Oxaliplatin-induced peripheral neuropathy: from pathogenesis to treatment.

Introduction
Since the 1970 s, with the discovery of cisplatin, platinum-based chemotherapeutics have merged and been widely applied in cancer chemotherapy [1, 2]. Platinum-induced neuropathy (CIPN) is a common adverse effect of cancer treatment [3, 4]. Neuropathy primarily arises from neuronal damage induced by platinum-based chemotherapy agents, particularly to peripheral nerve damage [1, 5]. With advancements in cancer therapies and prolonged survival, the management of platinum-induced neuropathy has received increasing attention. Oxaliplatin, the third-generation platinum-based chemotherapeutic agent after cisplatin and carboplatin, is the first platinum drug developed to overcome tumor cell resistance [6, 7]. Unfortunately, oxaliplatin-induced peripheral neuropathy (OIPN) remains a major adverse effect, compromising treatment adherence and patients’ quality of life. Furthermore, neurotoxicity persists as a prominent dose-limiting complication, and no validated preventive strategies have been established thus far [8]. This review aims to systematically analyze the clinical manifestations, pathogenesis, prevention, and treatment of OIPN; explore potential risk factors for its progression; and summarize the advancements in novel preventive and therapeutic strategies for OIPN.

Clinical manifestation

Clinical presentations
Oxaliplatin is unique among platinum-based chemotherapeutics in eliciting acute neurotoxicity. Clinically, OIPN is often subdivided into two distinct subtypes, acute and chronic, based on characteristics including incidence, symptomatology, duration, and pathogenesis.
The acute subtype is primarily defined by reversible symptoms of acute peripheral nerve hyperexcitability symptoms, including transient paresthesia, dysesthesia, and muscle cramps triggered predominantly by cold stimulation, which are commonly referred to as cold allodynia (abnormal pain from cold) or hyperalgesia [4]. It occurs in 85%–96% of patients within hours after infusion, lasting for a few days and typically resolving before the next oxaliplatin cycle [9, 10]. Among them, typical symptoms include perioral, pharyngeal, and laryngeal paresthesia/dysesthesia, as well as distal limb sensory disturbances triggered or exacerbated by cold (notably when drinking cold beverages). Uncommon symptoms related to the acute OIPN involve abnormal breathing or swallowing, muscle spasms or cramps, shortness of breath, jaw spasm, and fasciculations [11]. The primary mechanism underlying acute OIPN involves transient impairment of voltage-gated sodium channels (VGSCs) activation in dorsal root ganglion (DRG) sensory neurons, alongside disruptions in voltage-gated potassium channels (VGKCs) similar to those observed in neuromyotonia [12, 13]. These two ion channels are essential for neuronal membrane repolarization, and their dysfunction leads to excessive neurotransmitter release, repetitive neuronal firing, and pathological nerve hyperexcitability. These transient, dose-dependent, and reversible alterations trigger ectopic neuronal excitation, resulting in multiple neuromyotonic-type repetitive discharges and increased refractoriness in motor axons [14]. This mechanism partially accounts for the clinical manifestations of acute OIPN.
The chronic form of OIPN predominantly manifests as chronic sensory axonal neuropathy or neuronopathy characterized by anterograde nonlength-dependent neuronal degeneration [4]. Although the relationship between acute and chronic OIPN manifestations is not fully understood, the severity of acute neuropathy seems to predict the development of chronic neurotoxicity [9, 15]. Retrospective and prospective studies demonstrated that chronic OIPN was associated with threshold cumulative dose in symptomatic patients to range from 850 to 1800 mg/m2 and dose intensity (30.8 to 42.6 mg/m2/week) [16–18]. Findings from prospective clinical studies demonstrated that chronic OIPN occurred in 40%–93% of oxaliplatin-treated patients [4, 8, 9, 19]. Positive sensory symptoms and functional impairment signs typically involve both upper and lower limbs. Prolonged treatment may drive neuronopathy to evolve in nonlength-dependent pattern, affecting additional body segments with sensory ataxia [20]. Chronic OIPN sometimes exhibits fewer clinical neuropathy manifestations, whereas length-dependent “stocking-glove” sensory polyneuropathy signs and symptoms predominate, affecting 50%–70% of patients [4, 20, 21]. Interestingly, in certain cases of oxaliplatin-induced chronic neuropathy, no significant intraepidermal nerve fiber loss was found in either distal or proximal biopsies [22, 23]. These observations corroborate the presence of reversible neurotoxic effects and a length-dependent neuropathic pattern with temporal evolution.

