Introduction
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and disabling adverse effect associated with antineoplastic agents such as taxanes, vinca alkaloids, and platinum-based compounds. 1–4 Characterized by “glove-and-stocking” paresthesia, neuropathic pain, and motor deficits, CIPN significantly impairs patients’ quality of life and may necessitate dose reduction or discontinuation of chemotherapy, thereby compromising oncological outcomes and long-term survival. 5–9 Notably, CIPN can exhibit delayed onset or progressive worsening even after cessation of chemotherapy—a phenomenon known as the “coasting phenomenon”. 1 , 2 , 10 , 11 Although many studies conceptualize CIPN as a linear pathological cascade, 12–15 and a substantial body of literature has elegantly illuminated the critical roles of glial and neuroimmune signaling in this process, the dynamic integration of these intercellular crosstalk pathways into a comprehensive, self-sustaining “vicious cycle” remains underexplored. 16–18 Despite mechanistic heterogeneity across chemotherapeutic classes, diverse agents converge on a similar chronic neuropathic state, yet the unifying pathological circuitry underlying this convergence remains poorly defined. 13 , 19 To date, no pharmacological agent has demonstrated consistent efficacy for the primary prevention of CIPN. 8 , 14 , 20
This review aims to synthesize current evidence on CIPN pathogenesis and construct a dynamic “vicious cycle” model that spans from initial injury to chronic maintenance, integrating fragmented pathological observations into a coherent, interactive circuit. Based on this model, we systematically analyze the mechanisms and limitations of existing interventions from both modern Western medicine and traditional Chinese medicine (TCM), ultimately proposing a multi-target synergistic strategy designed to disrupt the self-perpetuating loop central to CIPN progression.
For this narrative review, we searched PubMed, Web of Science, CNKI, and Wanfang Data for articles published from database inception up to March 2026. Search terms included combinations of “chemotherapy-induced peripheral neuropathy,” “CIPN,” “vicious cycle,” “mitochondrial dysfunction,” “oxidative stress,” “ion channel,” “neuroinflammation,” “acupuncture,” “traditional Chinese medicine,” and “herbal medicine.” We also manually screened reference lists of retrieved articles and relevant reviews to identify additional studies. We included peer-reviewed original research, clinical trials, and systematic reviews that addressed the mechanisms, prevention, or treatment of CIPN, with a focus on literature published in English or Chinese. We excluded conference abstracts, case reports, and studies not directly related to CIPN pathophysiology or intervention.
Construction of the “Vicious Cycle” Model for the Pathogenesis of CIPN
Convergent Amplifier: Mitochondrial Dysfunction and Energy Crisis
The initiating mechanisms of CIPN differ across chemotherapeutic classes. Taxanes primarily disrupt microtubule dynamics and axonal transport, whereas platinum-based agents induce DNA adduct formation in dorsal root ganglion neurons. Despite this mechanistic heterogeneity, accumulating evidence suggests that mitochondrial dysfunction may represent a convergent downstream event that contributes to the amplification and maintenance of neuropathic pathology across multiple forms of CIPN. Multiple first-line chemotherapeutic agents accumulate preferentially in peripheral nerve tissues, where they disrupt mitochondrial morphology and bioenergetic capacity. 21 For instance, cisplatin and carboplatin induce elevated mitochondrial reactive oxygen species (ROS) production in Schwann cells, reduce mitochondrial membrane potential, and impair ATP synthesis, culminating in demyelination characterized by downregulation of myelin protein zero (MPZ) and upregulation of p75NTR. 22 Beyond bioenergetic failure, imbalance in mitochondrial dynamics constitutes another hallmark feature: chemotherapeutics perturb the equilibrium between fusion and fission. Evidence from copper overload models indicates that neurotoxic insults suppress fusion by downregulating Opa1, Mfn1, and Mfn2, while promoting fission via Drp1 upregulation, leading to pathological mitochondrial fragmentation. 23
PGC-1α, a master regulator of mitochondrial biogenesis, plays a pivotal role in preserving mitochondrial integrity, protecting peripheral nerves, and mitigating CIPN. 24 Additionally, therapy-induced senescence (TIS) has emerged as a systemic mechanism contributing to CIPN; the TIS phenotype observed in dorsal root ganglia (DRG) closely parallels mitochondrial dysfunction, suggesting that TIS-associated mitochondrial decline may serve as a persistent driver of neural injury following chemotherapy. 25 Thus, mitochondrial impairment may function not only as a bioenergetic disturbance but also as an important amplifier of downstream pathological cascades in CIPN.
Amplification Stage I: The Cascade of Oxidative Stress and DNA Damage
Mitochondrial dysfunction is closely associated with excessive ROS generation due to electron transport chain leakage, triggering profound oxidative stress. 26 This not only perpetuates mitochondrial injury—establishing a positive feedback loop—but also inflicts widespread damage on cellular DNA, proteins, and lipids. In cisplatin-induced models, activation of p38 MAPK has been identified as a key upstream event driving both oxidative stress and mitochondrial impairment; pharmacological inhibition of p38 MAPK markedly attenuates ROS production and confers neuroprotection. 27
ROS can induce single- or double-strand DNA breaks, activating DNA damage response pathways that, if unresolved, culminate in apoptosis. Concurrently, endoplasmic reticulum (ER) stress—frequently co-occurring with oxidative stress—is increasingly recognized as a contributor to CIPN pathogenesis. Sustained activation of the unfolded protein response (UPR) promotes neuronal apoptosis, whereas phytochemicals exert neuroprotective effects partly by alleviating ER stress, underscoring a tight interplay between oxidative and ER stress. 28 Flavonoids, for example, ameliorate CIPN largely through their potent antioxidant activity, which inhibits ROS-mediated neuronal injury and cell death. 29 Collectively, these findings indicate that oxidative stress functions not only as a consequence of mitochondrial damage but also as an independent amplifier of DNA damage and apoptosis, thereby constituting the first positive feedback loop in the vicious cycle.
Amplification Stage II: Ion Channel Remodeling and Abnormal Neuronal Excitability
As oxidative stress and mitochondrial damage intensify, sensory neurons undergo ion channel remodeling, leading to abnormal neuronal excitability—the electrophysiological substrate of CIPN symptoms. Chemotherapeutic agents alter the kinetics of voltage-gated sodium, calcium, and potassium channels, resulting in increased ectopic discharges and spontaneous activity. 30 Compromised ATP supply from dysfunctional mitochondria impairs Na⁺/K⁺-ATPase activity, lowering the threshold for membrane depolarization and promoting a hyperexcitable state. Flavonoids alleviate thermal hyperalgesia and mechanical allodynia by suppressing ion channel activation and ectopic firing. 29 Moreover, topical capsaicin nanocrystal gel modulates TRPV1 channel activity, significantly improving mechanical and thermal hypersensitivity while reducing neuroinflammatory markers, highlighting ion channel modulation as a strategic node for interrupting pain signaling. 31 Dysregulated ion channels also disrupt calcium homeostasis; mitochondrial calcium overload can trigger opening of the mitochondrial permeability transition pore, exacerbating cellular injury. 32 In neurological disorders, calcium-induced collapse of mitochondrial membrane potential is a core pathological mechanism, and this process similarly operates in CIPN: ion channel–mediated calcium influx further burdens mitochondria, creating a second self-reinforcing feedback loop. 33
Amplification Stage III: Neuroinflammation and Immune Cell Activation
Neuroinflammation serves as a critical bridge linking peripheral nerve injury to central sensitization within the CIPN “vicious cycle”. Chemotherapeutic agents not only directly damage neurons but also activate resident immune and glial cells in both the peripheral and central nervous systems. These activated cells release pro-inflammatory cytokines—including TNF-α, IL-1β, and IL-6—creating a neurotoxic microenvironment that further injures neurons. 30 Glatiramer acetate, for example, significantly attenuates paclitaxel-induced neuropathy by suppressing TNF-α and NF-κB while elevating the anti-inflammatory cytokine IL-10, underscoring the therapeutic relevance of inflammation modulation. 34 Similarly, a composite material derived from turmeric rhizome and nano-hydroxyapatite (TRE@NHA) exerts anti-CIPN effects partly by inhibiting cytokine production and reducing oxidative stress, illustrating the synergy between anti-inflammatory and antioxidant actions. 35 Mesenchymal stem cell (MSCs) therapy also demonstrates promise by reducing neuroinflammation and apoptosis via paracrine signaling, thereby promoting axonal regeneration and highlighting the regenerative potential of immune modulation. 36 Importantly, inflammatory mediators not only harm neurons but also reciprocally induce mitochondrial dysfunction and oxidative stress, forming a third positive feedback loop.
