dual-map overlay was employed to analyze the citation relationships of the journals located on the left and right sides of the map(Figure 10). The green path indicated that journals focusing on molecular studies frequently cited literature from journals in veterinary, animal, and general scientific disciplines. The orange paths showed that journals specializing in molecular biology, environmental studies, toxicology, and nutrition tended to reference journals focusing on biology, immunology, ecology, soil science, and oceanography.

The ferroptosis and DN research field represents a multidisciplinary domain that integrates knowledge from different scientific disciplines. This convergence was particularly evident in the biology impact of ferroptosis-related mechanisms. The field encompassed diverse areas, including biology, medicine, and nutritional science, underscoring the importance of interdisciplinary collaborations in driving continued research advancement in this area.

The evolutionary trajectory of ferroptosis in DN research (2018–2023) was represented by multi-dimensional measurement analysis (Figures 11–15). Keyword burst analysis identified “reactive oxygen” as the most intense keyword and “programmed cell death” as the longest-lasting concept (Figure 11), forming a core conceptual framework in the field. Notably, programmed cell death occurred with ferroptosis via p53-mediated solute carrier family 7 member 11 (SLC7A11) regulation and the nuclear factor erythroid 2-related factor 2 (Nrf2)antioxidant pathway. Animal model selection, primarily rats, was based on their robust physiological adaptability, which facilitated mechanistic studies. Key molecular pathways, including the GPX4-mediated regulation of lipid peroxidation and Gasdermin D (GSDMD)-related cross-regulation of pyroptosis, are fundamental pillars in ferroptosis research. The emergence of the “risk” concept in the literature signaled a growing focus on clinical translation. Our co-occurrence network analysis (Figure 12) confirmed that “diabetic nephropathy,” “oxidative stress,” and “lipid peroxidation” formed a stable triangular core (frequency > 50). Also, “renal disease” (centrality 0.27) and “disease progression” were critical bridging concepts, linking mechanistic studies to clinical implications. Time-series clustering (Figures 13–15) revealed a three-stage evolutionary pattern: 1) Foundational Phase (2017–2019): early studies focused on ferroptosis in renal tubular epithelial cells (RTECs) and highlighted NRF2 pathway roles in mitigating oxidative stress. A significant increase in related research projects and funding laid the groundwork for understanding ferroptosis mechanisms. 2) Mechanism Expansion Phase (2020–2023): research expanded to explore tryptophan metabolism and its implications for renal fibrosis, building on foundational ferroptosis knowledge. 3) Interdisciplinary Integration Phase (Post-2021): research paradigms from neurodegenerative diseases were incorporated, suggesting shared ferroptosis-related mechanisms across multiple organ systems. The emergence of clinical transformation concepts, such as “low-threshold intervention strategies,” marked a shift from basic mechanistic analysis to precision medicine approaches.

Each node represents a keyword and its size reflects keyword frequency occurrence in studies. The color gradient in nodes corresponds to the temporal aspect of keyword emergence. Nodes closer to purple indicate keywords that appear earlier in the timeline (2018), while nodes transitioning toward yellow represent keywords that had gained prominence more recently (2023). The connecting lines show co-occurrence relationships between keywords.

The cystine/glutamate antiporter System Xc⁻ has crucial roles maintaining redox balance, particularly in the central nervous system. This antiporter facilitates cellular cystine uptake, which is a critical step in glutathione (GSH) biosynthesis, and serves as a primary defense against oxidative damage (Figure 16). Pathway regulation occurs in several physiological and pathological conditions, including tumor metabolism and ferroptosis. Glutathione peroxidase 4 (GPX4) is a selenoprotein that uses GSH to reduce cytotoxic phospholipid hydroperoxides to non-toxic alcohols, thereby acting as the primary defense against ferroptosis (Wei et al., 2020; Conrad and Proneth, 2020). Axis dysregulation facilitates lipid peroxide accumulation, leading to ferroptosis initiation. In diabetic retinopathy models, ferrostatin-1 (Fer-1) alleviated hyperglycemia-induced suppression of the GSH/GPX4 axis, thereby restoring redox homeostasis in retinal cells (Shao et al., 2022). GPX4 knockout or its pharmacological inhibition directly induced ferroptosis across various cancer types (Adamiec-Organisciok et al., 2023). Additionally, in nasopharyngeal carcinoma cells (S18/5-8F), induced ferroptosis by berberine was effectively counteracted by GPX4 overexpression, further underscoring its pivotal role in modulating this iron-dependent cell death pathway (Wu et al., 2024).

