RRM2 and the ferroptosis-oxidative stress axis in diabetic kidney disease: Emerging insights from recent evidence

Abstract

Diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease worldwide despite advances in current therapies. In a recent study published in the World Journal of Diabetes, Gao et al demonstrated that RRM2 alleviates renal tubular ferroptosis via activation of the PI3K/Akt/Nrf2 signaling pathway. This finding provides new insight into the interplay between oxidative stress and regulated cell death in DKD. In this editorial, we discuss the key findings of this study, place them in the broader context of ferroptosis biology in diabetic complications, and critically evaluate their mechanistic and translational implications. While RRM2 emerges as a promising regulator of redox homeostasis and tubular integrity, further validation in vivo and careful assessment of safety are required before clinical translation. Targeting the RRM2-ferroptosis axis may represent a novel therapeutic direction for DKD.

Key Words: Diabetic kidney disease; Ferroptosis; Oxidative stress; RRM2; PI3K/Akt/Nrf2 signaling; Tubular injury

Core Tip: Recent evidence identifies RRM2 as a regulator of ferroptosis in diabetic kidney disease (DKD) through activation of the PI3K/Akt/Nrf2 pathway. This editorial highlights the significance of this finding, critically evaluates its limitations, and discusses its potential as a biomarker and therapeutic target in DKD.

This editorial refers to “RRM2 attenuates the renal tubular ferroptosis in diabetic kidney disease through PI3K/Akt/Nrf2 pathway” by Gao et al, 2025; https://doi.org/10.4239/wjd.v16.i11.111223.

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INTRODUCTION

Diabetic kidney disease (DKD) affects approximately 30%-40% of patients with type 2 diabetes and remains the leading cause of end-stage renal disease globally[1,2]. Although therapies such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists have improved renal outcomes, they do not fully prevent disease progression[3,4]. Increasing evidence suggests that tubular injury, rather than glomerular damage alone, plays a central role in DKD pathogenesis[5,6].

In this context, Gao et al[7] recently reported in the World Journal of Diabetes that RRM2 attenuates renal tubular ferroptosis via activation of the PI3K/Akt/Nrf2 signaling pathway[7-9]. This study provides a novel mechanistic link between metabolic stress, oxidative imbalance, and regulated cell death. Here, we discuss the significance of these findings and their implications for DKD research and therapy.

KEY FINDINGS OF THE STUDY

The study by Gao et al[7] integrates clinical and experimental data to identify RRM2 as a protective factor in DKD. Analysis of patient-derived datasets revealed that RRM2 expression is reduced in diabetic kidneys and positively correlates with antioxidant capacity. In vitro experiments using HK-2 cells demonstrated that RRM2 overexpression suppresses high glucose-induced ferroptosis, reduces lipid reactive oxygen species accumulation, and preserves mitochondrial integrity.

Mechanistically, the protective effects of RRM2 were shown to depend on activation of the PI3K/Akt/Nrf2 pathway. Pharmacological inhibition of PI3K/Akt signaling abolished the anti-ferroptotic effects of RRM2, suggesting that RRM2 acts upstream of this canonical antioxidant axis. These findings collectively position RRM2 as a regulator linking redox homeostasis and ferroptotic cell death in renal tubular epithelial cells.

FERROPTOSIS AND OXIDATIVE STRESS IN DKD

Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation and impaired antioxidant defenses[10,11]. In DKD, hyperglycemia-induced metabolic stress leads to excessive reactive oxygen species generation, iron accumulation, and disruption of redox balance[5,6]. Suppression of Nrf2 signaling further exacerbates oxidative injury, promoting tubular damage and fibrosis[12,13]. Accumulating evidence indicates that inhibition of ferroptosis can ameliorate renal injury in experimental models, highlighting its importance as a pathogenic mechanism[14-16]. The identification of upstream regulators of ferroptosis in DKD, however, remains incomplete[17,18]. In this regard, the discovery of RRM2 as a modulator of ferroptosis provides an important addition to the current framework[7,9].

MECHANISTIC INSIGHTS: THE RRM2-PI3K/AKT/NRF2 AXIS

The PI3K/Akt/Nrf2 pathway is a central regulator of cellular survival and antioxidant responses[8,12]. Activation of this pathway enhances the transcription of genes involved in glutathione metabolism, reactive oxygen species detoxification, and maintenance of mitochondrial function[13]. In DKD, impairment of PI3K/Akt signaling contributes to oxidative stress and cell death[6,19]. By linking RRM2 to this pathway, Gao et al[7] propose a regulatory axis in which RRM2 acts as an upstream modulator of antioxidant defense. This finding is particularly significant because direct pharmacological activation of Nrf2 has shown limited clinical success, suggesting that upstream regulation may provide a more effective strategy[20].

CRITICAL EVALUATION AND LIMITATIONS

Despite its strengths, several limitations should be considered when interpreting these findings. First, the clinical component of the study is based on cross-sectional data, which limits causal inference. Reduced RRM2 expression may be a consequence rather than a driver of DKD progression. Second, the mechanistic experiments rely primarily on a single tubular epithelial cell line (HK-2), and validation in animal models is lacking[14,15]. Given the complexity of DKD, it remains unclear whether the RRM2-ferroptosis axis operates similarly in other renal cell types, such as podocytes or mesangial cells[17,18]. Third, RRM2 is a key enzyme involved in DNA synthesis and cell-cycle regulation. Its upregulation has been implicated in tumor proliferation, raising potential safety concerns[21]. Therapeutic strategies targeting RRM2 must therefore carefully balance renoprotective effects with the risk of unintended proliferative signaling. Finally, the PI3K/Akt pathway has broad systemic effects, and its modulation may lead to off-target consequences. Long-term activation of this pathway could alter metabolic and immune responses in ways that are not yet fully understood[6].

FUTURE DIRECTIONS

Several key questions remain to be addressed. Prospective studies are needed to determine whether RRM2 can predict DKD onset or progression[5,22,23]. The upstream regulators of RRM2 expression under diabetic conditions require further investigation[24]. In addition, the development of targeted approaches, such as kidney-specific delivery systems or small-molecule modulators, will be critical for safe clinical translation[25,26]. Understanding how RRM2 interacts with other ferroptosis regulators and metabolic pathways will also be essential for defining its role within the broader DKD network[27-30].

CONCLUSION

The study by Gao et al[7] provides compelling evidence that RRM2 protects against ferroptosis in DKD through activation of the PI3K/Akt/Nrf2 pathway. This work advances our understanding of the interplay between oxidative stress and regulated cell death in diabetic complications. While further validation is required, targeting the RRM2-ferroptosis axis represents a promising direction for future therapeutic development in DKD (Figure 1).

Figure 1 Overview of the RRM2-PI3K/Akt/Nrf2 pathway in diabetic kidney disease. Reduced RRM2 expression under hyperglycemic conditions promotes ferroptosis and weakens PI3K/Akt/Nrf2 antioxidant defenses, leading to tubular injury and diabetic kidney disease progression. Multiple therapeutic nodes along this axis—including ferroptosis inhibition, antioxidant enhancement, and RRM2 upregulation—represent emerging targets for intervention. ROS: Reactive oxygen species; DKD: Diabetic kidney disease.