Incidence and range of severity
As summarized in Table 1, the incidence and severity of OIPN vary across studies. Using diverse neurological measures, Phase III and prospective studies report OIPN at Grade 1 (35.7%–63.1%), Grade 2 (18.7%–34.2%), and Grades 3 + (2.8%–22.2%) [24, 25]. These findings highlight that, in addition to the known cumulative dose and cycle-based dose effects on OIPN risk, the diagnostic and ascertainment criteria profoundly influence epidemiological outcomes. The heterogeneity of assessment tools underscores the importance of a formal framework for PIPN definition, classification, and measurement.

Pathogenesis
The pathogenesis of OIPN still remains elusive. The underlying pathogenesis of OIPN remains poorly understood. These clinical presentations of OIPN offer critical insights into investigating and elucidating its pathological mechanisms. Consistent with the clinical classification of OIPN, the molecular mechanisms underlying acute and chronic OIPN are distinct. In acute OIPN, ion channels, transporters, and glial cell dysfunction contribute to acute pain development. In contrast, the key molecular mechanisms underlying chronic OIPN encompass nuclear DNA damage, oxidative stress–induced mitochondrial impairment, and neuroinflammation. Additionally, there appears to be a link between acute oxaliplatin neurotoxicity development and vulnerability to chronic neuropathy; this is particularly intriguing given the disparate toxicity mechanisms.

Ion channel dysfunction
Existing studies suggest that multiple ion channels contribute to the pathogenesis of OIPN. The role of ion channels in the pathogenesis of OIPN is further discussed below, with the mechanism depicted in Fig. 1.

Na+ channel
The Na⁺ channels are central to the regulation of OIPN. Oxaliplatin treatment of DRG increased Na⁺ current and slowed Na⁺ channel inactivation. The accumulation of oxaliplatin metabolite oxalate impairs the functional properties of Na⁺ channels, causing prolonged channel opening and excessive excitation of DRG sensory neurons, and contributing to acute neurotoxicity [8, 9, 46]. Furthermore, administering Na⁺ channel blockers like lidocaine and mexiletine alleviates acute oxaliplatin-induced cold allodynia in rats [46]. Lacosamide, an antiepileptic drug and Na⁺ channel blocker, has been demonstrated to be an effective and well-tolerated symptomatic treatment for acute, painful OIPN [47].

K+ channel
K⁺ channels are implicated in the regulation of sensory neuronal excitability and pain processing pathways. To date, conflicting findings exist regarding the causal role of K+ channels in the pathogenesis of acute oxaliplatin-induced peripheral neurotoxicity. Oxaliplatin is not only known to damage DRG neurons primarily in voltage-gated sodium channels but also affects K⁺ channels. Notably, TREK/TRAAK channels knockout exaggerates mouse cold sensitivity and prevents oxaliplatin-induced cold hypersensitivity [48, 49]. Oxaliplatin reduces K2P channel expression, thereby altering the excitability of cold-specific fibers [50, 51]. Activation of axonal potassium (Kv7) channels suppress oxaliplatin-induced axonal hyperexcitability [52]. Studies have demonstrated that incubating sciatic nerve fibers with oxaliplatin functions as an antagonist of voltage-gated K⁺ channels, leading to channel dysfunction [9, 53]. Additionally, conflicting findings exist regarding the association between KCNN3 CAG repeat polymorphisms and increased risk of acute oxaliplatin-induced neurotoxicity [54–57].

