Kalamara TV, Andreikos DA, Dodos K, Georgiou E, Fotakopoulos G, Foroglou N, Kapoukranidou D, Georgakopoulou VE. MicroRNAs as diagnostic and prognostic biomarkers in chemotherapy-induced peripheral neuropathy: A systematic review. World J Clin Oncol 2026; 17(4): 117460 [DOI: 10.5306/wjco.v17.i4.117460]
Corresponding Author of This Article
Vasiliki E Georgakopoulou, MD, PhD, Department of Pathophysiology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, 17 Agiou Toma Street, Athens 11527, Greece. vaso_georgakopoulou@hotmail.com
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Oncology
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Systematic Reviews
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Apr 24, 2026 (publication date) through Apr 22, 2026
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World Journal of Clinical Oncology
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Kalamara TV, Andreikos DA, Dodos K, Georgiou E, Fotakopoulos G, Foroglou N, Kapoukranidou D, Georgakopoulou VE. MicroRNAs as diagnostic and prognostic biomarkers in chemotherapy-induced peripheral neuropathy: A systematic review. World J Clin Oncol 2026; 17(4): 117460 [DOI: 10.5306/wjco.v17.i4.117460]
Tsampika-Vasileia Kalamara, Konstantinos Dodos, Dorothea Kapoukranidou, Laboratory of Physiology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54124, Kentrikí Makedonía, Greece
Dimitrios A Andreikos, School of Medicine, Democritus University of Thrace, Alexandroupoli 68100, Anatolikí Makedonía kai Thráki, Greece
Elisavet Georgiou, Laboratory of Biological Chemistry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki 54124, Kentrikí Makedonía, Greece
George Fotakopoulos, Nikolaos Foroglou, Department of Neurosurgery, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki 54636, Kentrikí Makedonía, Greece
Vasiliki E Georgakopoulou, Department of Pathophysiology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens 11527, Greece
Co-first authors: Tsampika-Vasileia Kalamara and Dimitrios A Andreikos.
Author contributions: Georgakopoulou VE performed the research and analyzed the data and wrote the manuscript; Kalamara TV and Andreikos DA drafted substantial parts of the manuscript, performed the systematic literature search, participated in study selection (titles/abstracts and full texts), extracted, organized and verified data, contributed to the preparation of tables and figures; contributed to data interpretation; and assisted in its critical revision, and they contributed equally to this manuscript as co-first authors; Kalamara TV, Andreikos DA, Dodos K, and Georgakopoulou VE contributed to the design of the study; Dodos K, contributed to methodology; assisted in data extraction and synthesis, critical appraisal of included studies, participated in drafting and revising the methods and discussion sections; Georgiou E contributed to the interpretation of preclinical and translational data, critically reviewed the manuscript for scientific accuracy and coherence; Fotakopoulos G and Kapoukranidou D critically revised the manuscript for important intellectual content; Fotakopoulos G provided clinical expertise in neuro-oncology and chemotherapy-induced peripheral neuropathy, contributed to the interpretation of the clinical relevance of findings; Foroglou N provided neurosurgical and clinical oncology input, contributed to the interpretation of clinical implications and potential translational applications; Kapoukranidou D provided expertise in physiology and neurobiology, contributed to the interpretation of mechanistic aspects of microRNA involvement in chemotherapy-induced peripheral neuropathy. All authors have read and approved the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Corresponding author: Vasiliki E Georgakopoulou, MD, PhD, Department of Pathophysiology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, 17 Agiou Toma Street, Athens 11527, Greece. vaso_georgakopoulou@hotmail.com
Received: December 8, 2025 Revised: December 26, 2025 Accepted: March 20, 2026 Published online: April 24, 2026 Processing time: 134 Days and 20.4 Hours
Abstract
BACKGROUND
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent, dose-limiting toxicity of neurotoxic antineoplastic agents, yet clinicians lack minimally invasive biomarkers to predict susceptibility, monitor neuroaxonal injury and stratify long-term risk. Circulating microRNAs (miRNAs) are attractive candidates because they integrate stress and injury responses and can be robustly quantified in blood.
AIM
To systematically review human studies evaluating miRNAs as diagnostic or prognostic biomarkers of CIPN.
