TRPA1 in Chemotherapy-Induced Peripheral Neuropathy: A Promising Target for Immunomodulation and Anti-Inflammatory Therapy

Huini Yao; Mingzhu Li; Shengbo Jin; Jun Yu; Yuxin Jiang; Haozhe Piao; Ningxin Li; Qian Liu; Yue Shen; Sizuo Yan

doi:10.3791/69274

Review Article

TRPA1 in Chemotherapy-Induced Peripheral Neuropathy: A Promising Target for Immunomodulation and Anti-Inflammatory Therapy

DOI:

10.3791/69274

⸱

April 10th, 2026

Huini Yao¹^,² , Mingzhu Li¹ , Shengbo Jin³ , Jun Yu⁴ , Yuxin Jiang⁴ , Haozhe Piao⁵ , Ningxin Li² , Qian Liu⁴ , Yue Shen⁴ , Sizuo Yan²

¹Department of Integrated Traditional Chinese and Western Medicine Medical Oncology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, ²China Medical University, ³College of Acupuncture and Massage of Liaoning Traditional Chinese Medicine, ⁴Liaoning University of Traditional Chinese Medicine, ⁵Department of Neurosurgery, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute

Summary

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This review aims to explore the mechanistic role of transient receptor potential ankyrin 1 (TRPA1) in the pathogenesis of CIPN and evaluate its potential as a therapeutic target for immunomodulatory and anti-inflammatory intervention.

Abstract

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Chemotherapy-induced peripheral neuropathy (CIPN) is a common and serious clinical condition that results when a chemotherapeutic agent damages the peripheral nervous system and is usually characterized by abnormal pain in the distal limbs and increased sensitivity to hot and cold stimuli. However, few clinical treatments for CIPN are available, so it is critical to identify effective treatment modalities. Transient receptor potential ankyrin 1 (TRPA1), an injury receptor, can be activated by oxidative stress, inflammatory mediators, and hypothermic conditions during the pathogenesis and progression of CIPN. TRPA1 modulates the downstream inflammatory pathway and promotes the release of inflammatory factors and neuropeptides, resulting in abnormal immune regulation, which in turn leads to a neurogenic inflammatory response and pain signaling. In this study, the role of TRPA1 in the pathogenesis of CIPN is examined, the possibility of targeting TRPA1 to treat CIPN by inhibiting neuroinflammation is verified, and the prospects of using TRPA1 antagonists and natural herbs for the clinical treatment of CIPN are explored.

Introduction

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Cancer remains one of the major global public health challenges¹. Although chemotherapy plays a crucial role in improving cancer survival, it is often accompanied by severe adverse effects, among which CIPN is one of the most common and complex complications. CIPN is clinically characterized by symmetrical pain, paresthesia, and abnormal sensitivity to cold or heat in the distal extremities², and some patients may also experience impaired fine motor coordination³. The reported incidence of CIPN varies widely, ranging from approximately 50% to 90%, and about 30%-40% of cases may progress to chronic neurological complications², significantly reducing patients' quality of life and treatment compliance. The risk of developing CIPN is influenced by multiple factors, including the mode of administration (single dose, cumulative dose, or treatment duration), concomitant medications, age, anemia, higher body mass index (BMI), and pre-existing neuropathy²^,⁴^,⁵. Antineoplastic agents reported to induce varying degrees of neurotoxicity include platinum-based compounds, taxanes, vinca alkaloids, proteasome inhibitors (such as bortezomib), epigenetic or immunomodulatory drugs (such as thalidomide and lenalidomide), and microtubule inhibitors (such as eribulin)⁶.

Currently, pharmacological options for the management of CIPN remain limited. The American Society of Clinical Oncology (ASCO) recommends duloxetine as the only pharmacological intervention with evidence-based support for CIPN treatment. Clinical studies have demonstrated that duloxetine is effective in alleviating CIPN-related pain, with its therapeutic benefit being most pronounced in neuropathy induced by platinum-based chemotherapeutic agents, particularly oxaliplatin (OXA), whereas its efficacy in CIPN caused by other agents, such as taxanes and vinca alkaloids, appears to be more variable across studies⁷. Despite its demonstrated analgesic efficacy, the overall clinical benefit of duloxetine is moderate, as it primarily provides symptomatic relief rather than preventing CIPN or reversing underlying pathological changes. Moreover, although duloxetine is generally well tolerated, treatment may be accompanied by mild to moderate adverse effects, including fatigue, insomnia, and nausea, which may limit long-term adherence in some patients. Other commonly used agents, such as gabapentin and pregabalin, are employed for symptomatic management but have shown inconsistent or unsatisfactory therapeutic outcomes in CIPN⁸^,⁹. Therefore, there remains an urgent need to develop more effective preventive strategies and to identify novel therapeutic targets for CIPN.

In recent years, with the deepening understanding of the pathogenesis of CIPN, multiple mechanisms such as inflammatory response, oxidative stress, and alterations in neural plasticity have gradually attracted increasing attention¹⁰^,¹¹^,¹². Among these, oxidative stress and neuroinflammation are considered central contributors to the initiation and progression of neuronal injury in CIPN. Importantly, the TRPA1 channel, a redox-sensitive ion channel abundantly expressed in sensory neurons, has emerged as a key molecular mediator linking oxidative stress and inflammatory signaling to neuronal hyperexcitability and pain hypersensitivity¹³^,¹⁴. Distinct from TRPV1, which primarily senses noxious heat, and TRPM8, which detects cold stimuli, TRPA1 is characterized by its high sensitivity to various oxidative and electrophilic metabolites such as 4-hydroxynonenal (4-HNE)¹⁵. The activation of TRPA1 typically involves covalent modification of critical cysteine residues¹⁶, a unique mechanism that positions TRPA1 as a crucial molecular bridge linking chemotherapy-induced oxidative and lipid peroxidation stress to the development of pain hypersensitivity. Moreover, several animal studies have demonstrated a functional involvement of TRPA1 in chemotherapy-induced neuropathic pain. In particular, in OXA-induced neuropathy models, genetic ablation or pharmacological blockade of TRPA1 markedly alleviates cold and mechanical allodynia, indicating a crucial contribution of TRPA1 to the pathogenesis of CIPN¹⁷^,¹⁸.