Core Mechanism: Amplification Effect of Intercellular Signal Interaction on Vicious Cycle
The CIPN “vicious cycle” does not operate in neuronal isolation but emerges from a complex network of intercellular signaling interactions that amplify damage signals. Neurons injured by chemotherapy release damage-associated molecular patterns (DAMPs), which activate glial cells; in turn, these glia produce ROS and cytokines that feed back onto neurons, exacerbating mitochondrial dysfunction and ion channel remodeling. 29 , 37
Furthermore, the gut microbiota–brain axis plays a non-negligible role. Chemotherapy-induced gut dysbiosis may reduce microbial metabolites such as short-chain fatty acids (SCFAs), thereby diminishing their inhibitory influence on neuroinflammation and worsening neuropathy. 38 Disruption of metabolic coupling between Schwann cells and axons—driven by mitochondrial failure—also accelerates axonal degeneration. 22 These cross-cellular communication pathways form an expansive feedback network that stabilizes the vicious cycle, rendering it resistant to conventional interventions. However, it is important to explicitly note that the incorporation of the gut microbiota-brain axis into this CIPN vicious cycle is currently speculative. Because direct evidence linking short-chain fatty acids and microbiota dysbiosis specifically to CIPN remains sparse, this node is largely an extrapolation drawn from other neurodegenerative contexts (such as Parkinson’s disease). Therefore, its exact structural role within the CIPN cycle should be viewed as an emerging hypothesis requiring further direct experimental validation in chemotherapy-specific models.
Interactions Between Various Links and the Formation of a Vicious Cycle
The pathogenesis of CIPN converges into a tightly interconnected “vicious cycle”: diverse initial insults converge to induce mitochondrial dysfunction, leading to reduced ATP synthesis and a burst of reactive oxygen species (ROS); excessive ROS triggers oxidative stress, causing DNA damage and lipid peroxidation while concurrently activating endoplasmic reticulum (ER) stress; energy depletion and oxidative injury drive ion channel remodeling, resulting in neuronal hyperexcitability and ectopic discharges; damaged neurons release signaling molecules that activate neuroinflammation, and activated glial and immune cells secrete additional ROS and inflammatory mediators, which further aggravate mitochondrial damage and oxidative stress. This self-amplifying process is reinforced through intercellular crosstalk, ultimately culminating in irreversible axonal degeneration and chronic neuropathic pain. 37 , 39 Within this proposed framework, these interacting processes may be conceptually summarized as: mitochondrial dysfunction - oxidative stress and DNA damage - neuronal hyperexcitability - neuroinflammation (as shown in Figure 1 ). The “vicious cycle” model not only accounts for the “coasting phenomenon” but also provides a mechanistic rationale for developing multi-target, disease-modifying therapies. Effective disruption of this self-sustaining loop is essential to transition from symptomatic palliation to true disease modification. Figure 1 The “Vicious Cycle” Four-Component Model of CIPN Pathogenesis. A diagram illustrating the four stages of CIPN pathogenesis. At the center is a neuron, with arrows indicating progression through the stages. Stage 1, labeled ′Mitochondrial Dysfunction′, shows mitochondria with disrupted structure. Stage 2, ′Oxidative Stress and DNA Damage′, depicts reactive oxygen species and DNA damage. Stage 3, ′Neuronal Hyper-excitability′, illustrates ion channels with sodium and calcium ions. Stage 4, ′Neuroinflammation′, shows immune cells releasing inflammatory mediators like TNF-alpha and IL-1 beta. Each stage is connected by arrows with plus signs, indicating a cycle. The diagram visually represents the interconnected processes leading to chronic neuropathic pain. CIPN stages: mitochondrial issues, oxidative stress, neuron hyperactivity, neuroinflammation.
The three amplification loops described above—oxidative stress, ion channel remodeling, and neuroinflammation—do not occur in a strictly sequential order. Rather, they operate in parallel and mutually reinforce one another in a temporally dynamic manner. Although oxidative stress may be the earliest amplifier to emerge following mitochondrial injury, ion channel remodeling and neuroinflammation can develop concurrently or successively and may sustain the cycle even after the chemotherapeutic agent has been withdrawn.
The proposed model also offers a potential mechanistic explanation for the coasting phenomenon—the observation that CIPN can progress or emerge after chemotherapy has been discontinued. Once the initial chemotherapeutic insult has triggered the self-sustaining feedback loops (eg, mitochondrial dysfunction promoting oxidative stress, which further damages mitochondria; neuroinflammation generating cytokines that reinforce neuronal hyperexcitability, which in turn sustains glial activation), these loops may become independent of the original trigger. Consequently, the cycle can persist and even amplify after the chemotherapeutic agent has been cleared from the body. This interpretation, however, remains hypothetical and requires direct experimental testing.
Mechanism and Limitations of Modern Western Medicine Treatment Based on the “Vicious Cycle” Model
Drugs Targeting Mitochondrial Protection and Antioxidant Stress
PFT-μ specifically inhibits p53 translocation to mitochondria, thereby preserving mitochondrial membrane potential. 40 PGC-1α, as a central regulator of mitochondrial biogenesis, significantly ameliorates oxidative stress and sustains mitochondrial function upon activation. 24 Vinpocetine enhances mitochondrial biogenesis via the PGC-1α–NRF1–TFAM pathway, reducing mitochondrial ROS generation. 41 Alpha-lipoic acid (ALA) exhibits robust antioxidant and anti-inflammatory properties, while acetyl-L-carnitine (LAC) shows notable efficacy in patients receiving platinum-based regimens. 42 Antioxidants such as N-acetylcysteine, lipoic acid, and vitamin E suppress ROS production and lipid peroxidation in the spinal cord. 43 Ozone therapy and specific plant extracts (eg, ethanol extract from immature citrus peel) indirectly modulate oxidative stress by enhancing endogenous antioxidant defenses or inhibiting enzymes like NOX2. 44–46
Ion Channel Modulators and Their Efficacy Analysis
Meclizine and metabotropic glutamate receptor (mGluR) agonists—particularly mGluR8 and Group II mGluR agonists—alleviate hyperexcitability in DRG neurons by modulating calcium homeostasis. 47 The 8% capsaicin patch exerts analgesic effects through TRPV1 receptor desensitization and demonstrates potential disease-modifying capabilities. A single application significantly reduces both spontaneous and evoked pain in CIPN patients, and skin biopsy reveals regeneration and restoration of epidermal nerve fiber density, suggesting promotion of sensory nerve repair. 48 Mitragynine, by activating α2-adrenergic receptors and modulating brain-derived neurotrophic factor (BDNF) expression, offers insights into the cross-regulation between ion channels and neurotransmitter systems. 49
Targeted Effects of Anti-Inflammatory and Immunomodulatory Drugs
Duloxetine functions not only as a serotonin-norepinephrine reuptake inhibitor but also exerts anti-inflammatory and neuroprotective effects via inhibition of the p38 MAPK/NF-κB pathway, which may underlie its clinical efficacy in CIPN. 50 , 51 Monoclonal antibodies targeting MMP9 or its endogenous inhibitor TIMP1 reduce levels of IL-6 and TNF-α and prevent intraepidermal nerve fiber loss. 52 Additional strategies include targeting specific inflammatory mediators such as MMP9 and IRE1α, as well as supplementing with omega-3 fatty acids, all aimed at precisely inhibiting glial activation and pro-inflammatory cytokine production (eg, IL-6, TNF-α, IL-1β). 52–54 Activation of the Sonic hedgehog signaling pathway confers neuroprotection through mechanisms including anti-senescence effects. 55
Applications and Mechanisms of Neurotrophic Factors
The p75NTR modulator LM11A-31 and the novel compound CN016 show significant efficacy in preclinical models: the former normalizes neurotrophic signaling, while the latter suppresses macrophage-mediated neuroinflammation. 56 The humanized NGF monoclonal antibody DS002, by blocking NGF binding to TrkA, validates neurotrophic factor modulation as a viable therapeutic approach for CIPN. 57 Meanwhile, studies on mitragynine indicate that neurotrophic factors such as BDNF can exert dual effects, emphasizing the need for precise regulatory control. 49
Limitations of Existing Western Drug Treatments and the “Off-Target” Phenomenon
Despite substantial advances in mechanistic understanding and preclinical validation, translating these findings into effective clinical therapies remains challenging. A major challenge in current pharmacological management is disrupting the integrated “vicious cycle” of CIPN (as shown in Figure 2 ). It is important to note that not all conventional therapies are strictly single-target; for instance, agents like duloxetine and mesenchymal stem cells exhibit pleiotropic effects that modulate multiple pathways simultaneously. However, many standard small-molecule drugs predominantly act on specific nodes. For example, antioxidants such as ALA or LAC may alleviate oxidative stress, but without concurrent modulation of ion channel remodeling or neuroinflammation, symptom relief is often partial. Clinical trials have yielded inconsistent results, potentially due to variations in administration routes or chemotherapy regimens. 42 Furthermore, many agents lack disease-modifying capabilities or exhibit “off-target” effects. Gabapentin, pregabalin, and tricyclic antidepressants primarily provide symptomatic relief without halting neurodegeneration. 39 Although capsaicin patches show some neuroregenerative potential, most small-molecule drugs fail to achieve structural repair. 48 The differential efficacy of LAC—effective in platinum-treated but not paclitaxel-treated patients—suggests distinct underlying mechanisms across chemotherapeutic classes, implying that a universal single-target strategy is unlikely to succeed. 42 Timing also presents a critical barrier: interventions targeting the eIF4E complex may be effective early, but delayed treatment risks irreversible neurodegeneration, 58 multi-target combination strategies grounded in the “vicious cycle” model are urgently needed to enable a shift from symptom control to disease modification. Figure 2 Single-target drugs cannot block the “vicious cycle” of CIPN. The diagram illustrates the vicious cycle of chemotherapy-induced peripheral neuropathy (CIPN) across four stages. Stage 1 is mitochondrial dysfunction, depicted with damaged mitochondria inside a neuron. Stage 2 shows oxidative stress and DNA damage, represented by reactive oxygen species and DNA strands. Stage 3 is neuronal hyper-excitability, illustrated with ion channels and ions like sodium and calcium. Stage 4 is neuroinflammation, shown with microglia releasing cytokines such as tumor necrosis factor alpha and interleukin one beta. The cycle includes a single-target blockage, such as ion channel inhibitors, but highlights an ongoing pathological loop that bypasses this blockage. Arrows indicate the progression and feedback within the cycle. CIPN cycle: mitochondrial issues, oxidative stress, neuron hyperactivity, neuroinflammation.