METHODS
Following PRISMA guidelines, we searched PubMed, Cochrane Library, Scopus and conference proceedings from inception to August 2025 for observational studies including patients with malignant disease treated with neurotoxic chemotherapy, comparing those who developed CIPN with those who did not, and reporting differences in miRNA expression. Data on clinical setting, chemotherapy type, CIPN assessment, miRNA source and quantification methods, and direction of expression changes were extracted. Owing to clinical and methodological heterogeneity, we performed a qualitative synthesis.
RESULTS
Five studies (three prospective cohorts, one case-control, one retrospective) comprising 304 patients (137 with CIPN) were included. Malignancies included breast, gastric and colorectal cancer and multiple myeloma; neurotoxic regimens involved oxaliplatin, paclitaxel and bortezomib. Across studies, 30 unique miRNAs were investigated. In multiple myeloma, miR-191-5p, miR-23a-3p, miR-24-3p, miR-92 and miR-22-3p were upregulated in patients with CIPN, with miR-22-3p showing one of the largest expression differences. In oxaliplatin-treated gastric and colorectal cancer, hsa-miR-378f, hsa-miR-885-5p, hsa-miR-200c-3p, hsa-miR-4666a-3p and miR-3184-5p were downregulated and some correlated with CIPN severity, whereas 21 miRNAs showed no significant differences and paclitaxel-based studies reported no consistent miRNA-CIPN associations.
CONCLUSION
Current human data support the biological plausibility of circulating miRNAs - particularly miR-22-3p, hsa-miR-378f and miR-3184-5p - as candidate diagnostic and prognostic biomarkers for CIPN, but the evidence base remains small and heterogeneous. Standardized, adequately powered, longitudinal studies with harmonized CIPN phenotyping, assay platforms and reporting of effect sizes and predictive accuracy are required before miRNA-based tests can be translated into routine risk stratification and monitoring of CIPN.
Core Tip: This systematic review synthesizes, for the first time, the human evidence on miRNAs as minimally invasive biomarkers of chemotherapy-induced peripheral neuropathy. Across five observational studies, 30 circulating miRNAs were profiled, with a small subset (notably miR-22-3p, hsa-miR-378f and miR-3184-5p) showing differential expression in patients with CIPN. However, inconsistent signals across cancer types and regimens, together with limited sample sizes and heterogeneous methodologies, currently preclude clinical application. The review maps the most promising candidate miRNAs and delineates key design and reporting priorities needed to move miRNA-based CIPN diagnostics and prognostics towards clinical utility.
Citation: Kalamara TV, Andreikos DA, Dodos K, Georgiou E, Fotakopoulos G, Foroglou N, Kapoukranidou D, Georgakopoulou VE. MicroRNAs as diagnostic and prognostic biomarkers in chemotherapy-induced peripheral neuropathy: A systematic review. World J Clin Oncol 2026; 17(4): 117460
Chemotherapy-induced peripheral neuropathy (CIPN) remains one of the most frequent, disabling toxicities of modern systemic therapy, particularly with taxanes, platinums, vinca alkaloids, and proteasome inhibitors, however clinicians lack reliable tools to predict who will be affected or how severe the course will be[1,2]. Across diseases and drug classes, CIPN can require dose modifications and early discontinuation, with downstream consequences for treatment intensity and survival. Currently, no pharmacologic strategy reliably prevents CIPN, and guidelines emphasizes dose modification and symptomatic treatment, with duloxetine providing modest analgesic benefit for neuropathic pain in CIPN[2,3].
CIPN typically manifests as a symmetric, length-dependent sensory neuropathy that begins in the feet and later involves the hands, producing a stocking-glove pattern. Patients describe positive sensory phenomena, tingling, burning, and paroxysmal shooting or “electric” pains, as well as stimulus-evoked pain to light touch (allodynia), which evolve alongside sensory loss with accumulating exposure, involvement of large fibers leads to reduced vibration and joint-position sense, accompanied by hyporeflexia and sensory ataxia that undermine balance and manual dexterity during daily tasks[2,4] (Figure 1). Mechanistically, CIPN is multifactorial and agent-specific, with the data implicating peripheral neuroinflammation, altered neuronal excitability and channelopathy, oxidative stress, mitochondrial injury, cytoskeletal and axonal-transport derangements, and direct dorsal-root-ganglion (DRG) and distal axonal damage[4,5]. Platinums perturb ion-channel function and DRG excitability, taxanes act as noncanonical Toll-like receptor 4 ligands in sensory neurons and glia, and foster chemokine release and macrophage recruitment[6-8]. Paclitaxel triggers early chemokine up-regulation and mitogen-activated protein kinases (MAPK) activation in DRG neurons[9]. Across medications, mitochondrial dysfunction and microtubule-dependent axonal transport failure are recurring injury axes that help explain the distal, symmetric clinical phenotype[4,5] (Figure 2).