Independent of GPX4, the ferroptosis suppressor protein 1 (FSP1/AIFM2) was shown to use nicotinamide adenine dinucleotide phosphate (NAD(P)H) to regenerate reduced coenzyme Q10 (CoQ10H₂), which activated radical-trapping to neutralize lipid peroxides (Feng et al., 2020; Gotorbe et al., 2022; Nakamura et al., 2023). This membrane-associated system is in synergy with mitochondrial CoQ10 pools, particularly when GPX4 is dysfunctional (Xavier da Silva et al., 2023). Notably, FSP1 expression was inversely correlated with ferroptosis sensitivity in therapy-resistant cancers, emphasizing its therapeutic relevance as a ferroptosis modulator. Recent studies also indicated that FSP1 inhibitors synergized with GPX4-targeting agents to overcome ferroptosis resistance (Xavier da Silva et al., 2023).

The GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) axis has pivotal roles in the selective protection against phospholipid peroxidation, as evidenced by its involvement in antioxidant defense mechanisms and ferroptosis regulation. Under ferroptotic stress, upregulated GCH1 enhanced BH4 biosynthesis, which served as a radical scavenger and stabilized phospholipids containing polyunsaturated fatty acids (PUFAs). This function was essential as BH4 is a crucial cofactor in nitric oxide synthesis, and its disruption potentially elevated ROS production. Studies further reported that BH4 was involved in protein S-nitrosylation and showed increased expression in activated T cells. Dihydrofolate reductase (DHFR) was integral to maintaining BH4 levels, as it recycled dihydrobiopterin to sustain endothelial function, and it also formed a feedback loop that countered lipid peroxidation (Liang et al., 2023; Lee et al., 2021). Previous research has suggested that DHFR deficiency reduced BH4 synthesis and enhanced lipid peroxidation, as observed in aortic valve calcification. Notably, this pathway exhibited tissue-specific activity with pronounced effects in neuronal and renal cells, both of which were particularly vulnerable to PUFA oxidation (Lee et al., 2021).

Iron overload amplifies ferroptosis via two primary mechanisms: 1) Metabolic Regulation: Transferrin-bound Fe³⁺ enters cells via transferrin receptor 1 (TfR1)-mediated endocytosis, where it is reduced to Fe²⁺ by six-transmembrane epithelial antigen of prostate 3 (STEAP3) and stored in labile iron pools (LIP). The iron regulatory protein/iron-responsive element-binding protein 2 system was shown to post-transcriptionally regulate ferritin synthesis and iron export via ferroportin (FPN1) (Billesbølle et al., 2020; Keel et al., 2015). 2) Redox Cycling: Iron ions, particularly Fe²⁺, have pivotal roles catalyzing Fenton reactions, where Fe²⁺ reacts with hydrogen peroxide (H₂O₂) to generate Fe³⁺, hydroxyl radicals (·OH), and hydroxide ions (OH⁻). These molecules have high reactivity, initiating lipid peroxidation, which is a critical event in many biochemical reactions (Zhang et al., 2023a). Additionally, lipoxygenases were shown to propagate PUFA oxidation in an Fe²⁺-dependent manner, further promoting ferroptosis (Li et al., 2023a).