Analysis of the Mechanisms of Multi-Target Intervention in CIPN by Traditional Chinese Medicine
Regulation and Prevention of CIPN via Multiple Targets Through Acupuncture Therapy
Acupuncture is the most widely employed non-pharmacological intervention in traditional Chinese medicine (TCM) for CIPN and demonstrates clear advantages in multi-target modulation. A multicenter randomized controlled trial involving 168 CIPN patients found that acupuncture significantly improved FACT-Tax scores, particularly for symptoms such as hand numbness, tingling, and local discomfort. 59 Multiple studies confirm that acupuncture-related modalities—including manual needling, electroacupuncture, and transcutaneous electrical acupoint stimulation—effectively alleviate clinical symptoms, enhance nerve conduction velocity, and improve quality of life in CIPN patients, with favorable safety profiles and no serious adverse events. 60–76
Mechanistic investigations reveal that electroacupuncture exerts neuroprotective effects by inhibiting the thalamic paraventricular nucleus TRPC6/PKC pathway, reducing calcium influx, suppressing aberrant glutamatergic neuron activation, and reversing loss of intraepidermal nerve fibers and Merkel cells. 77 This mechanism directly targets the ion channel remodeling and neuronal hyperexcitability components of the CIPN vicious cycle. Additionally, acupuncture alleviates pain through modulation of the endogenous opioid system, enhances sensory nerve function via BDNF-mediated neural plasticity, and regulates both systemic and local inflammatory responses. 61
Acupoint selection patterns: Data mining analyses identify Zusanli (ST36), Quchi (LI11), Hegu (LI4), Taichong (LR3), and Sanyinjiao (SP6) as core acupoints for CIPN treatment, supplemented by Bafeng (EX-LE10) and Baxie (EX-UE9) for distal symptoms. This reflects foundational TCM principles of “treating flaccidity by focusing on the Yangming channels” and “selecting acupoints locally”. 66 , 78 , 79
Preventive application: Electroacupuncture initiated one day before chemotherapy and maintained throughout the treatment course demonstrates prophylactic potential. In a randomized controlled trial, the incidence of CIPN at 24 weeks was only 17.4% in the electroacupuncture group versus 72% in the conventional care group, with no cases of high-grade CIPN in the intervention arm, 80 However, these dramatic preventive effects must be interpreted with explicit caution. This finding derives from a relatively small trial lacking a sham-acupuncture control and rigorous blinding, which carries a high risk of performance and detection bias. Further large-scale, sham-controlled trials are required to confirm whether acupuncture truly mitigates initial neuronal injury to this extent.
Molecular Mechanisms and Multi-Target Effects of Active Components in Traditional Chinese Medicine
The active ingredients in traditional Chinese medicine hold potential for combating oxidative damage, reducing inflammation, and providing neuroprotection, which aligns with the multi-mechanism pathogenesis of CIPN. 81–83 Numerous clinical studies support the use of blood-activating and collateral-dredging herbs such as Salvia miltiorrhiza and Ligusticum chuanxiong for CIPN prevention and treatment. A systematic review and meta-analysis showed that such TCM formulations significantly reduce the incidence of both all-grade and high-grade CIPN (total effective rate: 77.19% vs 45.79% in controls) and markedly improve sensory and motor nerve conduction velocities. 84
Topical interventions such as herbal fumigation and external application significantly improve clinical symptoms, increase Karnofsky Performance Status (KPS) scores, reduce pain Numerical Rating Scale (NRS) scores, and alleviate TCM syndrome patterns. They also enhance nerve conduction velocity in the common peroneal and median nerves. With low publication bias and robust evidence, these approaches represent safe and effective therapeutic options. 85 Wenluotong (WLT), a topical TCM formulation used clinically for over a decade, demonstrates clear efficacy in CIPN management. Metabolomic studies suggest that WLT alleviates mechanical hypersensitivity in paclitaxel-induced CIPN rats by modulating linoleic acid and glycerophospholipid metabolism pathways. Key active components—including hydroxysafflor yellow A, icariin, epimedin B, and dihydroxybenzoic acid—are predicted by molecular docking to have favorable binding affinities to core proteins in these pathways, thereby reversing CIPN-related metabolic dysregulation. 86
Nevertheless, these efficacy figures should not be viewed uncritically. The “total effective rate” is a notoriously soft composite endpoint. Furthermore, many of the included primary studies are small-scale trials with recognized methodological flaws, including inadequate blinding and the absence of placebo controls. Consequently, these results carry a significant risk of bias and merely suggest potential efficacy rather than definitive proof.
The Regulatory Effect of Traditional Chinese Medicine Compounds on the Overall Microenvironment
Classic TCM compound prescriptions adhere to the monarch-minister-assistant-envoy compatibility theory. Through synergistic interactions among multiple constituents, they holistically regulate the patient’s pathological state, improve the local microenvironment at sites of nerve injury, and disrupt the CIPN vicious cycle at a systemic level. Recent advances in network pharmacology and experimental research have predicted potential targets for the molecular mechanisms of these formulas in CIPN treatment.
Huangqi Guizhi Wuwu Tang (Astragalus and Cinnamon Twig Five-Substance Decoction) is a classical TCM formula for blood impediment syndrome and is now widely applied in CIPN management. Network pharmacology predicts 63 active components in this decoction that interact with 41 core CIPN-related targets, primarily through modulation of inflammatory responses and nerve repair. The study also identified two novel potential targets—CDK7 and GSTM2—through computational prediction, highlighting the multi-component, multi-target, and multi-pathway nature of TCM compound prescriptions. 87 Subsequent in vitro experiments confirmed that medicated serum from Huangqi Guizhi Wuwu Tang significantly enhances the survival of cisplatin-injured PC12 cells. Transcriptomic profiling further revealed upregulation of the axon guidance pathway, indicating promotion of axonal repair during the early phase of neuronal injury in CIPN. 88
Taohong Siwu Decoction, a classic blood-activating and stasis-resolving formula, also demonstrates clinical efficacy in CIPN. Network pharmacology and molecular docking analyses predict 69 active components acting on 105 shared CIPN targets, including MYC, TNF, MAPK14, AKT1, ESR1, RELA, TP53, and HSP90AA1. Enriched pathways involve PI3K-Akt, NF-κB, and HIF-1 signaling—processes closely linked to inflammation and neuroprotection. Molecular docking confirms strong binding affinity between selected components and core targets, suggesting the molecular basis for its blood-activating and meridian-unblocking effects in CIPN treatment. 89
However, it is crucial to emphasize that network pharmacology and molecular docking only provide static computational predictions. The actual in vivo bioavailability of these complex multi-component formulas, and their precise pharmacokinetic profiles within the peripheral nervous system, remain to be rigorously validated by future pharmacological studies.