Specifically, TRPA1 is a redox-sensitive ion channel highly expressed in peripheral nociceptive neurons. Chemotherapeutic agents frequently induce mitochondrial dysfunction, oxidative stress, and lipid peroxidation in neurons, leading to excessive accumulation of reactive oxygen species (ROS) and lipid peroxidation products such as 4-HNE. These reactive molecules can covalently modify key cysteine residues of TRPA1 or alter its activation threshold, resulting in channel opening, Ca²⁺ influx, and neuronal depolarization, thereby amplifying pain transmission and inflammatory signaling¹⁹^,²⁰^,²¹. Previous studies have further demonstrated that TRPA1 is sensitive to cold and can be activated by endogenous inflammatory mediators, contributing to the development of cold-induced pain hypersensitivity²². In addition, TRPA1 has been shown to act as a mechanosensitive ion channel whose activity is modulated by the cellular redox state, participating in abnormal mechanical pain and hypersensitivity²²^,²³. Beyond neurons, TRPA1 is also expressed in multiple immune cell types, where its activation modulates cytokine release and inflammatory cascades, further amplifying peripheral neuro-inflammation²⁴. Collectively, the cold sensitivity, mechanosensitivity, and redox responsiveness of TRPA1 establish a clear mechanistic link between chemotherapy-induced oxidative stress and the ensuing pathological pain processes, thereby contributing to the initiation and maintenance of CIPN. Accordingly, targeting TRPA1 to disrupt the vicious cycle of oxidative stress and neuroinflammatory toxicity may represent a promising therapeutic strategy for the management of chemotherapy-induced peripheral neuropathic pain. In existing studies, intervention strategies targeting TRPA1 have been validated across multiple model systems. In vitro, DRG neuron cultures combined with calcium imaging are commonly used to verify the impact of TRPA1 activation on chemotherapy-induced neuronal excitability²⁵. In vivo, CIPN is typically induced in rodents using OXA, paclitaxel, or bortezomib, followed by pharmacological or genetic inhibition of TRPA1 and subsequent behavioral assessments such as cold and mechanical hypersensitivity¹⁷^,²⁶^,²⁷. At the therapeutic level, TRPA1 antagonists have demonstrated efficacy in alleviating neuropathic pain in preclinical models²⁸^,²⁹. Collectively, these findings provide a solid experimental basis for translational research targeting TRPA1 as a therapeutic strategy for CIPN.

Current research has already revealed a possible connection between TRPA1 and CIPN. However, these studies have mainly focused on the direct impact of TRPA1 on pain signal transmission and its local role in the inflammatory response. Yet, there is still a lack of systematic research and in-depth exploration of the mechanisms by which TRPA1 modulates immune responses to affect the overall pathological process of CIPN. Therefore, this article discusses the potential mechanisms of CIPN, with a focus on exploring the role of TRPA1 in CIPN pathogenesis. The current status of research on TRPA1 antagonists and natural herbs is also summarized to validate the feasibility of inhibiting TRPA1 to produce anti-inflammatory immune effects for the treatment of CIPN. The innovation of this article lies in systematically studying the role of TRPA1 in the pathogenesis of CIPN from an immune-regulatory perspective, overcoming previous research limitations that focused solely on its effects in nerve cells or local inflammation. In addition, it provides new targets and theoretical support for the development of drugs to treat CIPN, with great scientific significance and clinical application value.

Review and Perspective

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1. Potential mechanisms for CIPN

The pathomechanism of CIPN is complex and associated with chemotherapeutic drug-induced mitochondrial dysfunction, oxidative stress, immune system abnormalities, ion channel dysregulation, dorsal root ganglion (DRG) neuron damage, and disruption of the neuronal cytoskeleton²^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴². Table 1 provides an overview of the specific pathogenic mechanisms involved in CIPN.

Mitochondrial dysfunction and oxidative stress
Chemotherapeutic agents induce mitochondrial morphological alterations, bioenergetic disturbances, and excessive production of ROS, leading to mitochondrial structural damage, functional impairment, and oxidative stress¹²^,⁴³. These events activate immune cells, elevate proinflammatory cytokine levels, and trigger inflammatory signaling pathways, ultimately contributing to the development of CIPN. Specifically, platinum-based chemotherapeutic agents form platinum-DNA adducts that accumulate in the DRG, where they bind to nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). This promotes crosslinking, alters the structure and synthesis of nuclear DNA, induces DNA/mitochondrial damage, enhances ROS production, activates injury receptor-related channels, and induces neuronal apoptosis. There is also evidence that OXA induces neuropathic pain by activating astrocytes and upregulating proinflammatory cytokines in the mitogen-activated protein kinase (MAPK) pathway.

In addition to platinum-based compounds, other chemotherapeutic agents can impair mitochondrial integrity through diverse mechanisms. Paclitaxel interferes with both axonal and mitochondrial transport, leading to the opening of the mitochondrial permeability transition pore (mPTP). This event results in the loss of mitochondrial membrane potential, excessive generation of ROS, ATP depletion, calcium efflux, and mitochondrial swelling. Bortezomib, on the other hand, inhibits proteasome activity and disrupts cellular protein homeostasis, thereby inducing mitochondrial structural damage and functional impairment. These alterations are manifested as mitochondrial swelling and vacuolization, calcium dysregulation, suppression of the respiratory chain, decreased ATP production, and accumulation of ROS. Moreover, vincristine (VCR) inhibits microtubule polymerization, which compromises mitochondrial transport along axons and subsequently leads to reduced membrane potential, disturbed calcium homeostasis, and abnormal neuronal excitability. Collectively, these agents highlight the central role of mitochondrial dysfunction in the neurotoxic effects of chemotherapeutic drugs⁴¹^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷.

Similarly, mitochondrial dysfunction serves as a central regulator of proinflammatory signaling, while inflammation, in turn, exacerbates mitochondrial damage, thereby creating a vicious cycle of neurotoxicity³⁰^,³¹. Notably, the ROS generated during this process directly activate the redox-sensitive ion channel TRPA1, inducing calcium influx, neuronal hyperexcitability, and characteristic CIPN-associated symptoms such as cold and mechanical allodynia. Thus, oxidative stress acts as a pivotal nexus linking mitochondrial damage, TRPA1 activation, and the pathogenesis of CIPN. Figure 1 illustrates the mechanisms by which mitochondrial dysfunction and oxidative stress contribute to the development of CIPN.
Abnormalities in the immune system
1. Neuroimmune Interactions
  Neuroimmune interactions play a crucial role in the development and persistence of CIPN. Increasing evidence suggests that communication between the nervous and immune systems contributes significantly to its pathogenesis. Chemotherapeutic agents induce cellular stress and axonal injury, leading to the release of damage-associated molecular patterns (DAMPs) that activate Toll-like receptor 4 (TLR4) signaling on macrophages and glial cells. This activation promotes M1 macrophage polarization and the secretion of chemokines such as CCL2 and CXCL10, which recruit CD4⁺ and CD8⁺ T lymphocytes and B cells into the DRG, while reducing the number of anti-inflammatory T cells⁴⁸^,⁴⁹^,⁵⁰^,⁵¹. Although neutrophils are highly susceptible to the cytotoxic effects of chemotherapy, leading to systemic neutropenia, several studies have reported increased neutrophil activation and infiltration in the peripheral nervous system and DRG during chemotherapy-induced neuropathy³². Mast cells (MCs) further regulate proinflammatory responses by recruiting immune cells and releasing a variety of inflammatory cytokines. In addition, proinflammatory cytokines can suppress natural killer (NK) cells' activity, exacerbating neuroinflammation and oxidative stress and thereby promoting CIPN progression⁵².
  
