TO THE EDITOR
I read with great interest the recent study by Zheng et al[1], which investigates the effects of aucubin on diabetic neuropathic pain (DNP) and identifies Aldose reductase (also known as AKR1B1) as a key target.
DNP is a common, disabling complication of diabetes, affecting roughly 13%-35% of diabetic patients worldwide[2-4]. DNP arises from hyperglycemia-driven nerve injury and chronic inflammation in the peripheral and central nervous systems[5-7]. Among central mechanisms, spinal microglia have emerged as key mediators: In response to hyperglycaemia and damaged neurons, microglia undergo a metabolic shift toward glycolysis and adopt a pro-inflammatory phenotype, releasing cytokines (tumour necrosis factor-α, interleukin-1β, interleukin-6) that sensitize pain pathways[7,8]. This “immunometabolic” model of DNP is supported by recent studies showing that dysregulated microglial metabolism (e.g., increased glycolysis via hypoxia inducible factor-1α, pyruvate kinase isozyme type M2, or decreased mitochondrial function) amplifies neuroinflammation and pain[9,10].
In addition, aucubin has been shown to engage multiple intracellular signalling cascades that counteract the underlying pathogenic processes of DNP[11-15]. For example, aucubin activates the nuclear factor erythropoietin-2-related factor 2/heme oxygenase 1 antioxidant pathway, thereby suppressing reactive oxygen species (ROS) generation and the downstream nuclear factor kappa-B (NF-κB) signalling pathway in neuronal and glial cells[12]. By inhibiting the nuclear translocation of NF-κB, aucubin suppresses the transcription of pro-inflammatory genes[12]. Moreover, studies have demonstrated that aucubin modulates the members of the mitogen-activated protein kinase family (especially p38 and extracellular regulated protein kinases ½) and the phosphatidylinositol 3-kinase/protein kinase B (AKT) pathway, thus stabilizing mitochondrial function and reducing apoptotic signalling in neural tissues[11,13,15]. Finally, aucubin promotes mitophagy through the PTEN induced putative kinase 1 (PINK1)/parkin axis, thereby helping clear damaged mitochondria and restore metabolic homeostasis in microglia[14]. These convergent signalling events diminish microglial activation, decrease inflammatory cytokine release and restore oxidative phosphorylation, all of which are pivotal to alleviating DNP.
The AKR1B1 is another established contributor to diabetic complications[16,17]. Under hyperglycemia, AKR1B1 converts excess glucose to sorbitol (then fructose), causing osmotic stress, oxidative injury and pro-inflammatory signaling[18,19]. In animal models, AKR1B1 inhibitors (e.g. epalrestat) reduce sorbitol accumulation and ameliorate neuropathy, and polymorphisms in the aldose reductase gene are linked to neuropathic pain susceptibility[20-23]. Thus, AKR1B1 bridges metabolic dysregulation and inflammation in diabetes, making it a compelling target for DNP therapy.
Aucubin is a plant-derived iridoid glycoside with known anti-oxidative and anti-inflammatory properties[24,25]. Prior work has shown that aucubin alleviates inflammatory and neuropathic pain in rodents by suppressing glial activation and promoting cellular protective pathways[14,26]. For example, Yao et al[14] found that aucubin markedly reduced glial-mediated complete Freund’s adjuvant inflammatory pain via enhancing mitophagy (PINK1/parkin pathway) and lowering cytokine release. Given this background, Zheng et al’s investigation of aucubin in DNP is of high interest, as it links a natural compound, microglial metabolism and the aldose reductase pathway in the context of diabetic pain[1]. The authors report that aucubin markedly reduced pain and anxiety-like behaviors in streptozotocin (STZ)-induced diabetic mice and normalized microglial metabolism and inflammatory markers. Their integration of behavioral assays with molecular and bioinformatic analyses is commendable, and the work addresses the timely question of how metabolic regulation in microglia contributes to neuropathic pain. This letter offers a balanced discussion of the study’s strengths and limitations, focusing on mechanistic interpretation of AKR1B1’s role in microglial glycolysis and the translational implications of the findings.
STRENGTHS AND METHODOLOGICAL INNOVATIONS
Zheng et al[1] used the STZ-induced diabetes mellitus model in mice to systematically evaluate the behavioural and cellular outcomes of using aucubin in DNP treatment. They demonstrated that aucubin treatment significantly ameliorates mechanical allodynia, thermal hyperalgesia and anxiety-like behaviour in diabetic mice. These behavioural improvements are closely associated with normalization of the metabolic and inflammatory status of microglia in both STZ-treated animals and glucose-exposed microglial cultures.