Recent studies reported that ferroptosis was a key pathogenic mechanism underlying RTEC injury in DN; the process was driven by iron-dependent oxidative cascades. Research by Liu Zhangsuo’s team at Zhengzhou University highlighted a role for vitamin D receptor activation and its regulatory effects on ferroptosis (Wang et al., 2024a). In the diabetic microenvironment, RTEC degeneration was exacerbated by a self-perpetuating cycle of lipid peroxidation and glutathione depletion, fueled by hyperglycemia-induced oxidative stress, iron overload, and impaired antioxidant defenses (Jin et al., 2023). Mechanistically, chronic hyperglycemia induced mitochondrial dysfunction and activated NADPH oxidase, leading to excessive ROS production (Qiu et al., 2022). The resulting oxidative stress overwhelmed endogenous scavenging mechanisms, intensifying cellular damage. Furthermore, this oxidative milieu synergized with diabetes-associated iron dyshomeostasis, which was characterized by upregulated transferrin receptor expression and suppressed FPN1 levels. These alterations increased LIP levels, creating catalytic conditions for Fenton reactions where redox-active iron (Fe²⁺) reacted with H₂O₂ to generate ·OH. These radicals then propagated lipid membrane peroxidation, further exacerbating ferroptotic cell death in renal tubules (Balakrishnan and Kenworthy, 2024).

GPX4 pathognomonic depletion, exacerbated by system Xc⁻ transporter dysfunction under diabetic conditions, critically impaired cells to neutralize phospholipid hydroperoxides. This antioxidant collapse occurred in parallel with the Transforming growth factor-beta (TGF-β)-mediated upregulation of pro-ferroptotic pathways and suppressed Nrf2 signaling, effectively disabling multiple cellular defenses against oxidative injury. Histopathological analysis identified tubular ferroptosis hallmarks, including atrophy and interstitial fibrosis. Ultrastructural studies also identified mitochondrial shrinkage and increased membrane density in affected RTECs–unique morphological features were identified in ferroptosis and were distinguished from other cell death modalities, such as apoptosis or necrosis (Wang et al., 2024a).

The inflammatory microenvironment further amplified ferroptotic cascades via macrophage-derived pro-inflammatory cytokines, which not only enhanced iron retention via heme oxygenase-1 (HO-1) induction, but also depleted cysteine reserves, thereby compromising glutathione synthesis. These molecular disturbances established a vicious metabolic cycle where lipid peroxide accumulation was shown to alter membrane permeability, facilitating excessive iron influx and mitochondrial dysfunction, which in turn generated additional ROS. This self-sustaining RTEC loss mechanism in DN, driven by metabolic abnormalities and oxidative stress, underscored the progressive nature of the disease and highlighted the therapeutic potential of ferroptosis-targeted interventions. Thus, the current evidence has positioned iron chelators and GPX4 activators as promising therapeutic strategies. Preclinical models have also demonstrated that pathway modulation can attenuate both biochemical markers—including ACSL4 upregulation and glutathione depletion—as well as functional parameters, such as serum creatinine levels and proteinuria (Kim et al., 2021; Wang et al., 2022a; Ni et al., 2022; Guo et al., 2023).

Iron-dependent cell death in podocytes has emerged as a key driver of glomerular injury in DN. The process was mediated by a cascade of redox imbalances, membrane destabilization, and inflammatory amplification, ultimately resulting in pathological iron accumulation, where excess Fe²⁺ catalyzed Fenton reactions, converting H₂O₂ to ·OH. These highly reactive species overwhelmed endogenous antioxidant defenses, leading to an iron-ROS axis that induced catastrophic lipid peroxidation. This peroxidative stress preferentially targeted membrane-embedded PUFAs via non-enzymatic oxidation and acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated lipid remodeling. Peroxidative phospholipid bilayer degradation also disrupted podocyte structural integrity, resulting in foot process effacement and slit diaphragm protein redistribution (Kruger et al., 2018).