  Chemotherapeutic agents can also alter the expression of genes associated with immune and neuronal functions in sensory neurons. For example, VCR upregulates the expression of activating transcription factor 3 (Atf3) and neurotensin (Nts), thereby modulating chemokine release and promoting the recruitment of immune cells to the DRG, which in turn influences the neuroinflammatory response. OXA regulates the expression of prostaglandin-H₂ D-isomerase (Ptgds) and small nucleolar RNA host gene 1 (Snhg1), which are involved in the synthesis of inflammatory mediators and the modulation of neuronal plasticity, thereby affecting neuronal excitability and pain signal transmission. In contrast, cisplatin (CDDP) alters the expression of lipocalin-2 (Lcn2) and zinc finger homeobox 2 (Zfhx2), disrupting neuronal metabolic homeostasis and transcriptional regulation, and consequently promoting neuroinflammation and neuronal dysfunction⁵³. Collectively, the dysregulation of these gene expression profiles under chemotherapeutic stress reveals the complex interplay between neuronal injury and immune activation during the pathogenesis of CIPN.
  
  Moreover, TRPA1 is expressed not only in sensory neurons but also in immune cells such as macrophages and MCs, where it mediates the release of proinflammatory cytokines. This dual neuronal and immune expression of TRPA1 may serve as a key molecular link driving the neuroimmune crosstalk and inflammation underlying CIPN.
2. Exacerbation of Neuroinflammation
  Chemotherapeutic agents modulate the activation of and immune mediator secretion from satellite glial cells (SGCs) in the DRG, microglia and astrocytes in the spinal cord, and Schwann cells in the axons⁵⁴. Immune cell activation increases the levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-20 (IL-20), which promote neuroinflammation and neuronal sensitization; conversely, the expression of anti-inflammatory cytokines such as interleukin-10 (IL-10) and interleukin-4 (IL-4) is suppressed, impairing the resolution of inflammation. In parallel, chemokines including CCL2, CXCL1, CXCL12, CX3CL1, and CCL3 contribute to immune cell recruitment and glial-neuronal interactions. These changes collectively activate key inflammatory signaling pathways, such as MAPK and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which further enhance cytokine production and neuronal hyperexcitability⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹. Figure 2 illustrates the mechanisms by which immune system dysregulation induces CIPN.
  
  Importantly, recent studies have demonstrated that TRPA1 acts as a critical downstream effector and amplifier of these inflammatory cascades. Proinflammatory cytokines and oxidative mediators can sensitize or directly activate TRPA1 channels on sensory neurons, thereby linking neuroinflammation to increased neuronal excitability and pain hypersensitivity in CIPN⁶⁰^,⁶¹.
Ion channel dysregulation
1. Potassium channels
  Chemotherapeutic agents induce a neuroinflammatory response, leading to the aberrant expression of Kir4.1 channels, which promotes the activation of SGCs, the upregulation of glial fibrillary acid protein (GFAP), and the release of proinflammatory cytokines (e.g., TNF-α and IL-6). This exacerbates the excitability of DRG neurons and induces CIPN³³.
2. TRP Channels
  TRP channels are involved in the inflammatory response and neuropathic pain associated with CIPN and can be activated by chemotherapy-induced oxidative stress. Among them, the TRPA1 channel, predominantly localized in sensory neurons, mediates neurogenic inflammation by releasing neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP), which promote the recruitment of immune cells to sites of injury. Meanwhile, TRPA1 is also expressed in glial and immune cells, where its activation stimulates the release of proinflammatory cytokines and chemokines, further enhancing immune cell recruitment and amplifying the inflammatory response. Collectively, TRPA1 serves as a crucial bridge between the nervous and immune systems, contributing to enhanced inflammation and neuronal hypersensitivity in CIPN. Therefore, TRPA1 antagonism may alleviate pain through dual neuro-immune modulation by inhibiting the release of CGRP and SP, reducing neurogenic inflammation and immune cell recruitment, and lowering proinflammatory cytokine levels⁶².
  
  Singh et al. reported that OXA treatment increased the coexpression of transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential M8 (TRPM8) with TRPA1 in the DRGs of rats, leading to enhanced neuropathic pain behaviors. Notably, TRPA1 and TRPV1 share functional crosstalk in chemotherapy-induced pain signaling; however, current clinical applications mainly focus on the TRPV1 agonist capsaicin, which alleviates neuropathic pain by desensitizing TRPV1-expressing nociceptors³⁴. This provides insight for the future development of analgesic strategies targeting TRPA1. Collectively, TRPA1 acts as a critical integrator of oxidative stress, immune activation, and pain signaling, making it a promising target for both analgesic and anti-inflammatory therapies in CIPN.
DRG neuronal injury
1. Direct Neuronal Damage
  The DRG is the primary site affected by CIPN, but the mechanisms of neuronal damage differ among chemotherapeutic agents. Figure 3 depicts the distinct pathways involved in DRG neuronal injury induced by various drugs. For instance, PTX promotes macrophage infiltration into the DRG, which subsequently reduces the number of intraepidermal nerve fibers (IENFs) and accelerates the progression of CIPN³⁵. Platinum-based agents accumulate in DRG neurons, causing mitochondrial dysfunction, excessive ROS generation, and neuronal apoptosis. Thalidomide can directly induce DRG neuronal damage. Moreover, several chemotherapeutic agents alter the expression and function of sodium, potassium, and calcium ion channels, leading to neuronal hyperexcitability³⁶^,³⁷. Disruption of microtubule structures in the DRG further impairs axonal transport and triggers Wallerian degeneration, ultimately resulting in nerve fiber loss and impaired neural transmission³⁸.
2. Indirect immune-mediated damage
  In addition to direct neuronal toxicity, chemotherapeutic agents can indirectly injure DRG neurons through the activation of innate immune signaling. Cellular injury caused by these agents releases DAMPs, which in turn activate pattern recognition receptors (PRRs) such as TLR4 and the receptor for advanced glycation end products (RAGE). Activation of these receptors induces neuroinflammatory cascades, amplifies neuronal excitability, and exacerbates neuropathic pain³⁹. Collectively, these findings suggest that chemotherapeutic agents induce DRG injury through both direct cytotoxic mechanisms and indirect immune-mediated pathways, thereby contributing to the onset and progression of CIPN.
Disruption of the neuronal cytoskeleton
Previous studies have shown that microtubule depolymerization directly weakens the structural integrity of neurons and impairs their axonal elongation capacity. The disassembly of the cytoskeleton causes irregularities on the neuronal surface, and these mechanical alterations can serve as physical hallmarks of CIPN⁴⁰. Another study by Chine et al. was the first to demonstrate that Hsp27 can prevent CIPN by protecting axonal structure. Unlike traditional anti-inflammatory mechanisms, Hsp27 exerts neuroprotective effects by regulating apoptotic pathways and maintaining cytoskeletal stability⁴⁶.