Analysis of Key Intervention Points of Traditional Chinese Medicine in the “Vicious Cycle”
Mapping TCM interventions onto the “vicious cycle” model reveals precise targeting of critical nodes: at the stage of initial neuronal injury and mitochondrial dysfunction, TCM compound formulas exert protective effects that mitigate early damage. 87 , 88 Electroacupuncture can even prevent CIPN onset, substantially reducing incidence. 80 The antioxidant properties of TCM active components and formulas directly counteract the oxidative stress–DNA damage amplification cascade. 80–82 Acupuncture effectively modulates ion channel remodeling and neuronal hyperexcitability 77 and further reduces excitability via the endogenous opioid system to alleviate pain. 61 Both acupuncture and TCM also target neuroinflammation and immune activation: acupuncture modulates systemic and local inflammatory responses, lowering pro-inflammatory cytokines, 61 while TCM formulas inhibit inflammatory pathways to limit ongoing neuronal injury. 87 , 89 Moreover, intercellular signaling amplification—central to cycle maintenance—is addressed by TCM: blood-activating and collateral-dredging formulas enhance local perfusion and nutrient delivery, improving the neural microenvironment; 84 , 85 acupuncture promotes recovery of nerve conduction, thereby dampening damage signal propagation. 90 Traditional Chinese medicine (TCM) employs synergistic multi-component, multi-method, and multi-target strategies that simultaneously engage multiple critical nodes of the vicious cycle. This integrative capacity constitutes the core therapeutic advantage of TCM in CIPN management 71 , 72 , 91 , 92 (as shown in Figure 3 ). Figure 3 Multi-Target Collaborative Intervention of CIPN’s “Vicious Cycle”. The diagram illustrates a multi-target synergistic therapy for neuronal health. It shows four stages: Stage 1, Restored Mitochondrial Function, with mitochondria depicted; Stage 2, Neutralized Oxidative Stress and Repaired DNA, with reactive oxygen species and DNA; Stage 3, Stabilized Neuronal Excitability, with ion channels; and Stage 4, Resolved Neuroinflammation, with immune cells. Arrows indicate the flow of therapy effects, breaking the pathological loop. A needle represents the therapy application. Diagram of multi-target therapy stages for neuronal health improvement.
However, it is essential to explicitly clarify that the claim of “simultaneous” multi-node modulation is currently a composite inference synthesized from separate studies evaluating isolated endpoints across different models. At the same time, it is important to contextualize the current evidence within major oncology guidelines. For instance, the American Society of Clinical Oncology (ASCO) guidelines currently recommend duloxetine as the only agent with sufficient evidence for treating established CIPN, while rating the evidence for acupuncture and botanical therapies as inconclusive. Although this article cites numerous studies that reported positive results, these findings have not led to any changes in the guidelines, primarily because these trials suffered from methodological flaws such as small sample sizes, the absence of sham acupuncture controls, and a lack of independent replication of the findings.
Furthermore, a balanced perspective must acknowledge that the multi-target nature of TCM is not without significant limitations. While acting on multiple nodes provides holistic regulation, it inherently implies lower pharmacological specificity, complex pharmacokinetic interactions, and greater uncertainty in identifying the exact mechanisms of action. The difficulty in standardizing active dosages within compound formulas remains a major hurdle. Future research should prioritize large-sample, multicenter, rigorously designed randomized controlled trials to establish robust efficacy data and optimize intervention protocols for broader clinical implementation. 63 , 72 , 84 , 91
When advocating for the concurrent use of TCM during active cancer treatment, the potential for negative herb-drug interactions must be critically addressed. A paramount scientific concern is whether the potent antioxidant and anti-apoptotic properties of certain herbal medicines might inadvertently blunt the pro-oxidant, cytotoxic mechanisms that chemotherapeutic agents rely on for tumor eradication. Additionally, complex herbal formulas may interfere with the pharmacokinetics of chemotherapy drugs via cytochrome P450 enzyme induction or inhibition, potentially altering drug efficacy or exacerbating systemic toxicity. Although several short-term trials cited in this review report that TCM interventions do not compromise chemotherapy efficacy, these studies are rarely adequately powered to assess long-term oncological outcomes. In addition, no cited study has incorporated long-term oncological outcomes such as cancer recurrence or overall survival. Short-term safety and symptom relief do not equate to confirmation of non-interference with anti-tumor mechanisms. Therefore, future research must rigorously monitor tumor response rates, progression-free survival (PFS), and overall survival (OS) to definitively confirm that neuroprotective TCM strategies do not simultaneously protect the tumor.
The Synergistic Strategy of “Acupuncture Combined with Medication” to Break the Vicious Cycle
This paper proposes “acupuncture combined with traditional Chinese medicine” as a theoretical framework and develops corresponding synergistic strategies in the hope of breaking this closed loop; it must be clearly stated that this integrated therapy is currently still a hypothesis based on deduction rather than a clinically validated strategy, and that this approach embodies a deep integration of the holistic perspective of traditional Chinese medicine with modern systems biology.
Theoretical Basis of Acupuncture and Medicine Synergy
On the neurophysiological dimension, acupuncture rapidly suppresses ectopic discharges by modulating neuronal excitability (eg, via the TRPC6/PKC pathway) 77 and activates the endogenous opioid system for immediate analgesia; 61 meanwhile, herbal medicine persistently repairs mitochondrial function, stabilizes ion channel expression, and provides neurotrophic support (eg, Huangqi Guizhi Wuwu Tang promotes axonal regeneration). 88 Thus, acupuncture addresses acute symptoms while herbal medicine consolidates structural recovery, embodying the TCM principle of “treating symptoms in acute stages and addressing the root cause in chronic stages”.
On the immunological dimension, the combination regulates both systemic and local inflammation by reducing pro-inflammatory cytokines (eg, TNF-α, IL-1β); 61 acupuncture rapidly modulates immune cell trafficking and inhibits inflammatory cascades such as NF-κB and PI3K-Akt, while herbal formulas like Taohong Siwu Decoction suppress glial activation. 88 Together, they establish a sustained anti-inflammatory microenvironment—acupuncture interrupts inflammatory feedback acutely, whereas TCM maintains long-term immune homeostasis to prevent relapse.
At the metabolic level, the strategy enhances local microcirculation and neural perfusion, potentially via autonomic nervous regulation; herbal medicine (eg, Wenluotong) corrects CIPN-associated metabolic disturbances by modulating linoleic acid and glycerophospholipid pathways, 85 while acupuncture improves the metabolic milieu. This dual action synergistically restores metabolic homeostasis and mitigates oxidative stress.
These three complementary mechanisms converge on a unified objective: disrupting the positive feedback amplification nodes that sustain the vicious cycle.
To comprehensively break the CIPN cycle, the acupuncture-medication combination achieves precise complementation through a “spatiotemporal synergy” mechanism.
Temporally, acupuncture acts as an immediate interventional trigger. By rapidly modulating transient receptor potential (TRP) channels and local neuro-immune cross-talk, acupuncture provides swift suppression of neuronal hyperexcitability and acute pain signals. In contrast, herbal medicine (such as Huangqi Guizhi Wuwu Decoction) acts as a sustained modifier. It gradually accumulates active compounds to activate long-term survival and repair pathways, such as the PI3K/Akt signaling cascade, promoting continuous mitochondrial restoration and axonal regeneration.
Spatially, acupuncture effectively targets specific regional reflex arcs and systemic neuro-endocrine axes (eg, the gut-brain axis). Meanwhile, oral herbal formulations exert systemic pharmacological effects, improving systemic microcirculation and delivering active multi-target molecules directly to the damaged dorsal root ganglia (DRG) and peripheral nerve microenvironment. This precise temporal (rapid vs sustained) and spatial (network-axis vs systemic-molecular) complementation creates a robust synergistic blockade against the vicious cycle.
Indirect Experimental Evidence of Acupuncture and Medication Synergy
Acupuncture combined with oral herbal medicine represents a classical TCM paradigm grounded in the principle of “simultaneous regulation of qi and blood and unblocking of meridians”. In a rat model of cerebral infarction, this combination significantly increased intestinal short-chain fatty acids (SCFAs) while reducing serum IL-17 levels, with synergistic effects surpassing monotherapy. Correlation analysis revealed a strong negative association between SCFAs and IL-17, suggesting that acupuncture–herb synergy may powerfully suppress neuroinflammation via the gut–brain axis or related systemic immune pathways. 93
The integration of acupuncture with modern Western medicine is a growing trend in CIPN management. Multiple randomized controlled trials confirm its efficacy: in multiple myeloma patients with CIPN, acupuncture plus mecobalamin significantly outperformed mecobalamin alone in pain relief (VAS score), quality of life (FACT/GOG-Ntx score), and nerve conduction velocity (NCV) improvement. 94 Another trial similarly showed that the combination markedly reduced NCI-CTCAE toxicity grades, improved EORTC QLQ-CIPN20 scores, and enhanced nerve conduction function, with an excellent safety profile. 95
However, it must be explicitly acknowledged that direct experimental or clinical evidence proving that acupuncture combined specifically with herbal medicine breaks the CIPN cycle is currently lacking. The studies cited above—utilizing a cerebral infarction model and integrating acupuncture with a Western agent—serve only as indirect, mechanistic proof-of-concept extrapolations. While they provide a proof-of-concept for the benefits of combination therapy, they do not constitute direct evidence for the acupuncture-herb synergy proposed in our model. This highlights a critical gap in current research.