Ca2+ channel
Several studies have demonstrated disturbances in calcium homeostasis associated with platinum-based chemotherapy treatment. Acute treatment with oxaliplatin reduced the voltage-gated calcium current (ICa(V)) in P/Q-, T-, and L-type voltage-gated calcium channels (VGCCs) in a concentration-dependent manner, whereas the ICa(V) of N-type VGCCs remained unaffected [58]. Oxaliplatin treatment upregulates voltage-dependent calcium channel Cavα2δ−1 subunit expression in the spinal cord, potentially contributing to acute peripheral cold hypersensitivity. Moreover, pregabalin targets this Cavα2δ−1 subunit to prevent peripheral neuropathic pain effectively [59, 60].

Transient receptor potential (TRP) channels
TRP channels are a superfamily of cation-permeable ion channels widely expressed in sensory neurons, particularly in DRG. Oxaliplatin treatment upregulates TRPV1, TRPA1, and TRPM8 mRNA in cultured DRG neurons. In vivo, oxaliplatin-induced cold allodynia enhances TRPM8 and TRPA1 sensitivity and expression. TRPM8 blockade with capsazepine suppresses oxaliplatin-induced cold allodynia and TRPA1 modulation by Sigma-1 receptor prevents OIPN [61–63]. As previously reported, L-type Ca2+ channels/NFAT/TRPM8 pathway is a downstream mediator for oxaliplatin-induced cold hyperalgesia [64]. Furthermore, additional studies have shown that oxaliplatin enhances TRPM3 activity both in vitro and in vivo, a process critical for the development of OIPN [65].

HCN2
Hyperpolarization-activated cyclic-nucleotide-gated nonselective cation 2 (HCN2) channel plays a role in the development of oxaliplatin-induced neuropathic pain and the underlying mechanism involves the activation of the NMDAR subunit 1 (NR1)-mediated CaMKII signaling pathway [66, 67].

Transporters
Organic cation transporters (OCT2) are found and have functional similarities in human and mouse DRGs and may thus serve as a selective uptake transporter for oxaliplatin [9, 64]. Acute oxaliplatin treatment significantly enhanced cold and mechanical sensitivity and contributed to oxaliplatin-induced peripheral neuropathy in wild-type (WT) mice compared to OCT2 knockout mice [68]. Activation of the Na+/Ca2+ exchanger 2 (NCX2) leads to toxic Ca2+ accumulation. Additionally, the increase in intracellular calcium and proton concentration induced calcineurin-mediated inhibition of the Na+/H+ exchanger isoform-1 (NHE1); all these processes contribute to the development of OIPN [69, 70].

Glial cell dysfunction
Glia activation is known to increase following nerve injury, inflammation, and infection, with their activities primarily linked to the development, maintenance, and potentiation of neuropathic pain. Specifically, activation of astrocytes and microglia is observed in a rat model of OIPN; minocycline (a microglial inhibitor) and fluorocitrate (an astrocyte inhibitor) significantly attenuate oxaliplatin-evoked pain [71–73]. In addition to activating glial cells in the spinal cord and DRG, multiple oxaliplatin injections induce astrocyte and microglia activation in brain regions involved in pain processing, such as the thalamus, neostriatum, anterior cingulate cortex, somatosensory cortex 1 [72, 74]. Recent research has demonstrated that oxaliplatin exerts a direct and profound impact on the modulation and function of various proteins within satellite glial cells [74–76]. These findings indicate that glia may also play a pivotal role in the development and maintenance of OIPN.

DNA damage in sensory neurons
Platinum accumulates readily in DRG neurons due to their abundant fenestrated capillaries and lack of a blood–nerve barrier, with platinum-induced DNA adduct (Pt–DNA adducts) formation being another mechanism of OIPN [77, 78]. Enhancing apurinic/apyrimidinic endonuclease (APE)−1 function in the base excision repair pathway reverses platinum-induced DNA damage and neurotoxicity. Notably, compared with cisplatin, oxaliplatin forms fewer Pt–DNA adducts and exhibits lower neurotoxicity to DRG neurons [77, 79, 80]. This molecular mechanism may be associated with the USP10/XAB2/ANXA2 axis involved in DNA damage [81].

