Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005)

Heung Yong Jin

doi:10.4093/dmj.2025.0801

Articles

Page Path: HOME > Diabetes Metab J > Volume 49(6); 2025 > Article

Letter Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005): Heung Yong Jin; Diabetes & Metabolism Journal 2025;49(6):1351-1353.
DOI: https://doi.org/10.4093/dmj.2025.0801
Published online: November 1, 2025

2,078 Views
32 Download
1 Web of Science
1 Crossref
1 Scopus

Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Clinical Medicine of Jeonbuk National University Medical School-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea

Corresponding author: Heung Yong Jin

Division of Endocrinology and Metabolism, Department of Internal Medicine, Jeonbuk National University Medical School, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Korea E-mail: mdjinhy@jbnu.ac.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

prev next

Full Article

Download PDF

NOTES
REFERENCES
About this article

See the reply "Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005)" in Volume 49 on page 1356.

See the article "Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat" on page 990.

Current therapies for type 1 diabetes mellitus (T1DM) rely heavily on lifelong insulin replacement, which remains essential for glycemic control and survival. However, these treatments neither fully prevent long-term complications nor preserve residual β-cell function. This limitation highlights the urgent need for disease-modifying treatments that address the underlying autoimmune process in T1DM [1]. Recent advances in immunotherapy, such as anti-CD3 antibodies, have shown encouraging results in delaying the onset of T1DM in high-risk individuals. Emerging approaches including antigen-specific immunotherapy, regulatory T-cell enhancement, and cytokine-targeting agents aim to preserve endogenous insulin production and limit immune-mediated β-cell destruction. Early intervention, particularly during the pre-symptomatic phases of T1DM, is increasingly viewed as a critical window for effective immunomodulation [1]. However, challenges remain in accurately identifying at-risk individuals and ensuring the long-term safety and efficacy of these therapies. Moving forward, the development of personalized prevention strategies and β-cell preservation techniques is essential, as this research will be central to transforming the T1DM treatment landscape and preventing chronic complications. Therefore, efforts like those made by this study are highly important for patients with T1DM.

Previously, Piemonti et al. [2] reported that ladarixin (LDX), a CXC motif chemokine receptor 1/2 (CXCR1/2) inhibitor, did not lead to significant long-term improvements in β-cell function or glycemic control in patients with newly diagnosed T1DM. They observed a transient increase in C-peptide levels in some participants; however, this effect was not maintained during the research period. Based on these findings, they concluded that while the overall therapeutic benefit appears limited, short-term immunomodulatory effects may occur in certain subgroups. This study emphasized the need for further studies to clarify LDX’s potential role and the complexity of interleukin 8 and its receptors CXCR1/2 in T1DM, especially in early-stage T1DM [2]. A comprehensive overview of the broader therapeutic potential of targeting the CXC motif chemokine ligand 8 (CXCL8)–CXCR1/2 axis in T1DM was presented by Fousteri et al. [3]. In this work, the authors summarized how modulation of this pathway may extend beyond reducing neutrophil-mediated islet inflammation to include effects on immune regulation, β-cell stress responses, and tissue remodeling. They highlight the promise of early CXCR1/2 blockade in slowing disease progression and preserving β-cell mass, particularly in individuals at risk or in the early stages of T1DM. This review effectively consolidates the current understanding and positions CXCL8 and CXCR1/2 inhibition as a valuable adjunct to existing immunotherapeutic strategies in T1DM [3].

In addition, within the spectrum of diabetic complications, diabetic peripheral neuropathy (DPN) stands out as a notably diverse condition, shaped by a convergence of factors including metabolic irregularities, oxidative burden, mitochondrial impairment, chronic immune activity, and inflammatory cascades. According to Yang et al. [4], this complexity results in varied disease progression and treatment responses across diabetic patients. This review emphasized that while current pharmacological therapies target neuropathic pain, they fail to address the underlying mechanisms of nerve injury or halt disease progression. The authors highlighted the need for novel, mechanism-based therapies that move beyond symptomatic relief. Consequently, there is a pressing call for therapies that are rooted in pathophysiological mechanisms rather than mere symptom control. Forward-looking strategies such as individualized treatment plans based on molecular profiling, targeted repair of nerve structures, modulation of Schwann cell activity, and control of neuroimmune interactions are expected to shift the treatment paradigm [4].

However, despite encouraging findings from certain preclinical and clinical studies about the role of chemokines in DPN, and although new insights into the role of chemokines and their receptors in neuropathic pain have been suggested [5-7], the overall evidence base for chemokine-targeted therapies in DPN is still insufficient. However, as suggested by this study of Boccella et al. [8] , research on the therapeutic role and potential of CXCL8 and CXCR1/2 inhibition is still emerging as a novel therapeutic approach in DPN. In investigating DPN, the type of diabetes and the specific subtype of the condition are helpful to better understand the disease and develop targeted treatment strategies [9,10]. DPN in T1DM and type 2 diabetes mellitus (T2DM) differ in early metabolic abnormalities, structural progression, and pathological features. DPN in T2DM presents with milder, initially reversible functional defects despite similar hyperglycemia, while DPN in T1DM progresses more severely in the late structural phase. These differences are linked to variation in insulin signaling, affecting neurotrophic factor expression, neuro-skeletal and adhesive proteins, and nociceptive peptides [9]. In addition, DPN in T2DM is characterized by the combined effects of chronic hyperglycemia, insulin resistance, and associated comorbidities such as obesity and dyslipidemia. Based on these findings, more refined strategies aimed at individualizing treatment based on diabetes type and providing disease-modifying benefits are warranted in the management of DPN [11]. Besides, DPN is not a uniform entity but a spectrum of clinical phenotypes—painful, painless (asymptomatic), mixed, and motor-dominant—each driven by distinct pathophysiological mechanisms. Advanced diagnostic tools that will facilitate accurate phenotypic characterization and enable clinicians to better match therapeutic strategies to individual patient profiles are required for advanced DPN management in the future. Therefore, tailoring treatment with a shift toward precision medicine, involving both pharmacological and non-pharmacological interventions is also suggested for DPN management based on specific phenotypes [9].