Advantages of Acupuncture-Pharmacotherapy Synergy in Targeting Each Node of the Malignant Cycle
Acupuncture alone cannot directly restore mitochondrial structure, and herbal medicine alone acts slowly. However, their combination synergizes: acupuncture enhances local perfusion and energy metabolism, while herbal formulas (eg, Huangqi Guizhi Wuwu Tang) boost mitochondrial biogenesis, accelerating energy recovery. Antioxidants like ALA offer limited ROS clearance; in contrast, acupuncture upregulates endogenous antioxidant enzymes, and herbal medicine (eg, Wenluotong) scavenges free radicals and corrects metabolic imbalances, establishing a dual antioxidant defense. Ion channel modulators such as gabapentin alleviate symptoms without nerve repair; acupuncture rapidly suppresses ectopic firing, while herbal medicine stabilizes channel expression and promotes axonal regeneration, achieving “rapid symptom control + long-term repair”. Anti-inflammatory agents like duloxetine may interfere with chemotherapy; acupuncture provides localized anti-inflammatory effects without systemic interference, and herbal formulas (eg, Taohong Siwu Tang) inhibit the NF-κB pathway, jointly reducing pro-inflammatory cytokines without compromising anti-tumor immunity. Critically, in the context of cross-amplifying feedback loops, single-target approaches cannot simultaneously block multiple pathways. The acupuncture–herb combination, however, concurrently targets neurons, glial cells, microcirculation, and metabolic networks, disrupting positive feedback at multiple entry points to achieve comprehensive “cycle disruption” (as shown in Figure 4 ). Figure 4 The combination of acupuncture and medication synergistically blocks the “vicious cycle” of CIPN. The infographic illustrates the impact of acupuncture and traditional herbal medicine on various biological dimensions. On the left, acupuncture neuromodulation is depicted with a needle and wave pattern, labeled ′Rapid neuromodulation governed repair′. The central DNA-like structure represents different dimensions: Neural dimension with healthy sensory neuron and regenerating axon, resting microglial cells; Immune dimension with gut microbiome cells; Metabolic dimension with healthy microcirculation blood vessels and metabolic lipid networks. On the right, traditional herbal medicine molecules are shown, labeled ′Therapeutic molecular systemic repair′. The underlying text reads ′Underlying vicious cycle disrupted′. An infographic illustrating acupuncture and herbal medicine′s impact on neural, immune and metabolic dimensions.
The theoretical strength of this integrated strategy lies in its spatiotemporal complementarity: acupuncture delivers rapid neuromodulation and local microenvironment optimization, while herbal medicine provides sustained molecular repair and metabolic remodeling. Their synergy across temporal (acute vs chronic) and spatial (local vs systemic) dimensions enables coordinated targeting of multiple key nodes.
Conclusion and Outlook
This review systematically integrates the complex pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) and constructs a proposed “positive feedback vicious cycle” model as a testable hypothesis. Based on this model, we critically evaluate current interventions. While many conventional pharmacological treatments offer crucial symptomatic relief and some possess multi-pathway effects, fully dismantling the interdependent feedback nodes remains a significant clinical hurdle. In contrast, traditional Chinese medicine—through the synergistic actions of acupuncture, bioactive herbal constituents, and compound formulas—has the potential to simultaneously engage multiple critical links in the cycle. We further propose an integrative “acupuncture combined with herbal medicine” strategy as a research agendarequiring future investigation, theoretically leveraging acupuncture’s rapid regulation of the neuro-immune network alongside herbal medicine’s enduring repair of molecular pathways to achieve disruption from microscopic mechanisms to macroscopic phenotypes. This paradigm offers a novel theoretical foundation for the integrated management of CIPN, but it requires rigorous experimental and clinical validation before it can be considered a proven therapeutic approach.
Future Research Directions and Clinical Translation Pathways
Several Concrete Research Priorities and Testable Predictions Emerge From This Framework:
First, direct experimental evidence is urgently needed to test the hypothesis that acupuncture combined with herbal medicine can simultaneously modulate multiple nodes of the proposed cycle in CIPN-specific models. Existing synergy data are derived from stroke models and from trials pairing acupuncture with mecobalamin rather than herbal medicine; thus, dedicated CIPN studies are required to establish direct causality.
Second, we propose testable predictions regarding the quantitative “threshold” and “dose-response” relationships between key nodes. For instance, identifying the specific concentration of inflammatory cytokines required to significantly alter ion channel expression, or the extent of oxidative stress needed to trigger mitochondrial permeability transition, would transform the current qualitative model into a more precise, predictive framework.
Third, the existence of a potential “main switch” node—whose modulation may produce downstream effects surpassing those of other individual nodes—warrants systematic investigation. If such a master regulatory node is identified, it could serve as the most efficient therapeutic entry point for intervention.
Fourth, regarding study design, future clinical trials must strictly adopt multi-center, sham-controlled (for acupuncture), and placebo-controlled (for herbal medicine) designs. Standardized and validated endpoints, alongside adequate sample sizes, are essential to address the methodological shortcomings of the current evidence base. Furthermore, longitudinal oncological outcomes, including cancer recurrence and overall survival, must be incorporated to definitively rule out any interference with anti-tumor efficacy.
In conclusion, the vicious cycle model provides an integrative framework that reframes CIPN as a dynamic, self-sustaining system rather than a linear cascade. This reconceptualization directs future research toward multi-target, disease-modifying strategies. Ultimately, the acupuncture-herbal combination presents a conceptually promising but strictly hypothesis-driven strategy that awaits rigorous empirical validation.
Acknowledgments
All figures were created using BioRender and BioGDP.
Disclosure
The authors report no conflicts of interest in this work.
References
1. Xinyu C , Yumeng G , Ngan A , et al. Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy . Front Mol Neurosci . 2024 ; 17 : 1345811 . doi: 10.3389/fnmol.2024.1345811 PMC11039947 38660386
2. Zhirui T , Zhiqin C , Xiaochen Z , et al. An emerging aspect of cancer neuroscience: a literature review on chemotherapy-induced peripheral neuropathy . Cancer Lett . 2024 ; 611 : 217433 . 10.1016/j.canlet.2024.217433 39736454
3. Mathieos B , Samar H , Bruno G , et al. Methadone to treat chemotherapy-induced peripheral neuropathy (METACIN): study protocol . Pain Manag . 2025 ; 15 ( 5 ): 235 – 16 . doi: 10.1080/17581869.2025.2494495 PMC12118441 40289780
4. Tomoyoshi M , Maho T , Fumiko S , et al. Chemotherapy-induced peripheral neuropathy and sex hormones . Nihon Yakurigaku Zasshi Folia Pharmacologica Japonica . 2026 ; 161 ( 2 ): 109 – 114 . doi: 10.1254/fpj.25102 41765420
