First, Dr. Jin makes a meaningful contribution to the interpretation and larger context of our results by emphasizing the diversity/heterogeneity of diabetic peripheral neuropathy (DPN). While our data contribute an initial proof-of-concept that CXC motif chemokine receptor 1/2 (CXCR1/2) blockade has therapeutic potential for DPN to the current literature [2-4], how different DPN patients with unique underlying type 1 diabetes mellitus (T1DM) endotypes or patients with type 2 diabetes mellitus (T2DM) might respond to ladarixin (LDX) treatment for their DPN symptoms remains to be elucidated. Interestingly, the letter highlights that in T2DM, unlike in T1DM, initial DPN symptoms can appear unrelated to hyperglycemia levels. Based on this observation, we fully agree that extending our findings to T2DM is an essential step.

As Dr. Jin correctly emphasized, streptozotocin (STZ) has both diabetogenic and potential direct neurotoxic effects. We acknowledge that it might represent a limitation of the current model and we are considering complementary approaches in future studies, including genetic models of autoimmune diabetes, to better define the relative contributions of hyperglycemia and direct toxicity.

Moreover, we agree that evaluating different doses of LDX and various STZ protocols could provide important information regarding the therapeutic window and mechanism of action. Future studies will be designed to explore whether different dosing strategies influence both glycemic control and peripheral nerves and retinal structures.

We would also like to discuss the preferential protection of LDX on small or large nerve fibers that is also highly relevant [5-7]. In our ongoing experiments, we are including more detailed neurophysiological and morphological analysis to address this issue. These data may be helpful in clarifying the role of LDX in affecting pain versus motor components of neuropathic phenotypes.

Finally, the idea of establishing chemokine thresholds for DPN diagnosis and monitoring is persuasive. We plan to expand our chemokine profiling in both serum and neural tissues to investigate whether these molecules could serve as diagnostic or predictive tools.

In conclusion, we are grateful for Dr. Jin’s expert evaluation, which underscores the importance of continuing to investigate the interleukin-8–CXCR1/2 axis not only in β-cell preservation but also in the prevention of diabetic complications. We believe that this line of research, combined with precision medicine approaches, may contribute to the development of new disease-modifying therapies for diabetes.