Oxidative stress–induced mitochondrial dysfunction
OIPN is driven by both mitochondrial dysfunction and oxidative burst—along with the direct toxicity of superoxide anions (O₂⁻) in DRG neurons; these pathological changes further lead to electron transport chain dysfunction and cellular energy failure [82–84]. Moreover, treatment with the antioxidant acetyl-L-carnitine inhibits OIPN by preventing respiratory chain damage and preserving mitochondrial integrity [84]. Owing to the lack of DNA repair systems, oxaliplatin–DNA adducts cannot be repaired within either neuronal or nonneuronal mitochondria, resulting in an oxidative stress burden mediated by TRPA1 channels—whose role in OIPN has been discussed above [85–87]. In vitro studies have demonstrated changes in mitochondrial structure and function in rat neuronal cells exposed to oxaliplatin [9, 88, 89].

Neuroinflammation
OIPN is linked to heightened proinflammatory responses in DRGs and peripheral nerves. Administration of oxaliplatin upregulates the mRNA levels of proinflammatory cytokines and chemokines—an effect that enhances pain sensitivity, significantly increases the levels of interleukin (IL)−1β, IL-6, and TNF-α in DRG [90–93]. The IL-8 signaling pathway contributes to neuroinflammation, a process that drives progressive neural sensitization in OIPN models [94]. It has been reported that OHP-induced mechanical hyperalgesia and neuroinflammation are mediated by gut microbiota–related activation of Toll-like receptor 4 (TLR4) on macrophages and elevated levels of C–C motif chemokine 2 (CCL2) and C–C motif receptor 2 (CCR2) in dorsal root ganglion (DRG) neurons [91–93]. Further results suggest that oxaliplatin treatment upregulates ERK phosphorylation in rat DRG and induces chronic neuropathic pain [90]. Additionally, significant mechanical allodynia in oxaliplatin-treated male mice is accompanied by increased circulating levels of CD4⁺ and CD8⁺ T cells [91].

Prevention and treatment
Despite recent scientific advances that improve our understanding of the mechanism at the basis of OIPN, relatively few interventions exist to prevent or treat this condition. Although certain biological targets identified in preclinical studies have shown potential in nonhuman animal models, only a small subset of these targets has been successfully translated into clinical trials. In fact, the most recent systematic reviews focusing on OIPN treatment did not identify conclusive evidence of efficacy for any of the tested interventions. Notably, the Symptom Management and Health-Related Quality of Life Steering Committee of the National Cancer Institute has designated OIPN as a priority area for translational research in cancer care [77, 95]. Recent advances in preclinical studies have identified several novel targets for prevention and therapy. As detailed in Table 2, a range of emerging drug and compound candidates show promise in mitigating OIPN. These candidates cover multiple therapeutic modalities, including antioxidants, anti-inflammatory agents, neuroprotective peptides, and modulators of ion channels, each targeting key pathogenic pathways of OIPN. Notably, the identified preclinical targets of OIPN discussed in this overview may also serve as biomarkers to monitor OIPN toxicity and treatment response, facilitating personalized therapeutic strategies. In the current study, we provide a comprehensive overview of these emerging strategies, therapeutic targets, and candidate agents in Table 2 to inform future translational research and clinical practice for OIPN management.

Riluzole
Oxaliplatin disrupts extracellular glutamate homeostasis in the spinal cord, a disturbance that may contribute to the development of neuropathic symptoms. Riluzole, an FDA-approved medication for amyotrophic lateral sclerosis, has been shown to normalize elevated glutamate concentrations, restore reduced expression of glutamate transporter 1 (GLT-1), and suppress the development of OIPN in animal models [96]. It has been demonstrated to alleviate oxaliplatin-induced functional and morphological abnormalities in the peripheral nerves [49, 50]. Additionally, it is hypothesized that riluzole may exert its neuroprotective effects by interacting with the TREK and TRAAK channels [51]. Most recently, a phase I clinical trial showed that riluzole plus mFOLFOX6/bevacizumab is well tolerated in patients with metastatic CRC and may have clinical activity in patients whose disease is resistant to FOLFOX [97]. Another phase II, placebo-controlled, randomized, double-blind, multicenter prevention trial enrolled adult stage II/III CRC patients receiving adjuvant simplified FOLFOX4 [48].