5. Hana S , Irina V . Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy . Front Mol Neurosci . 2017 ; 10 : 174 . doi: 10.3389/fnmol.2017.00174 PMC5450696 28620280
6. Dariusz I , Adam N , Maciej K , et al. Chemotherapy-induced peripheral neuropathy - epidemiology and pathogenesis . Ginekologia Polska . 2016 ; 87 ( 4 ): 293 – 299 . doi: 10.17772/gp/61750 27321102
7. Ildikó I , Zsolt N , Judit D . Chemotherapy-induced peripheral neuropathy: characteristics, diagnosis and treatment . Magyar Onkologia . 2016 ; 60 ( 2 ): 165 – 175 . 27275643
8. Jamie B , Maryam F , David G , et al. Chemotherapy-Induced Peripheral Neuropathy: epidemiology, Pathomechanisms and Treatment . Oncol Therapy . 2021 ; 9 ( 2 ): 385 – 450 . doi: 10.1007/s40487-021-00168-y PMC8593126 34655433
9. Geehoon C , Sun K . Therapeutics for Chemotherapy-Induced Peripheral Neuropathy: approaches with Natural Compounds from Traditional Eastern Medicine . Pharmaceutics . 2022 ; 14 ( 7 ). doi: 10.3390/pharmaceutics14071407 PMC9319448 35890302
10. Nicolas K , Aurore C , Sakahlé C , et al. Long-Term Effects, Pathophysiological Mechanisms, and Risk Factors of Chemotherapy-Induced Peripheral Neuropathies: a Comprehensive Literature Review . Front Pharmacol . 2017 ; 8 : 86 . doi: 10.3389/fphar.2017.00086 PMC5323411 28286483
11. Antonio A , Sabrina B , Claudia C , et al. Pathophysiology and Therapeutic Perspectives for Chemotherapy-induced Peripheral Neuropathy . Anticancer Res . 2022 ; 42 ( 10 ): 4667 – 4678 . doi: 10.21873/anticanres.15971 36191965
12. Marios B , Vassilis G . Risk-reduction and treatment of chemotherapy-induced peripheral neuropathy . Expert Rev Anticancer Ther . 2017 ; 17 ( 11 ): 1045 – 1060 . doi: 10.1080/14737140.2017.1374856 28868935
13. Sandy E , Liang G , John H . A Comparative Review of Chemotherapy-Induced Peripheral Neuropathy in In Vivo and In Vitro Models . Toxicol Pathol , 2019 , 48 ( 1 ): 190 – 201 . doi: 10.1177/0192623319861937 PMC6917839 31331249
14. Yang L , Maryam L , Shuiying H . Emerging Pharmacological and Non-Pharmacological Therapeutics for Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy . Cancers . 2021 ; 13 ( 4 ): 1 . 10.3390/cancers13040766 PMC7918689 33673136
15. Nima Z , Mahla V , Mina M , et al. Mechanism-based Pharmacological Management of Chemotherapy-induced Neuropathic Pain from Preclinical Studies to Clinical Prospective: platinum-based Drugs, Taxanes, and Vinca Alkaloids . Curr Pharm Des . 2023 ; 29 ( 16 ): 1245 – 1265 . doi: 10.2174/1381612829666230515124044 37190803
16. Giulia F , Laura M , Guido C , et al. Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy . Front Immunol . 2021 ; 11 : 626687 . 10.3389/fimmu.2020.626687 PMC7890072 33613570
17. Hyun Y , Yugal G , Kalpna G . Crosstalk of Mast Cells and Natural Killer Cells with Neurons in Chemotherapy-Induced Peripheral Neuropathy . Int J Mol Sci . 2023 ; 24 ( 16 ). doi: 10.3390/ijms241612543 PMC10454469 37628724
18. Susanne R , Rika B , Fabian M-G , et al. The Role of Microcirculatory Dysfunction During Paclitaxel Treatment as a Critical Co-Factor for the Development of Chemotherapy-Induced Peripheral Neuropathy . Geburtshilfe Frauenheilkd . 2025 ; 85 ( 7 ): 710 – 723 . doi: 10.1055/a-2499-9856 PMC12208722 40599898
19. Guido C , Paola A , Andreas A , et al. Chemotherapy-induced peripheral neurotoxicity: a multifaceted, still unsolved issue . J Peripheral Nerv Syst . 2019 ; 24 ( Suppl 2 ): S6 – S12 . doi: 10.1111/jns.12337 31647155
20. Susan D , Ian K , Debra B , et al. The National Cancer Institute Clinical Trials Planning Meeting for Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy . J National Cancer Inst . 2019 ; 111 ( 6 ): 531 – 537 . doi: 10.1093/jnci/djz011 PMC7962883 30715378
21. Annalisa T , Sarah F . Mitochondrial dysfunction in the pathogenesis of chemotherapy-induced peripheral neuropathy . Inter Rev Neurobiol . 2019 ; 145 : 83 – 126 . 10.1016/bs.irn.2019.05.001 31208528
22. Xian W , Weifa Y , Leilei W , et al. Platinum-based chemotherapy induces demyelination of Schwann cells in oral squamous cell carcinoma treatment . Toxicol Appl Pharmacol . 2023 ; 481 : 116751 . 10.1016/j.taap.2023.116751 37944569
23. Michael A , Anatoly S , Rongzhu L , et al. Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy . Front Mol Neurosci . 2024 ; 17 : 1504802 . doi: 10.3389/fnmol.2024.1504802 PMC11655512 39703721
24. Mingzhu Z , Haibei H , Zheng Y , et al. PGC1α: an emerging therapeutic target for chemotherapy-induced peripheral neuropathy . Therap Adv Neurolo Dis . 2023 ; 16 : 17562864231163361 . doi: 10.1177/17562864231163361 PMC10041632 36993941
25. Mohammad A , Amr E , Sarah B , et al. Targeting therapy-induced senescence as a novel strategy to combat chemotherapy-induced peripheral neuropathy . Supp Care Cancer . 2024 ; 32 ( 1 ): 85 . doi: 10.1007/s00520-023-08287-0 38177894
26. Peng Z , Tianbing W . Role of mitochondrial ROS and antioxidants in neurological disorders . Chin J Shoulder Elbow (Electronic Edition) . 2018 ; 6 ( 4 ): 302 – 306 .
27. Yugal G , Donovan A , Kristen P , et al. Neuronal p38 MAPK Signaling Contributes to Cisplatin-Induced Peripheral Neuropathy . Antioxidants . 2025 ; 14 ( 4 ): 1 . 10.3390/antiox14040445 PMC12024185 40298791
28. Yugal G , Raghda F , Kalpna G . Endoplasmic Reticulum Stress in Chemotherapy-Induced Peripheral Neuropathy: emerging Role of Phytochemicals . Antioxidants . 2022 ; 11 ( 2 ). doi: 10.3390/antiox11020265 PMC8868275 35204148
29. Manaal S , Basma A , Kevin Z , et al. Flavonoids Alleviate Peripheral Neuropathy Induced by Anticancer Drugs . Cancers . 2021 ; 13 ( 7 ): 1 . 10.3390/cancers13071576 PMC8036789 33805565
30. Housem K , Anna C , d’Angelo Michele , et al. Molecular and Cellular Involvement in CIPN . Biomedicines . 2024 ; 12 ( 4 ). doi: 10.3390/biomedicines12040751 . PMC11048589 38672107
31. Sagar H , Pawan D , Gopal B , et al. Capsaicin nanocrystals burdened topical polymeric gel: an encouraging tactic for alleviation of paclitaxel-induced peripheral neuropathy . Int J Pharm . 2024 ; 669 : 125082 . 10.1016/j.ijpharm.2024.125082 39672314
32. Yuan W , Yan W , Ming M , et al. Research progress on the mechanism of mitochondrial dysfunction in chemotherapy-induced peripheral neuropathy . Adverse Drug React J . 2022 ; 24 ( 12 ): 658 – 663 .
33. Changze O , Binbin C , Xinli L , et al. Research Progress on Key Targets of Mitochondrial Damage in Ischemic Stroke and Intervention Mechanisms of Traditional Chinese Medicine . China J Chinese Materia Medica . 2025 ; 8 ( 15 ): 41 .
34. Sajad D , Mehdi G , Ahmad D , et al. Protective Effects of Glatiramer Acetate Against Paclitaxel-Induced Peripheral Neuropathy in Rats: a Role for Inflammatory Cytokines and Oxidative Stress . Neurochem Res . 2024 ; 49 ( 4 ): 1049 – 1060 . doi: 10.1007/s11064-023-04088-3 38252396
35. Chuangen L , Sriram K , Mariappan V . Beyond chemotherapy: exploring tree turmeric root and nano-hydroxyapatite for neuroprotective applications . Iran J Basic Med Sci . 2025 ; 28 ( 10 ): 1406 – 1416 . doi: 10.22038/ijbms.2025.84185.18205 PMC12399070 40896697
36. Khaled A-M , Lamiaa A , Hanan E-A . Mesenchymal stem cells in chemotherapy-induced peripheral neuropathy: a new challenging approach that requires further investigations . J Tissue Eng Regener Med . 2019 ; 14 ( 1 ): 108 – 122 . doi: 10.1002/term.2972 31677248
37. Flatters S , Dougherty P , Colvin L . Clinical and preclinical perspectives on Chemotherapy-Induced Peripheral Neuropathy (CIPN): a narrative review . Br J Anaesth . 2017 ; 119 ( 4 ): 737 – 749 . doi: 10.1093/bja/aex229 29121279
38. Dandan W , Binbin R . Research progress on the role and mechanism of butyric acid in the prevention and treatment of Parkinson’s disease . Med J Chin People’s Liberat Army . 2025 ; 50 ( 9 ): 1179 – 1185 .