Rather than detailing procedural techniques, the study effectively connects these behavioural and cellular findings to a coherent mechanistic framework. Aucubin was found to suppress microglial aerobic glycolysis and the expression of inflammatory cytokines hallmarks of neuroinflammation in DNP thereby restoring homeostasis. This supports the emerging notion that glycolytic reprogramming is a driver of microglia-mediated pain signalling in metabolic diseases.
An Innovative aspect of the study is the integration of computational and experimental strategies to identify aucubin’s molecular targets. Through network pharmacology and molecular docking, AKR1B1 was identified as the most plausible functional target, having a higher binding affinity for aucubin than matrix metalloproteinases (MMP) 2/9 do. This prediction was biologically validated by showing that aucubin downregulates AKR1B1 expression in the microglia of diabetic mice and that genetic silencing of AKR1B1 abrogates aucubin’s metabolic and anti-inflammatory effects. Thus, AKR1B1 emerges as a key node linking hyperglycaemia to microglial activation.
The study’s comprehensive design spanning in vivo phenotyping, metabolic flux assessment and gene/protein expression analyses provides robust evidence supporting the proposed mechanism. Importantly, aucubin’s effects were consistent across both in vivo and in vitro systems, strengthening its translational potential. Nevertheless, a few areas remain to be clarified. It is not yet clear whether aucubin inhibits the enzymatic activity of AKR1B1 or modulates its transcription. Additionally, the functional roles of MMP2/9 were not explored further, and the pharmacokinetics of aucubin were not evaluated, which limits insight into its clinical applicability.
In summary, the study boasts several strengths: (1) A multimodal approach linking behavior to cellular metabolism and molecular targets; (2) Identification of aldose reductase as a novel regulator of microglial glycolysis in DNP; (3) Demonstration that a natural compound with anti-oxidant properties can modify this pathway; and (4) Emphasis on both neuropathic pain and anxiety-like behaviors, reflecting the clinical spectrum of DNP. These aspects distinguish it from prior works focusing on single signaling pathways or analgesic endpoints alone.
FUTURE DIRECTIONS
We respectfully offer the following suggestions for future research to strengthen the mechanistic and translational insights.
Elucidate the aldose reductase-glycolysis pathway
Examine the metabolic consequences of AKR1B1 activity in microglia under high glucose (e.g., measure sorbitol/fructose, nicotinamide adenine dinucleotide levels) and determine how these changes signal to glycolytic enzymes or transcription factors. Investigate whether known aldose reductase replicate aucubin’s effects on microglial metabolism and inflammation.
Direct assays assessing AKR1B1 activity should be performed using purified recombinant AKR1B1 protein and one of its canonical substrates (e.g., glyceraldehyde) in the presence and absence of aucubin to determine kinetic parameters (IC50, Ki, etc.) and confirm whether aucubin acts as a competitive or non-competitive inhibitor.
Validate in primary cells and in vivo
Perform similar glycolytic flux and cytokine assays in primary microglia (mouse or human induced pluripotent stem cells-derived) and consider using conditional AKR1B1 knockout mice to assess pain and metabolic outcomes. This would confirm that findings in BV-2 cells translate to native microglia.
Assess pharmacological properties of aucubin
Determine aucubin’s blood and central nervous system bioavailability, half-life, and optimal dosing in animal models. Compare its efficacy to benchmark aldose reductase inhibitors in alleviating DNP symptoms.
Explore additional targets
Investigate the roles of MMP2, MMP9 or other predicted targets in the model, as these proteases have known involvement in pain signaling. This could clarify whether aucubin’s benefits involve multiple pathways.
Expand outcome measures
In future studies, include neuronal electrophysiology, glial markers, or imaging of neuroinflammation to see if AKR1B1 inhibition has broader effects on the nervous system, beyond microglial glycolysis.
COMPARISON WITH EXISTING LITERATURE
Zheng et al’s findings fit into a rapidly evolving landscape of pain research that emphasizes immunometabolism[1]. For example, Li et al[27] showed that Sirt3 downregulation in diabetic spinal microglia increases aerobic glycolysis and inflammation, exacerbating DNP; rescuing Sirt3 (or using metformin to block Akt/FOXO1) improved pain[26]. Similarly, Kong et al[28] identified the kinase Lyn as a promoter of glycolysis in spinal microglia after nerve injury: Lyn upregulation drove IRF5-mediated transcription of glycolytic genes and pro-inflammatory polarization, whereas a Lyn inhibitor (Bafetinib) reduced both glycolysis and pain behaviors. More recently, Hua et al[9] reported that PRMT6, a methyltransferase, is elevated in the spinal cord after nerve injury, stabilizing hypoxia inducible factor-1α and boosting pyruvate kinase isozyme type M2-driven glycolysis in microglia; PRMT6 inhibition lowered glycolysis and relieved pain and neuroinflammation[8]. Another group found that TNFAIP8 L2 (TIPE2) modulates microglial metabolism: Overexpression of TIPE2 shifted microglia from glycolysis toward oxidative phosphorylation and suppressed inflammatory activation, alleviating neuropathic pain[9].