Vinca alkaloids (such as vincristine, VCR) specifically bind to the β-tubulin ends, blocking spindle formation and axonal transport, leading to microtubule depolymerization and defects in neurite outgrowth⁴⁰. In contrast, paclitaxel stabilizes microtubules and prevents their depolymerization, thereby disrupting electrical signal transmission and mitochondrial transport within axons, which induces demyelination of peripheral nerve fibers⁴¹. Bortezomib, through a non-proteasomal pathway, induces excessive microtubule polymerization, inhibits neurite extension, and triggers axonal degeneration⁴².

These drugs collectively lead to axonal transport impairment, neuronal apoptosis, and loss of neural conduction, forming the core pathological basis of CIPN. In addition, activation of the RhoA/ROCK/LIMK/cofilin signaling pathway prevents actin filament remodeling, further inhibiting axonal regeneration⁶³. Cytoskeletal disruption also interacts with mitochondrial transport defects and calpain activation, forming a vicious "structure-energy-apoptosis" cycle that accelerates the progression of CIPN⁶⁴.

2. Mechanisms of CIPN associated with TRPA1

TRPA1 is a non-selective cation channel typically existing as a homotetramer in the cell membrane. It contains six transmembrane segments (S1-S6) characteristic of TRP channels. Among these, S1-S4 form the voltage sensor-like domain (VSLD), while S5 and S6 shape the pore through which ions pass. These regions are essential for the channel's activation and its role in sensing painful, thermal, and chemical stimuli⁶⁵. The long N-terminal region of TRPA1 contains multiple ankyrin repeat domains (ARDs), which mediate interactions with other proteins and contribute to channel regulation. This region also serves as a key site for modulation by kinases involved in pain signaling⁶⁶^,⁶⁷. At the C-terminus, the TRP-like domain connects to the transmembrane region and plays a central role in channel gating. Movement of this domain, together with rearrangements of S5 and S6, underlies channel opening and Ca²⁺ influx, which activates downstream signaling pathways involved in inflammation and pain⁶⁸^,⁶⁹. Overall, the ARDs, transmembrane helices (S1-S6), and TRP-like domain are the major structural features that determine TRPA1 activation and its role in pain and inflammatory signaling. Figure 4 illustrates the key structural domains of TRPA1 relevant to its activation by chemotherapeutic agents, while Table 2 summarizes the mechanisms of CIPN associated with TRPA1⁶¹^,⁶²^,⁷⁰^,⁷¹^,⁷²^,⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹^,⁸²^,⁸³.

Oxidative stress-mediated activation of TRPA1 in CIPN
1. Oxidative stress is a major contributor to both the antitumor efficacy and neurotoxicity of chemotherapeutic drugs⁸⁴.TRPA1 functions as a redox- and electrophile-sensitive ion channel that becomes activated under conditions of elevated oxidative stress during chemotherapy. Oxidized phospholipids (OxPAPCs) and other reactive oxygen species (ROS)-derived electrophiles covalently modify cysteine residues in the N-terminal domain of TRPA1, thereby activating the channel and promoting calcium influx. This activation leads to the release of neuropeptides and inflammatory mediators such as CGRP and SP, which mediate abnormal pain transmission and neurogenic inflammation in CIPN pathogenesis⁶¹^,⁷⁰. Meanwhile, peripheral inflammation triggered by chemotherapeutic drugs results in excessive generation and accumulation of ROS in sensory ganglia, which further activates and upregulates TRPA1, forming a ROS-TRPA1 positive feedback loop that amplifies inflammatory and mechanical hypersensitivity⁸⁵.
  
  CDDP-induced CIPN also relies on this mechanism, as CDDP promotes ROS production in oral tissues, which activates TRPA1 and leads to persistent orofacial pain⁸⁶. Similarly, OXA modulates TRPA1 activity through multiple mechanisms. On one hand, OXA directly activates TRPA1 via a glutathione-sensitive mechanism, leading to cytoplasmic acidification in DRG neurons⁷¹^,⁸⁷. On the other hand, OXA inhibits prolyl hydroxylase (PHD), thereby preventing hydroxylation of the proline residues in the N-terminal region of TRPA1, which enhances the channel's sensitivity to ROS and markedly increases its responsiveness to cold stimuli⁷¹. In addition, OXA activates the p38 MAPK signaling pathway, further promoting TRPA1-mediated cold hypersensitivity⁸⁸.
  
  Animal studies have provided strong evidence supporting these mechanisms. In OXA-treated wild-type mice, pronounced mechanical allodynia and cold hypersensitivity were observed, whereas these responses were significantly attenuated in TRPA1 knockout mice⁸⁹. Consistent findings were also obtained in a zebrafish larval model of CIPN, in which TRPA1 activation enhanced ROS production through promoting oxidative stress and pain signal transduction, thereby sustaining the pain response⁹⁰. Collectively, these findings indicate that TRPA1 functions as a critical nexus linking ROS sensing and pain amplification, forming a central pathway through which oxidative stress mediates neuropathic pain in CIPN.
The Role of TRPA1 in immune regulation and inflammatory pain
TRPA1 is a redox-sensitive, non-selective cation channel that is expressed in both the peripheral sensory nervous system and various immune cell types. It can be activated by chemotherapeutic drug-induced oxidative, nitrative, and aldehyde stresses, as well as by inflammatory mediators and electrochemical stimuli, thereby playing a critical role in inflammatory responses and pain sensitization during CIPN²⁴^,⁹¹^,⁹².
1. TRPA1 regulates immune cell-mediated neuroinflammation
  In the peripheral nervous system, TRPA1 is best characterized in DRG sensory neurons, where it serves as a key mediator of nociception. During chemotherapy, elevated levels of ROS, reactive nitrogen species (RNS), and aldehyde metabolites, primarily originating from injured neurons and surrounding Schwann cells, can directly activate neuronal TRPA1, leading to enhanced neuronal excitability and pain hypersensitivity⁹³. Meanwhile, in sensory neurons, TLR4 signaling has been shown to upregulate TRPA1 expression in DRG neurons, thereby enhancing pain hypersensitivity⁹⁴.
  