While this study of Boccella et al. [8], offers important and encouraging insights into the therapeutic potential of LDX in a streptozotocin (STZ)-induced T1DM model, further well-designed research will be valuable in strengthening the evidence base and exploring LDX’s broader applications in T1DM and DPN. First, the study does not address whether varying doses of LDX produce differential effects on glycemic control or peripheral nerve protection. Additionally, investigating whether LDX’s efficacy varies according to the severity of diabetes by different STZ dosages could help clarify its mechanism of action. Second, it would also be informative to determine whether LDX can be preferentially effective for small or large nerve fibers or both in DPN. Sometimes, the interpretation of latestage sensory test responses warrants caution, as they could reflect not only therapeutic effects but also the natural course of worsening in DPN with reduced sensitivity over time. Furthermore, distinguishing between the impact of sustained hyperglycemia and direct neurotoxicity of STZ in this STZ-induced diabetes model warrants careful attention in DPN research. Lastly, future studies should explore whether a specific chemokine threshold can be established for diagnosing DPN and whether these findings can be applied to DPN in T2DM.

NOTES

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Henriques FL, Buckle I, Forbes JM. Type 1 diabetes mellitus prevention: present and future. Nat Rev Endocrinol 2025;21:608-22.Article PubMed PDF
2. Piemonti L, Keymeulen B, Gillard P, Linn T, Bosi E, Rose L, et al. Ladarixin, an inhibitor of the interleukin-8 receptors CXCR1 and CXCR2, in new-onset type 1 diabetes: a multicentre, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 2022;24:1840-9.PubMed PMC
3. Fousteri G, Jones M, Novelli R, Boccella S, Brandolini L, Aramini A, et al. Beyond inflammation: the multifaceted therapeutic potential of targeting the CXCL8-CXCR1/2 axis in type 1 diabetes. Front Immunol 2025;16:1576371.Article PubMed PMC
4. Yang Y, Zhao B, Wang Y, Lan H, Liu X, Hu Y, et al. Diabetic neuropathy: cutting-edge research and future directions. Signal Transduct Target Ther 2025;10:132.Article PubMed PMC PDF
5. Zhang Y, Li C, Wang Z, Wang T, Zhou Y, Zheng L, et al. Blocking CXC motif chemokine ligand 2 ameliorates diabetic peripheral neuropathy via inhibiting apoptosis and NLRP3 inflammasome activation. Biol Pharm Bull 2023;46:672-83.PubMed
6. Pawlik K, Mika J. Targeting members of the chemokine family as a novel approach to treating neuropathic pain. Molecules 2023;28:5766.Article PubMed PMC
7. Baldimtsi E, Papadopoulou-Marketou N, Jenmalm MC, Wahlberg J. The role of chemokines in type 1 diabetes-associated neuropathy. Endocrinol Diabetes Metab 2023;6:e419.Article PubMed PMC
8. Boccella S, Morace AM, Giorgio C, Guida F, Perrone M, Manzo I, et al. Effects of CXCR1/2 blockade with ladarixin on streptozotocin-induced type 1 diabetes mellitus and peripheral neuropathy and retinopathy in rat. Diabetes Metab J 2025;49:990-1005.Article PubMed PMC PDF
9. Sima AA, Kamiya H. Diabetic neuropathy differs in type 1 and type 2 diabetes. Ann N Y Acad Sci 2006;1084:235-49.Article PubMed
10. Lee JE, Won JC. Clinical phenotypes of diabetic peripheral neuropathy: implications for phenotypic-based therapeutics strategies. Diabetes Metab J 2025;49:542-64.Article PubMed PMC PDF
11. Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol 2012;11:521-34.Article PubMed PMC

Figure & Data

References

Citations

Citations to this article as recorded by

Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005)
Song Jie Lu, Yi Tong Lin, Sheng Chen
Diabetes & Metabolism Journal.2026; 50(3): 621. CrossRef

PubReader
ePub Link

Cite this Article

Cite this Article: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005)

Diabetes Metab J. 2025;49(6):1351-1353. Published online November 1, 2025

DOI: https://doi.org/10.4093/dmj.2025.0801

XML Download

Related articles

Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005)

About this article

Jin HY. Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat (Diabetes Metab J 2025;49:990-1005). Diabetes Metab J. 2025;49(6):1351-1353.

DOI: https://doi.org/10.4093/dmj.2025.0801.

Download citation ↓