Lidocaine
Lidocaine exerts its analgesic effect primarily by blocking VGSCs, which are highly expressed in peripheral sensory neurons [98, 99]. Lidocaine was first evaluated for its efficacy in rodent models of OIPN, where it demonstrated significant alleviation of both cold and mechanical allodynia. In comparative preclinical studies, intravenous lidocaine reduced cold allodynia in rats given a single oxaliplatin injection [100]. Similarly, in rats with repeated OHP exposure, lidocaine specifically reversed cold and mechanical allodynia without affecting motor function, confirming its targeted action on nociceptive pathways [101]. In that small-scale study, intravenous lidocaine exerted a direct analgesic effect on OIPN, with a moderate long-term effect, and appeared to modulate the areas of cold and pinprick perception [102]. These initial observations paved the way for larger subsequent randomized clinical trials investigating lidocaine’s potential in managing OIPN.

Pregabalin
Pregabalin exerts its therapeutic effects on OIPN through a well-characterized mechanism that targets VGCCs in the central nervous system [103]. Preclinical studies have consistently demonstrated pregabalin’s efficacy in rodent models of OIPN. In three clinical cases, pregabalin, more potent than gabapentin, significantly reduced the severity of OIPN at lower doses [104]. In the present Phase III, randomized, double-blind, placebo-controlled study, findings indicated that preemptive administration of pregabalin during oxaliplatin infusions was well tolerated and safe, yet it failed to reduce the incidence of chronic pain associated with OIPN [105].

Calcium and magnesium infusion
Calcium and magnesium (Ca/Mg) infusions are promising strategies for preventing OIPN with a focus on preventing acute symptoms and potentially reducing chronic neuropathy risk. Their use is rooted in targeting oxaliplatin’s key neurotoxic mechanism of disruption of VGCCs [106]. A pivotal large phase III study in colorectal cancer patients receiving FOLFOX demonstrated that Ca/Mg infusion reduced the overall incidence of OIPN [107, 108]. However, another double-blind phase III study found no benefit of intravenous Ca/Mg over placebo in reducing the incidence of acute OIPN [109]. Additionally, two further cases showed that Ca/Mg infusions had no effect on either acute or chronic neurotoxicity induced by oxaliplatin [109–111]. Major clinical guidelines recognize Ca/Mg infusions as a standard of care for acute OIPN prevention but do not universally recommend them for chronic OIPN [112]. Given these inconsistent findings, the utility of Ca/Mg infusions for OIPN prevention requires further investigation.

Duloxetine
Duloxetine is a serotonin–norepinephrine reuptake inhibitor (SNRI) primarily used to treat major depressive disorder, generalized anxiety disorder, and chronic neuropathic pain. In the management of OIPN, it enhances the activity of descending pain inhibitory pathways and dampens the abnormal pain signaling generated by oxaliplatin-induced nerve damage. Nevertheless, while current clinical evidence remains insufficient, the American Society of Clinical Oncology (ASCO) still recommends duloxetine as a first-line pharmacologic option for treating established OIPN [112]. It also demonstrates utility in mitigating both acute OIPN symptoms and chronic OIPN manifestations. Moreover, an exploratory responder analysis suggests that patients with OIPN are more likely to experience benefits from duloxetine than those with paclitaxel-induced neuropathy [113]. However, duloxetine is not completely effective and does not work for all patients. Thus, optimizing its treatment schedule and identifying predictors of duloxetine response remain priorities for further research. In addition, the administration of duloxetine has been reported to be associated with fewer adverse effects compared with venlafaxine [114, 115]. Recently, a phase II/III study of duloxetine has been initiated to investigate two key aspects: the optimal dose of duloxetine and its efficacy in preventing pain symptoms caused by oxaliplatin in patients with stage II-III CRC.