In routine practice, CIPN is assessed with clinician-graded toxicity scales, most commonly the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), supplemented by patient-reported instruments such as the QLQ-CIPN20 and PRO-CTCAE[1,10]. However, CTCAE grading shows only moderate inter-rater reliability and limited sensitivity to early change, while prelabor rupture of membranes are more responsive for subjective symptoms yet quantify symptom burden rather than structural nerve injury and can exhibit floor effects at low severity[10-13]. Protein neuroaxonal markers such as neurofilament light show promise as correlates of paclitaxel-related neurotoxicity, yet require more evidence before clinical application[14-16]. Overall, there is a need for minimally invasive biomarkers that enable early detection, monitoring, and prognostication.
MicroRNAs (miRNAs) are potential candidates as they are post-transcriptional regulators with tissue- and context-dependent expression programs that integrate cellular stress responses[17,18]. Evidence has established that circulating miRNAs are measurable in serum and plasma, providing a practical substrate for liquid-biopsy development[19]. Research further codifies how extracellular vesicle, associated miRNAs should be isolated and reported and how quantitative polymerase chain reaction (PCR)-based assays should be designed and documented, reducing noise and enhancing reproducibility for translational biomarker studies. Mechanistically, circulating miRNAs exist not only within vesicles but also in Argonaute (AGO)-bound ribonucleoprotein complexes, broadening the biological routes by which neuronal injury may be reflected in the miRNA biomarkers[20,21]. Primary miRNA transcripts produced by RNA polymerase II are cleaved by the microprocessor complex to generate precursor hairpins, which are exported to the cytoplasm by exportin-5. Dicer ribonuclease III, together with cofactors such as TRBP/PACT, then produces approximately 22-nt duplexes from which a single guide strand is selectively loaded into AGO2 to assemble the effector complex[17,18,22,23]. Within peripheral nerve, neurons and Schwann cells release miRNAs by two carriers, extracellular vesicles and non-vesicular AGO2 ribonucleoprotein complexes. These extracellular species form a local endoneurial pool and, when barrier properties change with injury or inflammation, a fraction enters the circulation, where extracellular vesicle-enriched and AGO2-bound fractions are measurable in plasma or serum[19,20,24-26]. This pathway may link neuronal miRNA to liquid-biopsy readouts in CIPN (Figure 3).
The plausibility of miRNAs as indicators of neurotoxicity is high, as in the peripheral nervous system, miRNAs orchestrate Schwann-cell reprogramming, myelination dynamics, and the response to nerve injury, processes central to axonal integrity and repair[27]. Beyond development and regeneration, discrete miRNA families modulate neuropathic-pain signaling through effects on neuroinflammation, ion-channel expression, and pattern-recognition receptors in primary sensory neurons[28]. Notably, extracellular let-7 miRNAs can directly activate Toll-like receptor 7 in nociceptors and, in experimental systems, precipitate neuronal hyperexcitability and degeneration, linking miRNA dynamics to pain phenotypes via innate immune pathways[29,30]. These converging lines of evidence suggest that chemotherapy-injured neurons, glia, and immune cells could release miRNA signatures that are detectable in biofluids and that mirror the onset, trajectory, and persistence of CIPN. miRNAs have matured across oncology as biomarkers for diagnosis and risk stratification, with multiple clinical studies demonstrating feasible workflows and clinically informative signal in diverse solid tumors[31,32]. The purpose of this systematic review is to critically examine and synthesize the human evidence on miRNAs as diagnostic and prognostic biomarkers for CIPN. By integrating biologic plausibility with a rigorous assessment of clinically data, we aim to clarify the translational readiness of miRNA-based assays for CIPN.
MATERIALS AND METHODS
This systematic review is conducted in accordance with the PRISMA guidelines[33].