  Beyond neurons, Schwann cells also express TRPA1, which can be activated by oxidative stress. Activated Schwann cells amplify ROS signals and release inflammatory mediators, forming a "Schwann cell-neuron-TRPA1" feedback loop that sustains neuroinflammation and contributes to the development of CIPN⁷²^,⁷³. Animal studies have shown that depletion of sciatic nerve-resident macrophages markedly attenuates cancer-related pain induced by Schwann cell TRPA1 activation and oxidative stress, highlighting the interplay between Schwann cells and myeloid cells⁷³.
  
  In addition to sensory neurons, TRPA1 is functionally expressed in several immune cell populations, including macrophages, T cells, NK cells, and MCs²⁴^,⁷⁴^,⁹⁵. ROS, RNS, and metabolites generated during chemotherapy can activate TRPA1 in these cells, leading to diverse immune responses depending on the cell type⁹¹. In macrophages, TRPA1 suppresses proinflammatory activation, promotes an anti-inflammatory phenotype, and limits macrophage infiltration, thereby exerting anti-inflammatory and tissue-protective effects¹⁴^,⁹⁶. In lymphocytes, TRPA1 activation suppresses T cell activation and effector functions, negatively regulating T cell-mediated immune responses⁹⁷, whereas TRPA1-mediated Ca²⁺ influx may enhance NK cell cytotoxicity, modulating neuroinflammatory responses following nerve injury⁵²^,⁷⁴. In mast cells, TRPA1 activation has been implicated in stress-induced degranulation and proinflammatory signaling, contributing to the amplification of allergic and neurogenic inflammation²⁴^,⁷⁵.
  
  Together, these observations suggest that TRPA1 serves as a signaling hub linking neurons, Schwann cells, and immune cells, with elevated TRPA1 activation in each cell type contributing to the initiation and maintenance of CIPN. Figure 5 depicts the proposed mechanisms of TRPA1-mediated neuroimmune crosstalk and pain signaling in CIPN.
2. TRPA1 in inflammatory pain and CIPN-related nociception
  In the sensory nervous system, TRPA1 is predominantly localized in primary sensory neurons of the DRG, trigeminal ganglia (TG), and vagal ganglia (VG). Oxidative stress products, inflammatory mediators, and protein kinase signaling (PKA/PKC) induced by chemotherapeutic agents enhance TRPA1 phosphorylation and channel activity²⁶. Channel activation increases intracellular Ca²⁺ influx, triggering the release of neuropeptides such as SP, neurokinin A (NK-A), and CGRP, which promote vasodilation, plasma extravasation, and immune cell recruitment, thereby inducing neurogenic inflammation and pain sensitization⁶².
  
  Under inflammatory conditions, elevated levels of proinflammatory cytokines (IL-1 family, TNF-α, IL-6, IL-8) and chemokines (CXCL5/CXCR2) further augment ROS production and TRPA1 activation, leading to membrane depolarization and hyperexcitability of DRG neurons, ultimately contributing to neuropathic pain. Additionally, inflammatory mediators such as NGF upregulate TRPA1 expression, forming a positive feedback loop that sustains inflammation and pain¹⁴^,⁹⁸^,⁹⁹^,¹⁰⁰. TRPA1 also participates in both peripheral and central sensitization, thereby amplifying pain transmission¹⁰¹.
  
  Furthermore, TRPA1 promotes nociceptive signaling by modulating inflammation-related pathways. Upregulated TRPA1 increases Ca²⁺ influx and activates the pannexin-1 (PANX1) pathway, enhancing adenosine triphosphate (ATP) release. Extracellular ATP, acting as a neurotransmitter, further contributes to pain hypersensitivity¹⁰². Chemotherapeutic agents can also sensitize TRPA1 via activation of bradykinin B2 receptors and downstream PLC/PKCε signaling in mast cells, exacerbating CIPN-related pain¹⁰³. Conversely, opioid compounds such as loperamide have been shown to suppress TRPA1 and voltage-gated sodium channel (VGSC) activity, inhibit microglial activation and oxidative stress, and consequently alleviate hyperalgesia in CIPN¹⁰⁴^,¹⁰⁵.
  
  In summary, TRPA1 serves as a key molecular target linking oxidative stress and inflammatory signaling in CIPN. By coordinating bidirectional interactions between immune cells and sensory neurons, TRPA1 not only initiates and propagates inflammation but also amplifies pain, serving as a critical bridge between immune regulation, neuroinflammation, and nociceptive hypersensitivity.
3. TRPA1-mediated ion channel crosstalk and DRG neuronal sensitization
  TRPA1 is highly expressed in injured sensory neurons, particularly in the DRG, and acts as a key ion channel mediating CIPN. It modulates neuronal excitability and promotes nociceptive signal transmission through interactions with multiple ion channels. For example, activation of TRPV1 can enhance TRPA1 sensitivity, and both channels are often co-expressed, synergistically contributing to cold allodynia and mechanical hyperalgesia⁷⁶^,¹⁰⁶. In addition, TRPA1 exhibits complementary functions with the cold-sensitive channel TRPM8: TRPM8 mediates innocuous cooling sensations within the range of 25-28 °C, whereas TRPA1 is activated below 17 °C and is responsible for detecting intense, noxious cold stimuli. Abnormal activation of both channels has been implicated in the cold hypersensitivity commonly observed in CIPN patients⁷⁷. Chemotherapy-induced oxidative stress and enhanced Ca²⁺ channel activity can further activate TRPA1 channels, leading to frequent action potential firing dependent on voltage-gated Na⁺ channels (Nav1.7)⁷⁸^,⁷⁹. Moreover, Zn²⁺ can directly activate TRPA1 to promote the release of CGRP⁸⁰, whereas voltage-gated K^⁺ channels (Kv7) exert a negative regulatory effect on this process⁸¹. Collectively, the cooperative interaction between TRPA1 and other ion channels, including TRPV1, TRPM8, Ca²⁺, Na⁺, K⁺, and Zn²⁺ channels, amplifies neuronal excitability and nociceptive transmission in CIPN.
  
