RRM2 attenuates renal tubular ferroptosis in diabetic kidney disease via the PI3K/Akt/Nrf2 pathway: Strengths, limitations, and future research directions

Abstract

Diabetic kidney disease (DKD) has become the primary cause of end-stage renal disease. However, its pathological mechanism remains incompletely understood. Ribonucleotide reductase M2 (RRM2) is a small subunit of ribonucleotide reductases, which is involved in nucleotide metabolism and catalyzes the conversion of nucleotides to deoxynucleotides, thereby maintaining the deoxyribonucleoside triphosphate pools required for DNA biosynthesis, repair, and replication. This study establishes a novel connection between the enzyme RRM2—traditionally recognized for its role in DNA synthesis—and the pathological progression of DKD, thereby filling the gap in identifying the “bridge molecule” between ferroptosis and the PI3K/Akt/Nrf2 pathway.

Key Words: Type 2 diabetes mellitus; Diabetic nephropathy; Ribonucleotide reductase regulatory subunit M2; Oxidative stress; Ferroptosis; PI3K/Akt pathway; Renal tubular cells

Core Tip: Against the backdrop of challenges in early diagnosis and prevention of the progression of diabetic kidney disease (DKD), with the key molecules involved in its underlying mechanisms remaining unclear, this study confirms the protective effect of ribonucleotide reductase M2 on DKD. This protective effect shows relevant implications for DKD research.

TO THE EDITOR

We read the article entitled “RRM2 attenuates the renal tubular ferroptosis in diabetic kidney disease through PI3K/Akt/Nrf2 pathway” with great interest[1]. As readers with long-standing focus on diabetic complications, we are not only encouraged by the novel findings of this study but also contend that it is valuable to objectively discuss its merits and areas for refinement from the dual perspectives of clinical translation and scientific rigor. We anticipate that this discussion will serve as a useful reference for subsequent academic investigations.

Against the backdrop of the global rise in the prevalence of diabetic mellitus, diabetic kidney disease (DKD)—the leading cause of end-stage renal disease[2]—is inherently characterized by “challenges in early diagnosis and impeded progression control”[3]. Although previous studies have established that ferroptosis is a key mechanism of renal tubular injury[4] and the PI3K/Akt/Nrf2 pathway serves as the central mediator of antioxidant stress response[5], the key molecule link bridging these two processes remains elusive. This study, however, links ribonucleotide reductase M2 (RRM2)—a canonical enzyme involved in DNA synthesis—to the pathological progression of DKD. Through dual validation using clinical data and cell experiments, this study confirms that RRM2 may alleviate ferroptosis by activating the PI3K/Akt/Nrf2 pathway. This novel finding is anticipated to offer a new avenue for investigating the pathogenic mechanism underlying DKD. The strengths of this study are worthy of recognition. At the clinical level, 194 type 2 diabetes patients and 120 healthy controls were enrolled; stratified analysis revealed that serum RRM2 levels decreased with the progression of albuminuria severity. With 30 pg/mL as the cutoff, the area under the curve of serum RRM2 for distinguishing diabetic patients from healthy individuals was 0.958 (sensitivity: 86%, specificity: 95%). This supports RRM2’s clinical potential: Unlike urine albumin/creatinine ratio (susceptible to exercise/infection interference) or serum creatinine (insensitive in early renal impairment), RRM2—after multi-center validation—may address early DKD diagnosis gaps. At the mechanistic level, through a series of experiments including high glucose stimulation, RRM2 overexpression, and pathway inhibition, the study clearly demonstrates that the protective effect of RRM2 relies on activation of the PI3K/Akt/Nrf2 pathway. In particular, the rescue experiment—in which the protective effect is abrogated by blocking the pathway with LY294002 (a specific PI3K inhibitor)—not only makes the mechanistic conclusion more convincing but also provides a clear target for the development of subsequent targeted drugs. Other researchers have also explored the biological functions of RRM2. Zuo et al[6] believed that RRM2, a core small subunit of ribonucleotide reductases, plays an indispensable role in nucleotide metabolism. Specifically, it catalyzes the conversion of ribonucleotides to deoxyribonucleotides, a rate-limiting step that sustains intracellular deoxyribonucleoside triphosphate pools; these pools are critical for ensuring the fidelity of DNA biosynthesis, repair, and replication under physiological conditions. Beyond its canonical role in DNA metabolism, Lu et al[4] reported that RRM2 may mitigate ferroptosis in renal tubular cells by inhibiting labile iron accumulation and lipid peroxidation. Furthermore, RRM2-mediated activation of the PI3K/Akt/Nrf2 pathway is likely to enhance the transcription of antioxidant genes (e.g., HO-1) and ferroptosis-inhibitory (e.g., GPX4) genes, thereby strengthening renal protection in DKD.

However, from the perspectives of scientific research rigor and the practicality of clinical translation, there are several aspects that deserve further discussion. First, the clinical study employed a cross-sectional design, which merely demonstrates an association between RRM2 levels and DKD, but fails to establish the causal relationship that “a decrease in RRM2 leads to DKD progression”. For example, could there be other factors (such as inflammatory factors or metabolic disorders) that concurrently modulate RRM2 expression and induce renal tubular injury? Conducting prospective cohort studies in the future to track the association between dynamic changes in RRM2 levels in diabetic patients and the DKD risk would render the conclusions more robust. Second, the cell experiment did not rule out the interference of a hyperosmotic environment. The study used high glucose (30 mmol/L) to treat HK-2 cells to simulate the pathological environment, but did not set up an osmotic control (such as mannitol). Thus, it is impossible to determine whether the observed changes in ferroptosis are caused by high glucose alone or the combined effect of the hyperosmotic environment, which may have a certain impact on the accuracy of mechanistic interpretation. Third, the clinical samples were from a single center, and the study did not analyze whether the patients had comorbidities such as hypertension and hyperlipidemia, which may affect RRM2 expression and DKD progression. Consequently, the generalizability of findings based on single-center data is limited. If populations from different regions with different baseline characteristics can be included for external verification, the generalizability of RRM2 as a diagnostic biomarker for DKD will be more clearly demonstrated.

Despite these areas for refinement, the study offers valuable insights for DKD mechanistic research; it not only provides a novel “molecular clue” for DKD mechanism research but also establishes a research framework of “basic mechanism—clinical biomarker—therapeutic target”. To further advance the translation of this research into clinical practice, future scholarly efforts could focus on verifying the improvement effect of RRM2 overexpression on DKD in animal models, as well as developing small-molecule drugs that regulate RRM2 expression—both of which may help deepen understanding of RRM2’s role in DKD pathogenesis and expand its potential for clinical application.