Eligibility criteria
The literature search strategy was developed by identifying each element of the PICO framework (Population, Intervention, Comparison, Outcome)[34]. A search was performed for studies involving patients of any age treated with antineoplastic agents for malignant conditions (P) who experienced CIPN (I), comparing them with patients receiving the same agents without CIPN (C). The focus was on reports detailing differences in miRNA levels between the two groups (O). We excluded animal studies, case reports, case series, prior meta-analyses (if available), editorials, opinion papers, and narrative reviews.
Search strategy
We conducted a search of articles published in the electronic databases PubMed, Cochrane Library, Scopus, and gray literature, namely conference proceedings, from their inception until August 2025. No restrictions were placed on sample size, study setting, or publication language. We utilized Medical Subject Headings terms for both the intervention (CIPN) and the outcome (differences in miRNA levels), as well as free-text keywords. Boolean operators “OR” and “AND” were also employed.
Data extraction
After deduplication, two independent reviewers (Kalamara TV, Dodos K) screened all records at the title and abstract level and subsequently assessed the full text of eligible studies. Any disagreements were resolved through consultation with a third reviewer (Dodos K).
Data extraction from the eligible reports was conducted independently by two independent reviewers (Kalamara TV, Dodos K). Relevant information was recorded on a data collection form created in Microsoft Excel (Microsoft Corporation, Redmond, WA, United States). The extracted data included the following: First author, year of study, country of origin, type of malignancy, type of antineoplastic agent administered, number of participants, age and gender of participants, method of CIPN diagnosis, and the type, tissue, calculation method and differences in expression of miRNAs.
The Newcastle-Ottawa Scale[35] was employed by two independent reviewers (Kalamara TV, Dodos K) to assess the quality of the included observational studies. The studies were evaluated from several broad perspectives: Study groups, comparability between groups, and ascertainment of either the exposure or outcomes of interest. Based on this assessment, individual studies could receive up to 4 stars for selection, 2 stars for comparability, and 3 stars for outcomes, with a maximum total score of 9 stars. Any differing opinions among reviewers were resolved through discussion, consensus, or arbitration by a third senior reviewer (Dodos K).
Data synthesis
A meta-analysis was not conducted because of insufficient homogeneity among the studies, variability in outcome measures, and inadequate data. The studies addressing our research question showed significant differences in participant characteristics, with varying diagnoses and types of antineoplastic agents used, and they evaluated different types of miRNAs, making a meaningful quantitative synthesis impossible. Therefore, we chose to present a qualitative summary of the findings to offer a comprehensive understanding of the available evidence.
RESULTS
Data sources and selection process
As shown in the corresponding PRISMA flow diagram (Figure 4), our search strategy retrieved 569 results in total. After deduplication, we initially screened 526 records at the title and abstract level. Of these, 515 records were excluded. The remaining 11 records underwent a detailed full-text assessment. Five of them were eligible for inclusion in the qualitative synthesis[36-40]. Six studies were excluded for various reasons[41-46]. Two studies were excluded because they assessed different outcomes[41,42] and one study was preclinical[43]. Moreover, two studies were excluded as reviews[44,45]. Finally, the study by Kober et al[42] was excluded, as it was designed in order to investigate the role of specific single nucleotide polymorphisms in miRNAs in vincristine-related CIPN[46].
Figure 4 Flow diagram illustrating the study selection process.
Characteristics of the included studies
A comprehensive overview of the participants' baseline characteristics can be found in Table 1. In total, 304 participants were included, of which 137 (45%) diagnosed with CIPN. Of the participants, 74.3% were females. Most studies were prospective cohorts, except for one case-control study[39] and one retrospective study[40]. The research was conducted in various countries, including Ireland, South Korea (two studies), Poland, and Japan. The malignancies investigated comprised breast cancer (two studies), gastric cancer, colorectal cancer, and multiple myeloma, with a range of antineoplastic agents, including oxaliplatin (platinum compound), paclitaxel (taxane) and bortezomib (proteasome inhibitor), being utilized. All the studies used the NCI-CTCAE criteria[47] for CIPN diagnosis. Changes in miRNAs expression levels were assessed in whole blood or plasma samples through quantitative reverse transcription PCR (qRT-PCR) and microarray analysis techniques.
Table 1 Summary of the main characteristics of the studies selected in the systematic review, mean ± SD/median (range)/n (%).
The risk of bias appraised among the included studies is shown in Table 2. Study quality scores ranged from 6 to 7, thus, all of them were of good quality.