39. Jiacheng M , Annemieke K , Patrick D , et al. Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: targeting the source . Cancer . 2018 ; 124 ( 11 ): 2289 – 2298 . doi: 10.1002/cncr.31248 PMC5991994 29461625
40. Magdalena M , Jiacheng M , Karen K , et al. Inhibition of Mitochondrial p53 Accumulation by PFT-μ Prevents Cisplatin-Induced Peripheral Neuropathy . Front Mol Neurosci . 2017 ; 10 : 108 . doi: 10.3389/fnmol.2017.00108 PMC5394177 28458631
41. Guanghai N , Lin KL , et al. Vinpocetine alleviates chemotherapy-induced peripheral neuropathy by reducing oxidative stress and enhancing mitochondrial biogenesis in mice . Biomed Pharmacother . 2025 ; 190 : 118434 . doi: 10.1016/j.biopha.2025.118434 40774018
42. Dinicola S , Fuso A , Cucina A , et al. Natural products - alpha-lipoic acid and acetyl-L-carnitine - in the treatment of chemotherapy-induced peripheral neuropathy . Eur Rev Med Pharmacol Sci . 2018 ; 22 ( 14 ): 4739 – 4754 . doi: 10.26355/eurrev_201807_15534 30058711
43. Jonathan A , Vitória S , Raquel N , et al. Antioxidants Improve Oxaliplatin-Induced Peripheral Neuropathy in Tumor-Bearing Mice Model: role of Spinal Cord Oxidative Stress and Inflammation . J Pain . 2021 ; 22 ( 8 ): 996 – 1013 . doi: 10.1016/j.jpain.2021.03.142 33774154
44. Bernardino C , Gregorio M-S , Francisco R-E , et al. Modulation by Ozone Therapy of Oxidative Stress in Chemotherapy-Induced Peripheral Neuropathy: the Background for a Randomized Clinical Trial . Int J Mol Sci . 2021 ; 22 ( 6 ). doi: 10.3390/ijms22062802 . PMC7998838 33802143
45. Katarzyna S , Anna R , Pola J , et al. Ozone in Chemotherapy-Induced Peripheral Neuropathy-Current State of the Art, Possibilities, and Perspectives . Int J Mol Sci . 2023 ; 24 ( 6 ). doi: 10.3390/ijms24065279 . PMC10049472 36982352
46. Aelee J , Go-Eun C , Yoo-Jeong K , et al. Neuroprotective properties of ethanolic extract of Citrus unshiu Markovich peel through NADPH oxidase 2 inhibition in chemotherapy-induced neuropathic pain animal model . Phytother Res . 2021 ; 35 ( 12 ): 6918 – 6931 . doi: 10.1002/ptr.7304 34818693
47. John S , Matteo B , Ruben G , et al. Meclizine and Metabotropic Glutamate Receptor Agonists Attenuate Severe Pain and Ca2+ Activity of Primary Sensory Neurons in Chemotherapy-Induced Peripheral Neuropathy . J Neurosci . 2022 ; 42 ( 31 ): 6020 – 6037 . doi: 10.1523/JNEUROSCI.1064-21.2022 PMC9351649 35772967
48. Praveen A , Enas E , Rosario P , et al. Rational treatment of chemotherapy-induced peripheral neuropathy with capsaicin 8% patch: from pain relief towards disease modification . J Pain Res . 2019 ; 12 : 2039 – 2052 . doi: 10.2147/JPR.S213912 PMC6613356 31308732
49. Daniel F , Laila H , Jeffery F , et al. Neurotrophic and Adrenergic Mechanisms Contribute to the Anti-Allodynic Efficacy of the Kratom Alkaloid Mitragynine Against Chemotherapy-Induced Peripheral Neuropathy . Faseb j . 2022 ; 36 ( Suppl 1 ): 1 .
50. Jing M , Qiuyan Z , Chao Y , et al. Duloxetine, a Balanced Serotonin-Norepinephrine Reuptake Inhibitor, Improves Painful Chemotherapy-Induced Peripheral Neuropathy by Inhibiting Activation of p38 MAPK and NF-κB . Front Pharmacol . 2019 ; 10 : 365 . doi: 10.3389/fphar.2019.00365 PMC6465602 31024320
51. Yuting L , Peng Z , Qiuyan Z , et al. Duloxetine Attenuates Paclitaxel-Induced Peripheral Nerve Injury by Inhibiting p53-Related Pathways . J Pharmacol Exp Ther . 2020 ; 373 ( 3 ): 453 – 462 . doi: 10.1124/jpet.120.265082 32238452
52. Raquel T , Sang L , Temugin B . Monoclonal Antibody Targeting Matrix Metalloproteinase 9 Prevents and Reverses Paclitaxel-Induced Peripheral Neuropathy in Mice . J Pain . 2018 ; 20 ( 5 ): 515 – 527 . doi: 10.1016/j.jpain.2018.11.003 PMC6511475 30471427
53. Miriam F , Oriana G , Sarah P , et al. Leukocyte-intrinsic ER stress responses contribute to chemotherapy-induced peripheral neuropathy . Sci Trans Med . 2025 ; 17 ( 822 ): eady5288 . doi: 10.1126/scitranslmed.ady5288 PMC13215384 41160669
54. Jessica M , Fernanda G , Larissa B , et al. Omega-3-Enriched Fish oil reduces the chemotherapy-induced peripheral neuropathy in mice . Neuropharmacology . 2025 ; 271 : 110384 . 10.1016/j.neuropharm.2025.110384 40015508
55. Ying Z , Shu W , Qian H , et al. Sonic hedgehog restrains the ubiquitin-dependent degradation of SP1 to inhibit neuronal/glial senescence associated phenotypes in chemotherapy-induced peripheral neuropathy via the TRIM25-CXCL13 axis . J Adv Res . 2024 ; 68 : 387 – 402 . doi: 10.1016/j.jare.2024.03.006 PMC11785578 38479571
56. Li-Hsien C , Peng-Chan L , Yu-Min Y , et al. BDNF Val66Met protects oxaliplatin-induced peripheral neuropathy in patients with colorectal cancer . Sci Trans Med . 2026 ; 18 ( 837 ): eadx1436 . doi: 10.1126/scitranslmed.adx1436 41706872
57. Zhi-Juan L , Jie T , Lei T , et al. NGF monoclonal antibody DS002 alleviates chemotherapy-induced peripheral neuropathy in rats . Acta Pharmacol Sin . 2022 ; 43 ( 11 ): 2841 – 2847 . doi: 10.1038/s41401-022-00904-8 PMC9622678 35468993
58. Nilesh A , Prapti M , Thomas S-P , et al. Neuroimmune Consequences of eIF4E Phosphorylation on Chemotherapy-Induced Peripheral Neuropathy . Front Immunol . 2021 ; 12 642420 . 10.3389/fimmu.2021.642420 PMC8071873 33912169
59. Eran B-A , David H , Noah S , et al. Impact of acupuncture and integrative therapies on chemotherapy-induced peripheral neuropathy: a multicentered, randomized controlled trial . Cancer . 2022 ; 128 ( 20 ): 3641 – 3652 . doi: 10.1002/cncr.34422 35960141
60. Lin C , Lisen L , Jing X , et al. Efficacy of non-pharmacological interventions for chemotherapy-induced peripheral neuropathy: a systematic review and network meta-analysis for randomized controlled trials . Supp Care Cancer . 2026 ; 34 ( 3 ): 174 . doi: 10.1007/s00520-026-10316-7 41656406
61. Li-Juan C , Li-Tian Y , Jia-Yu W , et al. A Narrative Review of the Efficacy of Acupuncture in Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients . J Evid Based Integrat Med . 2026 ; 31 : 2515690X251411764 . doi: 10.1177/2515690X251411764 PMC12759135 41481481
62. Mei-Ling Y , Chin-Che H , Matthew L , et al. Effects of acupuncture-related intervention on chemotherapy-induced peripheral neuropathy and quality of life: an umbrella review . Complementary Ther Med . 2025 ; 89 : 103131 . 10.1016/j.ctim.2025.103131 39900253
63. Hongshuo S , Xin Y , Weijing F , et al. An umbrella review of the evidence to guide decision-making in acupuncture therapies for chemotherapy-induced peripheral neuropathy . J Cancer Res Clin Oncol . 2023 ; 149 ( 17 ): 15939 – 15955 . doi: 10.1007/s00432-023-05369-8 PMC11797277 37676268
64. Wendi C , Hengheng Z , Qingxi R , et al. Efficacy of acupuncture in the treatment of chemotherapy-induced peripheral neuropathy in cancer patients: a systematic review and meta-analysis J Cancer Survivorship . 2025 . doi: 10.1007/s11764-025-01869-3 40830723
65. Mei-Ling Y , Ru-Wen L , Pin-Hsuan Y , et al. Acupuncture-related interventions improve chemotherapy-induced peripheral neuropathy: a systematic review and network meta-analysis . BMC Complement Med Therap . 2024 ; 24 ( 1 ): 310 . doi: 10.1186/s12906-024-04603-1 PMC11334450 39160496
66. Yuxia J , Yunxia W , Jiayuan Z , et al. Efficacy and Safety of Acupuncture against Chemotherapy-Induced Peripheral Neuropathy: a Systematic Review and Meta-Analysis . Evid Based Complement Alternat Med . 2020 ; 2020 ( 1 ): 8875433 . doi: 10.1155/2020/8875433 PMC7669337 33224260