  Furthermore, intracellular pH homeostasis can modulate TRPA1 activity. The Na⁺/H⁺ exchanger 1 (NHE1) influences TRPA1 sensitivity by regulating intracellular pH. Under inflammatory or chemotherapy-induced injury conditions, TRPA1 and NHE1 interact in DRG neurons⁸⁷^,¹⁰⁷, and intracellular acidification enhances TRPA1 responsiveness, leading to increased action potential frequency and elevated release of neurotransmitters such as glutamate and CGRP⁸²^,⁸³. This process contributes to inflammatory pain and cold hypersensitivity and further sustains neuroinflammation. Conversely, inhibition of TRPA1 expression or function in DRG neurons markedly attenuates nociceptive transmission and neuroinflammatory responses¹⁰⁸.
  
  In summary, TRPA1 serves as a central molecular hub linking oxidative stress and ion channel signaling in CIPN. Through extensive crosstalk with multiple ion channels and intracellular regulatory mechanisms, TRPA1 promotes sensory neuron hyperexcitability and pain hypersensitization, representing a critical molecular target for the treatment of CIPN-associated pain. Figure 6 depicts the mechanism by which TRPA1 modulates neuronal excitability and enhances nociceptive signaling through interactions with various ion channels.

3. Potential of targeting TRPA1 for CIPN treatment

In the previous section, we elucidated how TRPA1 is a key target for alleviating CIPN by triggering a neuroinflammatory cascade response. The mechanism of action of TRPA1 is twofold: on the one hand, TRPA1 is directly modulated by the neuroinflammatory cascade and participates in the pathological process of CIPN; on the other hand, TRPA1 interacts with inflammatory signals, which in turn mediate neurotoxic responses and exacerbate neuronal damage. Therefore, targeted inhibition of TRPA1 can reduce oxidative stress and neuroinflammatory responses, attenuate pain signaling, and ultimately improve CIPN-related symptoms. Figure 7 depicts the proposed mechanisms through which inhibition of TRPA1, either by specific antagonists or natural herbal agents, mitigates neuropathic pain associated with CIPN.

TRPA1 antagonist
TRPA1 can be activated by exogenous substances (e.g., mustard oil and cinnamaldehyde) and endogenous substances (e.g., oxidative stress products and inflammatory mediators)⁶² to cause pain, itching, and inflammation¹⁰⁹. For this reason, TRPA1 has been recognized as a therapeutic target with broad application potential, including pain management, inflammatory diseases, and neurological disorders. Therefore, researching and developing TRPA1 antagonists are crucial.

Several TRPA1 antagonists have demonstrated potential therapeutic value in alleviating CIPN¹⁰⁹^,¹¹⁰^,¹¹¹^,¹¹²^,¹¹³^,¹¹⁴^,¹¹⁵^,¹¹⁶^,¹¹⁷. Their primary mechanisms involve suppressing TRPA1-mediated oxidative stress responses, calcium influx, and neuroinflammatory signaling, thereby exerting antagonistic effects on TRPA1 activity. In preclinical studies, the selective TRPA1 blocker HC-030031 significantly alleviated OXA- and CDDP-induced mechanical and cold hypersensitivity²⁸. Meanwhile, next-generation antagonists such as GRC-17536 and LY-3526318 have advanced to phase II clinical trials for diabetic neuropathy, chronic cough, and osteoarthritis-related neuropathic pain, showing good tolerability and preliminary efficacy¹⁰⁹^,¹¹³.

Table 3 provides a summary of the current development status and clinical applications of representative TRPA1 antagonists. These studies provide clinical evidence supporting the translational potential of TRPA1 antagonists in the treatment of neuropathic pain. However, most TRPA1 antagonists are still limited by low bioavailability and potential off-target effects¹¹⁵^,¹¹⁸^,¹¹⁹, and have not yet entered CIPN-specific clinical evaluation. Future research should focus on optimizing compound selectivity and pharmacokinetic properties, as well as designing clinical trials specifically targeting CIPN, to validate the therapeutic relevance of TRPA1 inhibition in this context.

In addition to direct antagonism, modulation of TRPA1 activity through other molecular targets has also shown promise in CIPN. Sigma-1 receptors exert regulatory functions on a variety of ion channels, and Sigma-1 receptor antagonists have been shown to significantly inhibit the plasma membrane expression and function of TRPA1 channels, thereby preventing the progression of pain symptoms in OXA-induced CIPN model mice⁸⁹. A study by Trevisan et al. demonstrated that the symptoms of CIPN hypersensitivity induced by bortezomib could be effectively prevented and alleviated by the concomitant use of the TRPA1 antagonist HC-030031 or the antioxidant α-lipoic acid prior to or at the time of chemotherapy¹²⁰. Furthermore, in the context of chemotherapeutic drug-induced neurotoxicity, TRPA1 inhibitors are able to mitigate neurological damage by reducing calcium-dependent proinflammatory signaling.

In summary, TRPA1 antagonists play important roles in the prevention and treatment of CIPN by modulating the function and inhibiting the activity of this channel, among other mechanisms, to attenuate pain hypersensitivity and alleviate nerve damage.
Modulators of TRPA1 activity as new options for CIPN treatment
TRPA1 is involved in the pathological processes of CIPN through the neuroinflammatory cascade response and neurotoxic injury and may be a new target for the treatment of CIPN.

Several studies have demonstrated that certain natural herbs and their active components are closely associated with the regulation of TRPA1 channel activity and exhibit biological effects such as anti-inflammatory and analgesic actions, thereby providing potential strategies for the prevention and treatment of CIPN. For instance, liquiritin has been shown to possess significant anti-inflammatory properties¹²¹, while allicin exhibits analgesic potential due to its antioxidant and anti-inflammatory characteristics¹²²; both compounds are involved in the modulation of TRPA1 channel activity. Based on these findings, it is speculated that these natural compounds may alleviate CIPN-related pain perception and neuroinflammatory responses through the regulation of TRPA1 activity, thus exerting potential therapeutic effects. Further studies have revealed that menthol exhibits a bidirectional regulatory effect on TRPA1 channels, activating TRPA1 at low concentrations while inhibiting its activity at higher concentrations. Appropriate use of menthol may therefore modulate TRPA1 activity to achieve analgesic and anti-inflammatory effects in patients with CIPN¹²³. Similarly, cinnamon, traditionally used as a warming therapy to promote blood circulation, contains cinnamaldehyde as its principal active component. Li et al. reported that cinnamaldehyde activates TRPA1 receptors, promoting thermogenesis in brown adipose tissue and thereby helping to maintain body temperature and alleviate cold sensitivity¹²⁴. Moreover, cinnamaldehyde enhances the antioxidant response by activating nuclear factor erythroid-related factor 2 (Nrf2)¹²⁵. Collectively, menthol, by inhibiting TRPA1 at higher concentrations, may relieve mechanical and cold allodynia characteristic of CIPN, whereas cinnamaldehyde, through its TRPA1-activating and Nrf2-mediated antioxidant mechanisms, may counteract chemotherapy-induced oxidative stress and improve cold intolerance in CIPN patients. Additionally, bergenin monohydrate, ligustrazine, saikosaponin, and water extracts of Notopterygium incisum have been shown to reduce neuropathic pain¹²⁶^,¹²⁷^,¹²⁸^,¹²⁹.