Compared to these studies, the current work by Zheng et al[1] is novel in linking the polyol pathway to microglial immunometabolism. While the above reports highlight intrinsic cell regulators (Sirt3, Lyn, PRMT6, TIPE2) of glial metabolism, Zheng et al[1] implicates an extracellular metabolic factor: Aldose reductase. In essence, aucubin’s inhibition of AKR1B1 appears to prevent excess fructose production and ROS that would otherwise reprogram microglia toward glycolysis and inflammation. This raises a unique cross-talk: Diabetic metabolic dysregulation (polyol flux) drives central immune cell metabolism. In contrast, other interventions like curcumin broadly suppress neuroinflammation-curcumin has been shown to reduce pain hypersensitivity by inhibiting spinal microglial and astrocyte activation[29,30]-but the precise metabolic target was unclear. Aucubin’s advantage is that it addresses both systemic glucose imbalance and microglial activation. Finally, the use of a phytochemical aligns with growing interest in natural products for neuropathy; indeed, numerous reviews note that plant-derived compounds (e.g. curcumin, resveratrol, berberine) can modulate pain pathways[31]. However, few have been shown to specifically correct glial metabolism via aldose reductase. Thus this study’s novelty lies in identifying AKR1B1 as the mechanistic bridge and demonstrating a concrete effect of a plant glycoside on this axis.
CLINICAL RELEVANCE
The findings of Zheng et al[1] carry substantial translational promise for DNP. Current treatments antidepressants, antiepileptics and topical agents often provide only partial relief and bring with them significant side effects. AKR1B1 is already a validated target in diabetic complications: For example, the aldose reductase inhibitor epalrestat is used clinically in Japan to slow neuropathy progression and newer inhibitors such as ranirestat are in clinical trials. If aucubin or its optimized analogues can be shown to directly inhibit AKR1B1 (via enzyme assays) and restore microglial homeostasis in primary-cell models, while also demonstrating blood-brain barrier penetration and favourable pharmacokinetics, they can become novel therapeutic agents for DNP.
Importantly, Zheng et al[1] report that aucubin not only reverses mechanical and thermal hypersensitivity but also alleviates anxiety-like behaviour in diabetic mice, addressing the frequent comorbidity of mood disturbances in DNP. Aucubin’s established safety profile given its prevalent use in traditional medicinal herbs may accelerate its clinical development. Early-phase human trials could measure safety, target engagement (e.g., peripheral sorbitol/fructose ratios) and preliminary analgesic efficacy using quantitative sensory testing. Ultimately, combining AKR1B1 inhibition with rigorous glycaemic control could offer a dual benefit limiting both metabolic flux and neuroinflammation thereby advancing treatment beyond symptomatic relief to address core DNP pathophysiology.
CONCLUSIONS
Zheng et al[1] provide compelling evidence that aucubin mitigates DNP by suppressing AKR1B1-mediated microglial glycolysis and inflammation. We note that the authors’ original discussion of these results is comprehensive and well-contextualized, further reinforcing the validity of their conclusions. The work is scientifically rigorous and logically consistent, fitting well within the emerging literature on microglial immunometabolism. Compared to prior studies, it is novel in identifying aldose reductase as the central node linking hyperglycaemia to neuroinflammation. Clinically, it reinforces the value of targeting metabolic pathways (the polyol pathway and glycolysis) in DNP treatment. Going forward, it will be important to confirm these findings using other DNP models and to test whether aucubin directly inhibits the enzymatic activity of AKR1B1 or acts via gene regulation. In summary, this study advances our understanding of mechanisms underlying DNP and introduces a promising natural compound for use in DNP therapy.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Endocrinology and metabolism
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade A, Grade B, Grade B
Novelty: Grade A, Grade B, Grade B
Creativity or Innovation: Grade A, Grade B, Grade B
Scientific Significance: Grade A, Grade A, Grade B
P-Reviewer: Pal B; Pandurangan H S-Editor: Fan M L-Editor: A P-Editor: Xu ZH