Venlafaxine
Venlafaxine, a more selective SNRI, differs from duloxetine in that direct clinical evidence supporting its use for OIPN remains sparse, largely derived from small observational studies or extrapolation from other neuropathic pain conditions. A retrospective study of 32 patients with OIPN found that venlafaxine reduced pain scores of patients, with concurrent improvements in cold allodynia and paresthesia [116]. A pilot randomized, placebo-controlled, double-blind study on 50 patients has been reported, and its analysis failed to demonstrate any efficacy of venlafaxine [117]. To date, no high-quality RCTs specifically evaluating venlafaxine for OIPN have been published, which limits its recommendation in clinical guidelines.

Lorcaserin
Lorcaserin, a selective serotonin 5-HT₂C receptor agonist originally approved for weight management, has emerged as a potential candidate for OIPN management [113]. Most data supporting lorcaserin’s role in OIPN come from rodent models of oxaliplatin-induced neuropathy, with consistent demonstrations of antiallodynic effects. Currently, there are two clinical trials focused on lorcaserin for treatment of OIPN. One is a randomized phase II study that compares lorcaserin with duloxetine in the treatment of chronic OIPN. The other is a phase I open-label trial which investigates the efficacy of lorcaserin in treating CIPN among patients with stage I–IV gastrointestinal or breast cancer.

Calmangafodipir
Calmangafodipir is a novel mixed metal complex originally developed for antioxidant and neuroprotective effects. It is designed to mimic manganese superoxide dismutase (MnSOD), a key enzyme that neutralizes cellular reactive oxygen species (ROS). Calmangafodipir targets OIPN’s core pathophysiological driver, which is oxaliplatin-induced oxidative stress and neuronal damage. Its mechanism of action involves ROS scavenging via MnSOD mimicry, mitochondrial protection, and inhibition of neuroinflammation [118, 119]. A randomized, double-blind, placebo-controlled phase II study was conducted in patients with metastatic colorectal cancer. Results showed that calmangafodipir appears to prevent the development of OIPN, with no apparent impact on tumor outcomes [120]. Two international trials have been initiated to evaluate the efficacy and safety of calmangafodipir for prevention of OIPN. However, the POLAR clinical studies failed to meet their primary endpoint [121, 122].

L-Carnosine
L-Carnosine, a naturally occurring dipeptide composed of beta-alanine and histidine, is formulated in combination with alpha-lipoic acid and has emerged as a potential supportive agent for managing OIPN [123]. Its role is rooted in antioxidant, anti-inflammatory, and neuroprotective properties [124, 125], though clinical evidence remains primarily from preclinical models and small-scale human studies. A prospective randomized controlled study indicated that L-carnosine exerted a neuroprotective effect against oxaliplatin-induced peripheral neuropathy in colorectal cancer patients by targeting Nrf-2 and NF-κB pathways [126].

GM1
Monosialotetrahexosylganglioside (GM1) enrichment in membrane domains mediates neurodifferentiation and neuroprotection against various stressors. As a critical component of neural cell membranes, it plays essential roles in maintaining nerve structure and function, making it a promising candidate for OIPN management [127, 128]. The retrospective study demonstrated that GM1 significantly reduced the incidence of OIPN [129]. A randomized controlled trial suggested that GM1 played an effective neuroprotective agent against OIPN in patients with gastrointestinal tumors [130]. Recently, a clinical trial has indicated that GM1 can relieve patients from the symptoms of acute neuropathy. However, there is no evidence to support the use of GM1 in preventing cumulative neurotoxicity [131].

Dasatinib and nilotinib
Dasatinib and nilotinib second-generation tyrosine kinase inhibitors (TKIs) are approved pharmaceuticals used in the treatment of chronic myeloid leukemia [132]. They produce their potential neuroprotective effects by suppressing Src kinases or c-Abl (a member of the Abl family kinases) activity that is activated by oxaliplatin-induced oxidative stress in peripheral sensory neurons [133]. In a phase II study, nilotinib and dasatinib are currently being studied in an ongoing phase IB trial as repurposed drugs [9, 77].

TRK-750
A study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of TRK-750 in CRC patients with CIPN following oxaliplatin-containing chemotherapy in the adjuvant setting. However, due to the COVID-19 pandemic, the study was withdrawn.

