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.