In the diabetic environment, synergistically impaired GSH regeneration occurred via the downregulation of system Xc⁻ and suppressed glutamate-cysteine ligase, which hampered GPX4-mediated lipid hydroperoxide reduction. This antioxidant collapse fostered conditions conducive to ferroptosis, which were further exacerbated by tumor necrosis factor-α(TNF-α)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated inflammation, which in turns upregulated iron importers, such as TfR1, while concurrently suppressing FPN1, as shown in osteoarthritis studies (Wang et al., 2023; Jing et al., 2021). Resultant iron retention then established a self-sustaining cycle wherein iron-generated ROS inactivated nephrin and podocin via oxidative modification, compromising the filtration barrier and triggering proteinuria (Alli et al., 2023). Damaged podocytes were shown to further release damage-associated molecular patterns which recruited macrophages. Infiltrating immune cells perpetuated injury by stimulating collagen deposition and α-SMA expression viainterleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3)-mediated pathways, as shown in podocyte injury in focal segmental glomerulosclerosis. Janus kinase 2 (JAK2)/STAT3 signaling was also implicated in this process, thereby establishing links between ferroptosis and progressive glomerulosclerosis (Tao et al., 2018).

Mitochondrial dysfunction was shown to further amplify this cascade by disrupting electron transport chain activity, leading to superoxide leakage that synergized with cytoplasmic ROS pools. Ultrastructural studies identified swollen mitochondria with disrupted cristae in iron-overloaded podocytes, coinciding with upregulated NADPH oxidase 4 (Kahveci et al., 2020). This enzyme is a major ROS source in diabetic glomeruli, with studies confirming its overexpression in podocytes and roles propagating oxidative stress. Clinical correlation analyses also revealed that urinary podocyte-derived extracellular vesicles, enriched in peroxidized lipids, were correlated with disease progression, positioning ferroptosis biomarkers as potential prognostic tools. Emerging therapeutic strategies have targeted this axis, including liproxstatin-1-mediated lipid radical quenching and dexrazoxane-driven iron chelation, which have shown promise in preserving podocyte density and attenuating albuminuria in DN preclinical models (Feng et al., 2023a).

Ferroptosis is a central mediator of endothelial injury in DN. This pathology is sustained by a self-reinforcing triad process of oxidative stress, iron dysmetabolism, and inflammatory amplification, as evidenced by a growing body of research on ferroptosis mechanisms in disease progression.

Hyperglycemia-induced mitochondrial uncoupling and subsequent NADPH oxidase activation led to superoxide bursts that overwhelmed endothelial antioxidant defenses. This oxidative stress depleted GSH reserves and impaired GPX4 activity, critical failures that permitted uncontrolled lipid peroxidation. The resulting redox imbalance is further exacerbated by iron overload, a condition frequently associated with diabetes. Within this context, excess Fe²⁺ was shown to catalyze Fenton reactions, converting H₂O₂ to ·OH, which preferentially oxidized membrane phospholipids enriched with arachidonic acid and adrenic acid (He et al., 2019). The resultant peroxidative cascade disrupted endothelial barrier function, primarily via caveolin-1 oxidation and vascular endothelial-cadherin internalization. This molecular disruption was clinically manifested as microalbuminuria and capillary leakage, further contributing to vascular complications in DN (Kyselova et al., 2020).