Table 2 New Castle Ottawa Scale for quality assessment of observational studies.
In the reviewed studies, a total of 30 unique miRNAs were identified. The expression levels of miRNAs were categorized based on their regulation status. The findings revealed differential expression of specific miRNAs, with instances of downregulation and upregulation linked to CIPN across the studies (Table 3). A total of five miRNAs were identified as upregulated in the study by Łuczkowska et al[39] on multiple myeloma, which included miRNA-191-5p, miRNA-23a-3p, miRNA-24-3p, miRNA-92, and miRNA-22. Additionally, five miRNAs exhibited downregulation in the studies conducted by Ju et al[37] and Ju et al[38] in gastric and colorectal cancer patients, specifically hsa-miR-885-5p, hsa-miR-378f, hsa-miR-200c-3p, hsa-miR-4666a-3p, and miR-3184-5p. Furthermore, 21 miRNAs showed no significant difference in their expression levels. This category includes miRNAs evaluated in the studies by Ju et al[37], Davey et al[36] and Noda-Narita et al[40], comprising miR-222-3p, Let-7a, miR-21, miR-145, miR-155, miR-195, miR-451a, miR-6849-5p, miR-1290, miR-4476, miR-204-3p, miR-6846-5p, miR-6870-5p, miR-5008-5p, miR-1249-5p, miR-6806-5p, miR-4718, miR-619-5p, miR-4462, and miR-4539. Notably, miR-23a-3p was common between the studies by Łuczkowska et al[39], where it was upregulated, and Noda-Narita et al[40], where no difference in expression was observed. These results showcase the complexity of miRNA regulation in the context of the studied malignancies.
Table 3 Differentially expressed microRNAs associated with chemotherapy-induced peripheral neuropathy and their predicted target genes and biological pathways.
Peptidyl-serine phosphorylation. Regulation of alternative mRNA splicing. Gastric cancer signaling. Neurotrophin signaling. Mitogen-activated protein kinase signaling. Adenosine monophosphate-activated protein kinase signaling
miR-451a: No difference; miR-6849-5p: No difference; miR-1290: No difference; miR-4476: No difference; miR-204-3p: No difference; miR-23a-3p: No difference; miR-6846-5p: No difference; miR-6870-5p: No difference; miR-5008-5p: No difference; miR-1249-5p: No difference; miR-6806-5p: No difference; miR-4718: No difference; miR-619-5p: No difference; miR-4462: No difference; miR-4539: No difference
Qualitative assessment of heterogeneity (Table 4) demonstrates that included studies differed substantially in miRNA detection platforms (microarray, small RNA sequencing, predefined qRT-PCR panels), biological matrices (whole blood, plasma, serum), timing of biospecimen collection, and operationalization of CIPN (grade thresholds, cycle-based definitions, and dichotomization strategies). Although all studies employed NCI-CTCAE criteria, variability in grading cut-offs and assessment timing likely contributed to inconsistent miRNA signals across cancer types and treatment regimens.
Table 4 Qualitative assessment of clinical and methodological heterogeneity across included studies.
Effect size and diagnostic performance of reported miRNAs
Where reported by the primary studies, quantitative effect size measures including fold changes, P values, and diagnostic performance metrics were extracted and are summarized in Supplementary Table 1. In oxaliplatin-treated gastric cancer, Ju et al[37] reported marked downregulation of hsa-miR-378f (fold change -4.62, P = 0.0006), alongside significant reductions in hsa-miR-885-5p, hsa-miR-200c-3p and hsa-miR-4666a-3p. In colorectal cancer patients receiving 5-fluorouracil, leucovorin, and oxaliplatin, hsa-miR-3184-5p showed moderate discrimination for CIPN, with an area under the receiver-operating-characteristic curve (AUC) of 0.78, sensitivity of 73% and specificity of 75%[38]. In multiple myeloma, Łuczkowska et al[39] reported good diagnostic performance for several upregulated miRNAs, with miR-22-3p demonstrating the highest AUC (0.81). In contrast, paclitaxel-based studies did not report consistent or statistically robust effect size estimates after correction for multiple testing[36,40]. Overall, the availability and type of effect size measures varied substantially across studies.