APX3330 and APX2009
Loss of apurinic/apyrimidinic endonuclease (APE)−1 function increases sensitivity of sensory neuronal cultures to oxaliplatin [79]. APX330 is an oral selective inhibitor of Ape1/Ref-1 redox activity that enhances APE1 DNA repair activity in sensory neurons and has been shown to provide neuroprotection against OIPN [134]. APX2009 is effective in preventing or reversing platinum-induced CIPN while not affecting the anticancer activity of platins [79].

EMA401
EMA401, also known as olodanrigan, is an orally active selective angiotensin II type 2 receptor (AT2R) antagonist that is in Phase IIb clinical development as a novel analgesic for the relief of chronic pain [135]. Preclinical studies in rodent models consistently demonstrate EMA401’s neuroprotective and analgesic effects in OIPN [136].

Other potential candidate agents
Metformin, a widely prescribed first-line antidiabetic drug, has emerged as a potential repurposed agent for OIPN with preclinical evidence highlighting its ability to protect against axonal degeneration [137]. Compound porcine cerebroside and ganglioside (CPCG), an injectable compound preparation derived from porcine brain tissue, clinically used for neurorepair in traumatic brain injury and hypoxic-ischemic encephalopathy, has recently gained attention for OIPN management due to its unique neuroprotective properties without compromising chemotherapy efficacy [138]. The combination of zinc with melatonin employed as a preventive approach was found effective in attenuating neurotoxicity induced by oxaliplatin [139]. Additionally, topiramate administration has emerged as a promising new strategy for preventing acute and chronic OIPN in a well-established preclinical model [13].
AT2R angiotensin II type 2 receptor, CIPN chemotherapy-induced peripheral neuropathy, CPCG Compound porcine cerebroside and ganglioside, GLT-1 glutamate transporter 1, GM1 Monosialotetrahexosylganglioside, MnSOD manganese superoxide dismutase, OXAIPN oxaliplatin-induced peripheral neurotoxicity, SNRI serotonin-norepinephrine reuptake inhibitor, TKIs tyrosine kinase inhibitors, VGCCs voltage-gated calcium channels, VGSCs voltage-gated sodium channels