Table 4 summarizes the natural herbal sources of TRPA1 ligands and their possible mechanisms in alleviating CIPN. These findings highlight the potential of TCM components in mitigating neurotoxicity in CIPN. Although a variety of natural compounds have been identified as TRPA1 modulators with potential therapeutic effects, most of them remain at the in vitro and animal research stages, and the evidence for their efficacy in CIPN is mainly derived from preclinical models. In contrast, only menthol has limited human proof-of-concept evidence and ongoing registered clinical trials¹³⁰. These findings collectively suggest that while TRPA1-targeting natural products show great promise in alleviating CIPN-related neurotoxicity, further well-designed clinical studies are needed to validate their translational potential and therapeutic efficacy.

Natural TRPA1 modulators identified from plant extracts not only provide new therapeutic perspectives for pain management but also represent potential natural sources for the treatment of CIPN. Increasing evidence indicates that natural compounds can alleviate chemotherapy-induced neurotoxic symptoms by suppressing TRPA1 overactivation or exerting bidirectional regulatory effects on the channel, thereby achieving both analgesic and anti-inflammatory outcomes. However, despite their promising preclinical potential, systematic clinical validation remains insufficient. Moreover, these compounds typically exhibit multi-target and multi-pathway regulatory characteristics, making it difficult to define the specific contribution of TRPA1 modulation to their overall therapeutic effects. Future studies should focus on elucidating the molecular mechanisms through which natural TRPA1 modulators influence CIPN, exploring the synergistic interactions between TRPA1 and other ion channels or signaling pathways, and conducting well-designed clinical trials to confirm their efficacy and safety. Such efforts will be essential for translating TRPA1-targeting natural agents into practical strategies for CIPN management.

4. Discussion

According to the latest statistics from the International Agency for Research on Cancer (IARC), there will be nearly 20 million new cases of cancer in 2022, and approximately 50% of those cancer patients will eventually die from cancer or its complications. IARC projections also indicate that the number of new cancer cases per year will exceed 35 million in 2050. Cancer is therefore a major public health concern worldwide and one of the major contributors to the global burden of disease¹. Although novel therapies for cancer (e.g., targeted therapies and immunotherapy) continue to be researched and developed, chemotherapy still plays a central role in the treatment of cancer. CIPN is a common side effect of chemotherapy and affects the course of treatment and its efficacy. However, the pathogenesis of CIPN is unclear but may be related to mitochondrial dysfunction, oxidative stress, abnormalities in the immune system, ion channel dysregulation, and DRG neuron damage². Currently, only duloxetine has been recommended by the ASCO for pain management in CIPN patients, Despite its demonstrated analgesic efficacy, the overall clinical benefit of duloxetine is moderate, as it primarily provides symptomatic relief rather than preventing CIPN or reversing underlying pathological changes⁸. Therefore, exploring the potential targets of CIPN is important for drug development and precision therapy.

TRP channels, which are key mediators of nociceptive signaling, have been receiving increasing attention in the context of the development of CIPN therapies. Among the TRP channels, TRPA1 has been suggested to be a key factor in the induction of pain hypersensitivity by a variety of chemotherapeutic agents¹³¹. Therefore, this study focuses on the role of TRPA1 in the pathogenesis of CIPN and further elucidates the mechanisms by which it mediates neuropathic pain, as illustrated in Figure 8. This channel is activated by oxidative stress to elicit abnormal mechanical pain and cold hypersensitivity⁶¹^,⁷⁰^,⁷¹ and is involved in inflammatory nociception by modulating immune cells to mediate neuroinflammation⁶²^,⁷²^,⁷³^,⁷⁴^,⁷⁵. In addition, TRPA1 channels interact with TRPV1, TRPM8, and voltage-gated channels such as Ca²⁺, Nav1.7, Zn²⁺, and Kv7. These interactions amplify neuropathic and inflammatory pain responses⁷⁶^,⁷⁷^,⁷⁸^,⁷⁹^,⁸⁰^,⁸¹. Such synergistic modulation has significant clinical implications. Because TRPA1, TRPV1, and TRPM8 are co-expressed in sensory neurons and can mutually regulate each other's activity, dual or multi-target inhibitors are capable of producing more pronounced analgesic effects than those targeting TRPA1 alone. Moreover, this synergistic interaction allows each compound to achieve comparable analgesic efficacy at lower doses, thereby reducing potential adverse effects. Similarly, the DRG, a target of CIPN neurotoxicity, is affected by TRPA1. The activation of TRPA1 enhances the excitability of DRG neurons, which in turn promotes the release of neurotransmitters from the DRG, leading to increased hypersensitivity to nociceptive symptoms⁸²^,⁸³. In conclusion, TRPA1 can exacerbate neuropathic pain in CIPN patients by inducing a neuroinflammatory cascade response. Thus, antagonizing TRPA1 can effectively alleviate the inflammatory and painful symptoms of CIPN, which also suggests that the application of TRPA1 antagonists and natural herbs is crucial.

The efficacy of TRPA1 antagonists has been effectively demonstrated in animal models. For example, in TRPA1 KO mice and upon the application of TRPA1 antagonists (e.g., HC-030031), chemotherapeutic drug-induced neuropathic pain symptoms are significantly attenuated⁸⁶^,⁸⁹. However, there are still limitations to the application of TRPA1 antagonists, as clinical trials for patients with CIPN have not yet been conducted, suggesting that the safety and efficacy of TRPA1 antagonists in humans need to be further evaluated and confirmed. For instance, differences in TRPA1 expression patterns and sensitivity to antagonists between rodents and humans may lead to discrepancies between preclinical and clinical outcomes. In addition, the conversion of experimental doses from animals to humans remains uncertain, further increasing the complexity of drug development.

