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

doi:10.4093/dmj.2025.1232

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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): Song Jie Lu¹, Yi Tong Lin¹, Sheng Chen²; Diabetes & Metabolism Journal 2026;50(3):621-622.
DOI: https://doi.org/10.4093/dmj.2025.1232
Published online: April 30, 2026

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¹Fujian University of Traditional Chinese Medicine, Fuzhou, China

²Department of Ophthalmology, The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China

Corresponding author: Sheng Chen

Department of Ophthalmology, The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou 350016, China E-mail: chenshengwang02@163.com

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.

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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.

We read with great interest the Letter by Jin [1] regarding the pivotal study by Boccella et al. [2] on the effects of ladarixin (LDX), a CXC motif chemokine receptor 1/2 (CXCR1/2) inhibitor, in a streptozotocin (STZ)-induced rat model of type 1 diabetes mellitus (T1DM) and its complications. The authors are to be commended for highlighting the dual potential of targeting the CXC motif chemokine ligand 8 (CXCL8)-CXCR1/2 axis not only in modulating the autoimmune process of T1DM but also in mitigating its microvascular complications, namely peripheral neuropathy and retinopathy. This perspective rightly shifts the focus beyond mere glycemic control towards disease-modifying strategies, an urgent need in diabetes management. We wish to elaborate on several insightful points raised, with a particular emphasis on the implications for diabetic retinopathy (DR) and the intriguing intersection between neuropathic and retinal pathology in diabetes, drawing directly from the compelling data presented in the original article.

First, the authors’ experimental design, which delineates early (weeks 4–8) and late (weeks 8–12) treatment phases post- STZ induction, is particularly elegant and clinically astute [2]. This paradigm elegantly disentangles the disease-modifying potential from the complication-management potential of LDX. It directly models two critical clinical scenarios: intervention in new-onset diabetes versus treatment in established disease with advanced complications. The finding that late LDX failed to reverse hyperglycemia or β-cell loss yet still robustly protected against neuropathy and retinopathy is the study’s most transformative insight. It suggests a therapeutic window for LDX even after metabolic dysfunction is entrenched, addressing a profound unmet need for the vast population living with long-standing T1DM and early complications, where intensive glycemic control often fails to halt disease progression.

Second, the concomitant amelioration of STZ-induced markers in both the retina (e.g., citrullinated histone H3 [CitH3], vascular endothelial growth factor [VEGF], and CD34) and the dorsal root ganglion/sciatic nerve (e.g., tumor necrosis factor-α, interleukin 1β) by late LDX treatment is striking. This parallel protection points to the CXCL8-CXCR1/2 axis as a potential shared ‘neuro-inflammatory’ pathway driving diverse diabetic microvascular complications. It positions LDX not merely as an organ-specific therapy but as a potential ‘multi-complication’ modulator. From an ophthalmic perspective, this raises a fascinating question: does LDX’s benefit in DR stem primarily from modulating resident retinal glia (microglia, Müller cells), inhibiting neutrophil infiltration via NETosis (as suggested by reduced CitH3/myeloperoxidase [MPO]), or protecting the retinal neurons and vasculature directly? The significant reduction in retinal VEGF and CD34 is highly encouraging, suggesting LDX may interfere with early pro-angiogenic signaling.

Third, a nuanced finding from the original data warrants further discussion. Figure 6 [2] shows that late LDX treatment normalized retinal CXCL8 and CXCR1 protein levels, but curiously, not CXCR2. The authors appropriately note the differential biology of these receptors. This specificity could be clinically informative. Does it indicate a predominant effect of LDX on specific retinal cell types (e.g., glia) that primarily express CXCR1, or a differential feedback mechanism between receptors? Clarifying the cellular cytotype-specific regulation of CXCR1/2 in the diabetic retina in response to LDX could refine our understanding of its precise site of action within the neurovascular unit and identify predictive biomarkers for response.

Finally, we fully endorse Jin’s proposed future directions. Investigating dose-response relationships and differential effects on small versus large nerve fibers is crucial. Translating these preclinical findings requires studies that integrate advanced ocular imaging (e.g., optical coherence tomography angiography to quantify vascular changes) with functional assessments (e.g., pattern electroretinogram for ganglion cell function and quantitative sensory testing for neuropathy). This multimodal approach will determine if CXCR1/2 blockade truly preserves function, not just molecular markers. The intriguing dissociation between CXCR1 and CXCR2 regulation also presents a specific mechanistic question for future research.

In conclusion, Boccella et al. [2] have provided robust preclinical evidence that positions CXCR1/2 inhibition as a unique strategy capable of uncoupling complication progression from glycemic control. As ophthalmologists and clinician-scientists, we are particularly encouraged by the prospect of an oral agent that might concurrently address diabetic nerve damage and sight-threatening retinal disease. This work successfully frames LDX not just as a β-cell preservation agent but as a potential multi-target therapy for diabetic complications, meriting vigorous clinical investigation in patients across the spectrum of T1DM, especially those already burdened by its devastating sequelae.

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

REFERENCES

1. 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;49:1351-3.Article PubMed PMC PDF
2. 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.PubMed PMC

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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. 2026;50(3):621-622. Published online April 30, 2026

DOI: https://doi.org/10.4093/dmj.2025.1232

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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)

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Lu SJ, Lin YT, Chen S. 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. 2026;50(3):621-622.

DOI: https://doi.org/10.4093/dmj.2025.1232.

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