67. Chien T-J , Chia-Yu L , Ching-Ju F , et al. The Efficacy of Acupuncture in Chemotherapy-Induced Peripheral Neuropathy: systematic Review and Meta-Analysis . Integr Cancer Ther . 2019 ; 18 : 1534735419886662 . doi: 10.1177/1534735419886662 PMC7242803 31833790
68. Zhonghang X , Xingbo W , Yuanyu W , et al. The effectiveness and safety of acupuncture for chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis . Front Neurol . 2022 ; 13 : 963358 . doi: 10.3389/fneur.2022.963358 PMC9574072 36262831
69. Man-Suk H , Hye-Yoon L , Tae-Young C , et al. A systematic review and meta-analysis of the efficacy of acupuncture and electroacupuncture in treating chemotherapy-induced peripheral neuropathy . Medicine . 2020 ; 99 ( 17 ): e19837 . doi: 10.1097/MD.0000000000019837 PMC7220547 32332632
70. Lixia P , Yue Y , Jing G , et al. The effectiveness and safety of acupuncture/electroacupuncture for chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis . Acupuncture Med . 2022 ; 41 ( 2 ): 73 – 85 . doi: 10.1177/09645284221076512 35695033
71. Noah S , Eran B-A . Integrative Approaches to Chemotherapy-Induced Peripheral Neuropathy . Current Oncol Rep . 2020 ; 22 ( 3 ): 23 . doi: 10.1007/s11912-020-0891-2 32048067
72. Jialin G , Hongqun Z , Miao H , et al. Complementary and alternative medicine in relation to chemotherapy-induced peripheral neuropathy: a narrative review . Explore . 2023 ; 20 ( 2 ): 181 – 187 . doi: 10.1016/j.explore.2023.08.010 37652788
73. Mian W , Ziwen P , Alex M . Recent advances in managing chemotherapy-induced peripheral neuropathy: a systematic review . Eur J Oncol Nurs . 2022 ; 58 : 102134 . 10.1016/j.ejon.2022.102134 35421796
74. Ryan D , Gabriel A , Marissa D-J , et al. Evidence-Based Treatment of Pain in Chemotherapy-Induced Peripheral Neuropathy . Curr Pain Headache Rep . 2023 ; 27 ( 5 ): 99 – 116 . doi: 10.1007/s11916-023-01107-4 37058254
75. Katie J , Stephen W , David Z , et al. Pharmacological and Nonpharmacological Management of Chemotherapy-Induced Peripheral Neuropathy: a Scoping Review of Randomized Controlled Trials . J Palliat Med . 2022 ; 25 ( 6 ): 964 – 995 . doi: 10.1089/jpm.2021.0512 PMC9145589 35128938
76. Jessica M , Michael G , Namrata S , et al. Updates in the Treatment of Chemotherapy-Induced Peripheral Neuropathy . Current Treat Opt Oncolo . 2022 ; 23 ( 1 ): 29 – 42 . doi: 10.1007/s11864-021-00926-0 PMC9642075 35167004
77. Yi-Yang J , Xue L , Feng-Xian H , et al. Electroacupuncture alleviates chemotherapy-induced peripheral neuropathy and anxiety by reducing TRPC6/PKC-dependent activation of glutamatergic neurons in the paraventricular thalamic nucleus . Neuroscience . 2025 ; 592 : 97 – 110 . doi: 10.1016/j.neuroscience.2025.11.031 41290068
78. Zhaoxue L , Jennifer M , Benjamin M , et al. Treatment of Chemotherapy-Induced Peripheral Neuropathy in Integrative Oncology: a Survey of Acupuncture and Oriental Medicine Practitioners . J AlternComplementary Med . 2017 ; 23 ( 12 ): 964 – 970 . doi: 10.1089/acm.2017.0052 28661695
79. Jialin G , Miao H , Xinxing W , et al. Data mining analysis reveals key acupoints and meridians for the treatment of chemotherapy-induced peripheral neuropathy . Explore . 2022 ; 19 ( 1 ): 71 – 77 . doi: 10.1016/j.explore.2022.04.003 35437224
80. Yao ZX , Renjie G , et al. Electroacupuncture for the prevention of chemotherapy-induced peripheral neuropathy: a randomized controlled trial . Chin Acupun Moxibust . 2024 ; 44 ( 12 ): 1388 – 1394 . doi: 10.13703/j.0255-2930.20240222-k0001 39658376
81. Gihyun L , Sun K . Therapeutic Effects of Phytochemicals and Medicinal Herbs on Chemotherapy-Induced Peripheral Neuropathy . Molecules . 2016 ; 21 ( 9 ): 2 . 10.3390/molecules21091252 PMC6273821 27657026
82. Bei-Yu W , Chun-Ting L , Yu-Li S , et al. A review of complementary therapies with medicinal plants for chemotherapy-induced peripheral neuropathy . Complementary Ther Med . 2018 ; 42 : 226 – 232 . 10.1016/j.ctim.2018.11.022 30670246
83. Lin Z , Hui Y , Jing W , et al. The Therapeutic Potential of Antioxidants in Chemotherapy-Induced Peripheral Neuropathy: evidence from Preclinical and Clinical Studies . Neurotherapeutics . 2023 ; 20 ( 2 ): 339 – 358 . doi: 10.1007/s13311-023-01346-8 PMC10121987 36735180
84. Zhaoyi L , Huimin J , Qingying Y , et al. The Method of Activating Blood and Dredging Collaterals for Reducing Chemotherapy-Induced Peripheral Neuropathy: a Systematic Review and Meta-Analysis . Evid Based Complement Alternat Med . 2019 ; 2019 : 1029626 . doi: 10.1155/2019/1029626 PMC6590582 31281395
85. Quan-Yao L , Fei-Hong C , Ying L , et al. External Treatment With Chinese Herbal Medicine for Chemotherapy-Induced Peripheral Neuropathy: a Systematic Review and Meta-Analysis . Front Pharmacol . 2022 ; 13 : 764473 . doi: 10.3389/fphar.2022.764473 PMC8894889 35250555
86. Fei-Ze W , Wen-Juan X , Deng B , et al. Wen-Luo-Tong Decoction Attenuates Paclitaxel-Induced Peripheral Neuropathy by Regulating Linoleic Acid and Glycerophospholipid Metabolism Pathways . Front Pharmacol . 2018 ; 9 : 956 . doi: 10.3389/fphar.2018.00956 PMC6127630 30233366
87. Jialin G , Guo-Li W , Yu-Zhu M , et al. Exploring the Possible Mechanism and Drug Targets of Huang-Qi-Gui-Zhi-Wu-Wu Decoction for the Treatment of Chemotherapy-Induced Peripheral Neuropathy on Network Pharmacology . Evid Based Complement Alternat Med . 2020 ; 2020 ( 1 ): 2363262 . doi: 10.1155/2020/2363262 PMC7704154 33299447
88. Jie C , Yuan D , Jing W , et al. RNA-seq revealed the protective effect of Huangqi Guizhi Wuwu Decoction against cisplatin induced PC12 cell injury . Internat J Neurosci . 2024 ; 135 ( 12 ): 1384 – 1394 . doi: 10.1080/00207454.2024.2392123 39155776
89. Meiyu Z , Liu L , Yonghong T , et al. The mechanism of Taohong Siwu decoction in treating chemotherapy-induced peripheral neuropathy: a network pharmacology and molecular docking study . Transl Cancer Res . 2024 ; 13 ( 7 ): 3842 – 3853 . doi: 10.21037/tcr-24-1019 PMC11319946 39145055
90. Thomas F , Edda K , Nida C , et al. Acupuncture improves chemotherapy-induced neuropathy explored by neurophysiological and clinical outcomes - The randomized, controlled, cross-over ACUCIN trial . Phytomedicine . 2022 ; 104 : 154294 . doi: 10.1016/j.phymed.2022.154294 35785559
91. Jie H , Xiaoshu Z , Alan B . Effects of Nonpharmacological Interventions in Chemotherapy-Induced Peripheral Neuropathy: an Overview of Systematic Reviews and Meta-Analyses . Integr Cancer Ther . 2020 ; 19 : 1534735420945027 . doi: 10.1177/1534735420945027 PMC7476348 32875921
92. Zhaoshuo Y , Mei M , Qiang D , et al. Exploration of Clinical Advantageous Diseases in Traditional Chinese Medicine: chemotherapy-induced Peripheral Neuropathy . Chin J Exp Traditional Med Formulae . 2025 ; 31 ( 19 ): 288 – 298 .
93. Zhen K , Peiyi L , Zhuangzhi C , et al. Synergistic Effect of Acupuncture and Traditional Chinese Medicine on Cerebral Infarction in Rats: roles of Short-Chain Fatty Acids and Interleukin-17 . Int J Gene Med . 2025 ; 18 : 7231 – 7242 . doi: 10.2147/IJGM.S566274 PMC12682294 41362754
94. Xiaoyan H , Lijuan W , Hongfei S , et al. Acupuncture combined with methylcobalamin for the treatment of chemotherapy-induced peripheral neuropathy in patients with multiple myeloma . BMC Cancer . 2017 ; 17 ( 1 ): 40 . doi: 10.1186/s12885-016-3037-z PMC5223334 28068938
95. Jinqun X , Qing Z , Xue N , et al. The therapeutic effect of acupuncture in the treatment of chemotherapy-induced peripheral neuropathy: a randomized controlled trial . Front Oncol . 2025 ; 15 : 1500410 . 10.3389/fonc.2025.1500410 PMC12040932 40308502