Conclusions and future directions
OIPN remains a prevalent and clinically impactful adverse effect of oxaliplatin-based chemotherapy, with distinct clinical, pathological, and mechanistic features that shape its management. Clinically, OIPN presents as two primary phenotypes: acute neurotoxicity and chronic neurotoxicity. Mechanistically, OIPN arises from interconnected pathways: oxaliplatin-induced DNA damage, oxidative stress, neuroinflammation, and ion channel dysfunction and so. These pathways converge to cause axonal degeneration, synaptic damage, and sensory signaling aberrations. In terms of prevention and treatment, progress has been made in both repurposed agents and novel therapeutics. Preventive strategies range from ion channel-targeted therapies, neurotransmitter-based therapies, antioxidants, anti-inflammatory therapies, targeting chemotherapeutic drug transporters, targeting APE function to lipid peroxidation inhibitors. Therapeutic interventions include late-phase agents and investigational candidates and dasatinib/nilotinib. A multitude of novel promising targets have emerged for the prevention and/or the treatment of OIPN. Notably, several of these targets are currently advancing into clinical trials. Should multiple agents demonstrate efficacy in clinical investigations, future studies will need to focus on identifying the optimal target for individual patients, alongside determining the appropriate dosing regimen to maximize therapeutic benefit while minimizing adverse effects. Significantly, effective OIPN management must balance neuroprotection with preservation of oxaliplatin’s antitumor efficacy, a criterion that is met by most emerging agents in preclinical and early clinical studies.
The evolving understanding of OIPN’s heterogeneity has driven targeted intervention development. Clinically, distinguishing acute from chronic OIPN is critical: acute symptoms are often transient and manageable with supportive care (e.g., Ca/Mg infusions), while chronic OIPN requires long-term neuroprotective strategies due to its risk of irreversibility. Pathological classification (axonopathy vs. neuronopathy) further refines patient stratification; for example, neuronopathy may require more aggressive interventions (e.g., neurotrophic factors) given its association with neuronal loss. Mechanistic insights have enabled rational drug design: targeting PARP1 addresses DNA damage-related energy depletion, while AT₂R antagonism directly counters ion channel dysfunction and neuroinflammation. Repurposed agents like zinc-melatonin offer advantages of established safety profiles and low cost, making them accessible for resource-limited settings, though their efficacy requires validation in large RCTs.
Despite progress, several gaps persist. First, clinical assessment variability hinders consistent OIPN diagnosis: while tools like the EORTC QLQ-CIPN20 and Brief Pain Inventory (BPI) capture patient-reported outcomes, objective measures (e.g., nerve conduction velocity and quantitative sensory testing) are underutilized, leading to potential underdiagnosis of mild-to-moderate OIPN. Second, predictive biomarkers remain elusive, as no validated markers (e.g., plasma ROS levels and DRG neuron gene expression) currently exist to identify patients at high risk of OIPN, and this absence limits personalized prevention. Third, irreversible chronic OIPN lacks effective treatments: most agents (e.g., duloxetine, the only FDA-approved drug for CIPN pain) alleviate symptoms but do not reverse established axonal damage. Novel approaches targeting axonal regeneration show preclinical promise but require clinical translation. Fourth, drug–drug interaction concerns persist, though emerging data confirm no impairment of oxaliplatin’s antitumor efficacy—a critical reassurance for oncology practice.
To advance the clinical management of OIPN, several priorities should be prioritized for immediate consideration. Foremost among them is the development of predictive and responsive biomarkers. Specifically, high-throughput sequencing and imaging technologies, such as bulk RNA sequencing or single-cell RNA sequencing of DRG neurons, and advanced imaging modalities (e.g., PET scans targeting DRG neurons) should be strategically leveraged. These tools not only facilitate the identification of robust predictive biomarkers to stratify patients at risk of OIPN prior to oxaliplatin initiation but also enable real-time monitoring of treatment response. In advancing OIPN management, prioritizing combination therapy development is critical. This is due to OIPN’s multifactorial pathophysiology—interconnected pathways (e.g., neuroinflammation and oxidative stress) drive neuronal damage, making single agents insufficient. Preclinical data in oxaliplatin-treated rodents show this combination reduces chronic OIPN severity and improves DRG neuron survival [139]. Early preclinical data support synergistic effects, but clinical trials are needed. Beyond validating combination therapies, long-term efficacy studies also constitute a key priority in OIPN research. Most current trials focus on short-term OIPN (i.e., ≤ 6 months postchemotherapy initiation), yet chronic OIPN—characterized by potential irreversible sensory damage—often persists or emerges beyond this timeframe. Thus, long-term follow-up (≥ 1 year) is essential to comprehensively evaluate the ability of both single-agent and combination interventions to prevent irreversible neuronal damage, sustain symptom relief, and ultimately improve quality of life in OIPN survivors. Such long-term assessments will also help clarify whether interventions maintain safety profiles over extended periods, a critical consideration for translating preclinical and short-term clinical findings into durable, patient-centric OIPN management strategies. Two more priorities boost real-world relevance. First, addressing OIPN research disparities (underrepresenting elderly patients and those with comorbidities like diabetes/preexisting neuropathy) ensures interventions are generalizable. Excluding these groups limits validity, as they may need tailored approaches (e.g., diabetes-related OIPN risk). Finally, integrating patient-reported outcomes (PROs, e.g., EORTC QLQ-CIPN20 and BPI) with objective measures (e.g., NCV, QST, and skin biopsy) gives a fuller OIPN burden/treatment benefit assessment. For example, a therapy may improve axonal function but not reduce patient-reported pain—insights missed with single measures, guiding better management.
In summary, OIPN’s complexity demands a multifaceted approach, combining mechanistic research, personalized risk stratification, and targeted interventions. With ongoing advancements in drug development and biomarker discovery, the goal of minimizing OIPN-related morbidity while preserving chemotherapy efficacy is increasingly achievable.