DISCUSSION
This systematic review examined the role of miRNAs in CIPN, highlighting the differential expression of various miRNAs associated with this debilitating condition. The results of this systematic review illuminate the crucial role of miRNAs in relation to CIPN. Our analysis identified a total of 30 unique miRNAs across the studies, revealing a complex landscape of miRNA expression changes associated with CIPN. Specifically, we noted that certain miRNAs were consistently upregulated or downregulated, providing insights into their potential roles in the pathophysiology of CIPN. For instance, the upregulation of miRNAs such as miRNA-191-5p, miRNA-23a-3p, and miRNA-24-3p suggests a possible involvement in neuroinflammatory processes or cellular stress responses, which are known contributors to neuropathic pain[48].
It is of significant interest that the case-control study by Łuczkowska et al[39] underscores the increased expression of miR-22-3p as a significant marker for CIPN in patients with multiple myeloma, noting one of the largest differences in expression between the neuropathic group and controls. The study mentions that miR-22-3p regulates over 600 genes and highlights its extensive influence on various biological processes. Further analysis revealed that these target genes play critical roles in neurogenesis (e.g., NTRK2, NYAP2, ERBB3, SNAP91), neuronal differentiation (e.g., ERBB4, GLDN, NFIB), and neuron generation (e.g., GLDN, HIPK1, WNT1). Furthermore, the involvement of miR-22-3p in cell differentiation, chromatin organization, and histone modification suggests a multifaceted role in neuronal health. These insights not only position miR-22-3p as a promising biomarker for CIPN, but also open avenues for exploring its potential as a therapeutic target in neuropathic conditions.
Importantly, the biological plausibility of these associations is reinforced by established functional roles of several identified miRNAs in pathways directly implicated in CIPN pathogenesis. miR-22-3p has been shown to regulate key mediators of oxidative stress and mitochondrial homeostasis, including sirtuin 1 and specificity protein 1, thereby influencing redox balance, neuronal survival, and stress resilience. Dysregulation of miR-22-3p may thus exacerbate chemotherapy-induced mitochondrial dysfunction and oxidative injury in dorsal root ganglion neurons, a central mechanism in platinum- and proteasome-inhibitor-related neurotoxicity. In parallel, miR-22-3p has been linked to apoptotic signaling and neuronal differentiation pathways through targets such as TP53INP1, NTRK2, and ERBB family members, aligning with observed neuroaxonal degeneration in CIPN[27,28,39].
Similarly, downregulated miRNAs identified in oxaliplatin-treated cohorts plausibly intersect with known injury pathways. hsa-miR-200c-3p is a well-characterized regulator of epithelial-mesenchymal transition, cytoskeletal remodeling, and neuronal apoptosis, with documented involvement in oxidative stress responses and MAPK-dependent cell-death signaling. Its suppression may therefore facilitate maladaptive stress responses and apoptotic vulnerability of sensory neurons under cumulative chemotherapy exposure. hsa-miR-378f, which demonstrated one of the strongest associations with CIPN severity, targets genes involved in mitochondrial metabolism, AMP-activated protein kinase signaling, and pain-related pathways, providing a mechanistic link between metabolic stress, altered neuronal excitability, and clinical neuropathic symptoms[37].
Conversely, downregulated miRNAs may indicate disrupted regulatory pathways essential for neuronal health and function. Τhe first study by Ju et al[37] indicates the role of miRNA expression in gastric cancer patients undergoing chemotherapy with oxaliplatin, identifying four miRNAs with reduced expression - hsa-miR-378f, hsa-miR-885-5p, hsa-miR-200c-3p, and hsa-miR-4666a-3p. Remarkably, hsa-miR-378f was significantly correlated with the severity of CIPN symptoms, suggesting its critical involvement in CIPN mechanisms. Bioinformatics analyses revealed that target genes of hsa-miR-378f are linked to important biological pathways, including apoptosis and pain signaling pathways such as MAPK and AMP-activated protein kinase. These findings indicate the potential of miRNAs as biomarkers and therapeutic targets for managing CIPN in gastric cancer patients receiving oxaliplatin-containing chemotherapy.
Additionally, a second study by Ju et al[37] explored the role of circulating miRNAs as potential biomarkers for predicting CIPN in colorectal cancer patients undergoing oxaliplatin treatment. Specifically, miR-3184-5p emerged as significantly downregulated in patients who received six or more cycles of oxaliplatin. Functional analyses of target genes associated with miR-3184-5p revealed their involvement in immune response and actin cytoskeleton dynamics, which are relevant to pain mechanisms in CIPN. Additionally, the study observed increased cortisol levels with the progression of chemotherapy, suggesting a link between stress responses and neuropathic pain. Overall, these findings position miR-3184-5p as a promising biomarker for CIPN.