The hypoxic diabetic microenvironment further propagates endothelial ferroptosis through hypoxia-inducible factor 1-α(HIF-1α)-mediated transcriptional reprogramming. Although initially an adaptive response, chronic HIF-1α stabilization paradoxically enhanced HO-1 expression, leading to redox-active iron release from heme catabolism. This liberated iron fueled ROS generation, exacerbating oxidative stress and accelerating ferroptotic cell death. The iron-ROS axis was then shown to act synergistically with tumor necrosis factor-α(TNF-α)/interleukin-1β(IL-1β)-driven inflammation, where activated macrophages secreted S100A8/9 alarmins, which suppressed FPN1 expression, trapping iron in endothelial cells (Guggisberg et al., 2022; Simmen et al., 2019). Simultaneously, advanced glycation end products downregulated system Xc⁻, thereby limiting cystine uptake and glutathione synthesis, effectively disabling the GPX4-mediated repair of oxidized phosphatidylethanolamines. Molecular profiling analysis identified an ACSL4-dominated lipid remodeling program in diabetic endothelial cells, which preferentially incorporated oxidation-prone PUFAs into membrane phospholipids (Singh et al., 2019). This metabolic shift, compounded by a suppressed Nrf2 pathway, established a lipid peroxidation-prone phenotype. Ultrastructural diabetic endothelial ferroptosis hallmarks included fragmented mitochondrial cristae and dilated endoplasmic reticulum, changes that correlated with increased urinary isoprostane levels, which were key peroxidation byproducts linked to declined glomerular filtration rates (Qiao et al., 2023).

Therapeutic strategies targeting this axis demonstrated multimodal efficacy in mitigating endothelial ferroptosis. Deferoxamine, an iron chelator, effectively reduced LIP levels, whereas liproxstatin-1 terminated lipid radical chain reactions, collectively preserving endothelial tight junction integrity in preclinical models. Notably, endothelial-specific GPX4 overexpression attenuated albuminuria and improved peritubular capillary density, further validating ferroptosis as a critical therapeutic target against DN. Emerging biomarkers, such as 4-hydroxynonenal (4-HNE)-modified proteins in circulating endothelial microvesicles, allowed for the non-invasive monitoring of ferroptotic activity. These biomarkers highlighted crucial links between molecular mechanisms and clinical applications, as evidenced by recent studies exploring ferroptosis in cancer treatment and neurodegenerative diseases (Zheng et al., 2021).

Emodin is a rhubarb-derived anthraquinone and was shown to reverse diabetes-induced Nrf2 suppression by modifying Keap1 cysteine levels, thereby enhancing cellular antioxidant defenses. Transcriptomic profiling indicated that emodin upregulated approximately 78% of Nrf2-regulated genes, including ferritin heavy chain 1 (FTH1) and SLC7A11, in hyperglycemic podocytes. This transcriptional activation was associated with restored glutathione synthesis and increased iron storage capacity, both of which protected against ferroptotic injury. In addition to its antioxidant properties, emodin also exhibited hypoglycemic effects, reducing fasting blood glucose levels by 30% in Zucker rat diabetes models. Notably, its dual-action mechanisms resulted in a 50% greater reduction in albuminuria when compared to pure Nrf2 activators in comparative studies (Ji et al., 2023).

Beyond its role as a sodium-glucose cotransporter 2 inhibitor, dapagliflozin was shown to confer ferroptosis-specific protection by stabilizing SLC40A1, thereby enhancing cellular iron export. In proximal tubule cells, dapagliflozin treatment increased iron efflux by 2.3-fold, leading to a 40% reduction in renal LIP levels. This decrease in intracellular iron levels mitigated Fenton reaction-derived ·OH generation, effectively reducing oxidative stress-mediated tubular injury. Clinical correlation analyses further supported its translational potential, with dapagliflozin-treated patients exhibiting 35% lower urinary 8-isoprostane levels when compared with those receiving standard care (Wang et al., 2024b).

The SHYS capsule is a traditional Chinese medicine formulation and a multitarget ferroptosis intervention with system-level effects. Network pharmacology analyses reported 12 bioactive components in SHYS that targeted key ferroptosis regulators, including astragaloside IV (GPX4 stabilization), salvianolic acid B (HO-1 induction), and liquiritin (FPN1 upregulation). In db/db mouse models, SHYS demonstrated comparable reno-protective effects to Fer-1, while uniquely preserving mitochondrial cristae integrity - a structural feature associated with ferroptosis resistance (Lv et al., 2023).