The presence of miR-23a-3p in both upregulated[39] and non-differential[40] expression categories across studies highlights the complexity and context-dependent roles of miRNAs in CIPN. This duality may reflect variations in the biological environment or methodological differences in the studies. In the study by Łuczkowska et al[39], the focus was on multiple myeloma with a median age of participants around 65 years, while Noda-Narita et al[40] examined breast cancer in a younger cohort, with a median age range of 34 years to 74 years. The differences in cancer types, treatment regimens (bortezomib in the former and paclitaxel in the latter), and demographic factors such as age and gender distribution could be factors contributing to the variability in miRNA expression.
Moreover, the methodologies employed for miRNAs quantification - microarrays and qRT-PCR in the first study and microarray hybridization in the second - might also account for discrepancies in results. These findings emphasize the necessity for further investigation into the functional roles of these miRNAs and their interactions in the neurotoxicity landscape.
In reviewing the studies that investigated the effects of paclitaxel on CIPN, both Davey et al[36] and Noda-Narita et al[40] reported no significant differences in miRNA expression between patients with CIPN and those without. Davey et al[36] conducted a prospective cohort study with 101 participants, primarily female breast cancer patients, using whole blood samples analyzed via qRT-PCR. Similarly, Noda-Narita et al[40] performed a retrospective cohort study involving 84 breast cancer patients, utilizing plasma samples analyzed through microarray hybridization. In both studies, the lack of significant variation in miRNA expression might suggest that paclitaxel’s effects on CIPN are not mediated by changes in miRNA profiles or that the timing and methods of detection may not have captured relevant differences.
It is of great importance, that the identification of specific miRNAs associated with CIPN could enhance clinical strategies for patient management. By developing miRNA profiling as a routine assessment, healthcare providers could better predict which patients are at higher risk for developing CIPN. This could facilitate timely interventions, such as adjusting chemotherapy regimens or implementing neuroprotective strategies, ultimately improving patient outcomes and quality of life. The stability of miRNAs in biological fluids[49] enhances their suitability as non-invasive biomarkers, making them ideal candidates for further clinical exploration.
In current clinical practice, CIPN risk stratification and monitoring rely mainly on symptom-based grading systems and, less commonly, objective neurophysiological testing. Clinician-reported scales such as the NCI-CTCAE are widely used and feasible, but they show only moderate inter-rater reliability and limited sensitivity to early change, while patient-reported outcome measures (e.g., QLQ-CIPN20 and PRO-CTCAE) are more responsive to subjective symptoms but quantify symptom burden rather than structural nerve injury and may demonstrate floor effects at low severity[10-13]. Nerve conduction studies and related neurophysiological assessments provide objective evidence of large-fiber dysfunction and can support differential diagnosis, yet their routine use in oncology settings is constrained by cost, specialized expertise, patient burden, and limited sensitivity to small-fiber-predominant neuropathy that often contributes substantially to painful CIPN phenotypes[4,5].
Circulating miRNAs offer complementary advantages relative to these tools. As minimally invasive blood-based markers, they are scalable, repeatable across treatment cycles, and may capture early molecular stress or injury responses before clinically overt neuropathy becomes apparent, enabling a potential “lead time” for intensified monitoring or preventive strategies. However, miRNA biomarkers currently face important translational limitations compared with established clinical tools: Variability in biological matrices (serum vs plasma vs whole blood), platform-dependent quantification (microarray, sequencing, qRT-PCR), normalization strategies, and incomplete reporting of effect sizes and diagnostic performance metrics reduce comparability across studies and hinder definition of clinically actionable thresholds[36-40]. Accordingly, the most realistic near-term clinical role for miRNAs is as an adjunct to symptom scoring systems and (where available) objective testing - integrated into multimodal prediction models - rather than as a standalone replacement for established CIPN assessment methods[1,2,10].
Despite the valuable insights gained from this review, there are limitations that warrant consideration. The main limitations of this synthesis stem from the scale and heterogeneity of the evidence base. Only five studies met the inclusion criteria, comprising 304 participants of whom 137 had CIPN, across multiple countries and cancer types, with a female predominance of 74.3%. The cohorts span distinct clinical contexts, breast, gastric, colorectal cancer, and multiple myeloma, and different treatment modalities including oxaliplatin, paclitaxel, or bortezomib. This study heterogeneity precluded quantitative synthesis and constrains biological integration. Outcome ascertainment was based on NCI-CTCAE; the extracted data did not provide harmonized grade thresholds or assessment schedules, impeding alignment of case definitions and the examination of chronicity across reports. The analytic granularity of the miRNA results was limited, as thirty unique candidates were catalogued, twenty-one showed no significant differences, and signals were inconsistent across settings (e.g., miR-23a-3p upregulated in one cohort and unchanged in another). Two paclitaxel studies reported no case-control differences in circulating miRNA expression. Effect sizes with uncertainty and diagnostic or predictive performance metrics were not available in the extracted results, precluding assessment of discrimination, calibration, or clinical utility. The relatively small number of included patients limits the strength and persuasiveness of the evidence and precludes quantitative synthesis; therefore, the identified miRNA signals should be considered exploratory and require validation in larger, standardized cohorts. Collectively, these features limit the precision and generalizability of inferences that can be drawn from the current literature.
Future studies should aim to standardize the methods used for miRNA analysis to facilitate comparability across research. Large, longitudinal studies that track miRNA levels before and after chemotherapy initiation could provide deeper insights into their role in CIPN development. Furthermore, exploring the functional mechanisms of these miRNAs in neuronal pathways may unravel novel therapeutic targets to mitigate CIPN. By advancing our understanding of miRNA dynamics in CIPN, we can pave the way for improved treatment strategies that enhance patient outcomes and quality of life during antineoplastic therapy.
CONCLUSION
In summary, our systematic review highlights the intricate involvement of miRNAs in CIPN and their potential as diagnostic and prognostic biomarkers. Our analysis identified a complex landscape of miRNA expression changes associated with CIPN, with specific miRNAs demonstrating distinct upregulation or downregulation patterns linked to various malignancies and antineoplastic agents. Notably, miRNAs such as miR-22-3p and hsa-miR-378f show promise in reflecting the underlying biological processes contributing to CIPN, suggesting their utility in predicting patient susceptibility and guiding treatment interventions. The identification of specific miRNAs with altered expression patterns provides valuable insights into the underlying mechanisms of neurotoxicity associated with various chemotherapeutic agents.
Given the high prevalence of CIPN and its significant impact on patient quality of life, the potential of these miRNAs as diagnostic and prognostic biomarkers is particularly promising. The ability to predict which patients are at higher risk for developing CIPN could lead to earlier interventions and more personalized treatment strategies, ultimately enhancing therapeutic outcomes.
By advancing our understanding of the relationship between miRNAs and CIPN, we can contribute to the development of innovative approaches aimed at preventing and managing this debilitating condition, thereby improving the overall patient experience during antineoplastic therapy.
To translate these signals into clinically usable tools, next-generation studies should follow a stepwise validation pathway. First, candidate miRNAs identified here (e.g., miR-22-3p, hsa-miR-378f, miR-3184-5p) should be verified using analytically robust, scalable assays suitable for clinical laboratories, such as standardized qRT-PCR panels or digital droplet PCR with pre-specified normalization strategies and external spike-in controls, ideally performed in a central reference laboratory to reduce inter-site technical variability. Second, multicenter prospective cohorts should collect baseline samples prior to neurotoxic chemotherapy and serial samples at harmonized exposure milestones (cycle-based and cumulative-dose-based) and during follow-up to capture persistence. CIPN phenotyping should be standardized by combining clinician grading (e.g., NCI-CTCAE) with patient-reported outcomes (e.g., QLQ-CIPN20/PRO-CTCAE) and, where feasible, objective measures (quantitative sensory testing and/or nerve conduction studies), enabling consistent case definitions and severity trajectories. Third, biomarker performance should be evaluated with predefined endpoints and reporting of discrimination and calibration (AUC with confidence intervals, effect sizes, and correction for multiple testing), followed by external validation in an independent cohort and assessment of clinical utility (e.g., risk stratification thresholds linked to dose modification, intensified monitoring, or preventive strategies). Such collaborative, harmonized designs would provide the evidence required to move miRNA-based assays from biological plausibility to clinically credible prediction and monitoring of CIPN.
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