In addition, the precise mechanisms by which TRPA1 functions as a therapeutic target in CIPN have not yet been fully elucidated, and its tissue-specific roles require further investigation. Given the broad expression of TRPA1 in sensory neurons, Schwann cells, and immune cells, delineating its specific functions across different cellular contexts remains challenging. Most existing studies rely on systemic TRPA1 antagonists, making it difficult to precisely attribute observed effects to specific cellular compartments. It should be emphasized that TRPA1 expressed in sensory neurons directly mediates nociceptive signaling, whereas TRPA1 in Schwann cells and immune cells primarily regulates inflammatory and microenvironmental processes that secondarily modulate pain sensitivity. Therefore, tissue-specific deletion of TRPA1 would provide important mechanistic insights. Neuronal-specific loss of TRPA1 could clarify its direct role in nociceptor excitability and pain transmission, whereas Schwann cell-specific deletion may elucidate how TRPA1-driven oxidative stress and glial-neuronal interactions promote sustained neuroinflammation. Importantly, immune cell-specific TRPA1 knockout models (e.g., in macrophages or T cells) would help define the contribution of immune TRPA1 signaling to neuroimmune crosstalk and inflammatory regulation in CIPN. Such approaches would substantially deepen our understanding of tissue- and cell-specific TRPA1 functions and facilitate the development of more precise therapeutic strategies. Meanwhile, multiple aspects of TRPA1 antagonism in the treatment of CIPN remain to be further explored. For example, whether TRPA1 exhibits differential functional roles in CIPN induced by distinct chemotherapeutic agents, and how its activity can be more precisely modulated to achieve optimal therapeutic efficacy, remain important unresolved questions.

In this context, the combined use of TRPA1 antagonists with natural herbal compounds or traditional Chinese medicine formulations represents a promising therapeutic approach. Such combination therapy may not only reduce drug-related toxicity but also enhance efficacy through multi-target synergistic effects. Overall, antagonizing TRPA1 can modulate immune responses and interrupt neuroinflammatory cascades, thereby effectively mitigating neurotoxicity and neuronal damage, offering new insights and potential strategies for the clinical management of CIPN.

Conclusions

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This review comprehensively explores the intricate relationship between TRPA1 and CIPN, as well as the potential anti-inflammatory effects of TRPA1 antagonism in its treatment. Preclinical studies have shown that pharmacological inhibition or genetic deletion of TRPA1 can suppress neuroinflammation, reduce neuronal excitability, and mitigate neurotoxicity, thereby producing anti-inflammatory and analgesic effects that may help alleviate the symptoms of CIPN. However, there are still some limitations in the current research. Future studies should further explore the specific molecular mechanisms underlying TRPA1's involvement in CIPN, optimize targeting strategies, and conduct large-scale clinical trials to verify the safety and efficacy of TRPA1 antagonists. This will provide more precise and effective treatment options for patients with CIPN.

Oxaliplatin-induced CIPN diagram, ROS, apoptosis, mitochondrial DNA, MAPK pathway, astrocytes.
Figure 1: Mitochondrial dysfunction and oxidative stress-induced CIPN mechanisms. Platinum-based chemotherapeutic agents form platinum-DNA adducts that accumulate in the DRG, where they bind to nDNA and mtDNA. This induces DNA/mitochondrial damage, enhances the production of ROS, and induces neuronal apoptosis. There is also evidence that OXA induces neuropathic pain by activating astrocytes and upregulating proinflammatory cytokines in the MAPK pathway. Please click here to view a larger version of this figure.

Immunology process diagram: DRG cell changes, immune mediators, signaling pathways, gene expression.
Figure 2: Mechanisms of CIPN induction by abnormalities in the immune system. (A) Chemotherapeutic agents lead to macrophage activation, increases in the numbers of T lymphocytes (CD4⁺), cytotoxic T cells (CD8⁺), and B cells in the DRG, and a decrease in the number of anti-inflammatory T cells and neutrophils. MCs contribute to the progression of CIPN by recruiting immune cells and releasing a variety of inflammatory cytokines in CIPN, thereby decreasing the activity of NK cells, which in turn exacerbates neuroinflammation and oxidative stress. (B) Chemotherapeutic agents modulate the activation of and immune mediator secretion from via SGCs in the DRG, microglia and astrocytes in the spinal cord, and Schwann cells in the axons, resulting in increased excitability of sensory neurons and intensified pain hypersensitivity in CIPN. (C) Activation of immuno-inflammatory signaling pathways, such as MAPK and NF-κB, also plays an important role in exacerbating neuroinflammatory responses. (D) Chemotherapeutic agents can also activate immune cells and enhance neuroinflammatory responses by increasing TLR4 and triggering associated gene dysregulation. Please click here to view a larger version of this figure.

Chemotherapy-Induced Peripheral Neuropathy (CIPN) diagram, showing drug interactions and effects.
Figure 3: DRG is a major target for chemotherapeutic agents to trigger CIPN. (A) PTX can lead to macrophage infiltration into the DRG, which in turn triggers a decrease in the number of IENFs. (B) Platinum drugs accumulate in the DRG, leading to mitochondrial dysfunction and increased ROS levels, which, in turn, promote neuronal apoptosis. (C) Thalidomide can directly damage the DRG. (D) Chemotherapeutic agents can also damage DRG neurons by altering sodium, potassium, and calcium ion channels, disrupting microtubule structure, and activating PRRs. Please click here to view a larger version of this figure.

TRPA1 ion channel diagram, depicting Ca²⁺ flow in cell membrane affecting pain, temperature, inflammation.
Figure 4: The key structural domains of TRPA1 relevant to its activation by chemotherapeutic agents. The TRPA1 channel contains six transmembrane α-helical fragments (S1-S6). Among them, S1-S4 constitute the VSLD, and S5 and S6 form a concave pore loop structure. Both the NH2 and COOH ends of the TRPA1 channel are located in the cytoplasm. One of the longer NH2 termini contains ARDs and the Cdk5 site, whereas the C-terminus of TRPA1 contains a TRP-like domain and is linked to the transmembrane structural domain. Channel activation can cause Ca²⁺ influx, which in turn triggers a series of cell signaling pathways, such as those that regulate gene expression, promote cell proliferation, and induce inflammatory responses.The structure of TRPA1 dictates its function in sensing pain and heat/cold sensitivity. Please click here to view a larger version of this figure.

TRPA1 signaling pathway diagram; inflammation to pain neuroconduction; CIPN; educational biology.
Figure 5: TRPA1 regulates immune cell-mediated neuroinflammatory nociception. Immune cells (macrophages, Schwann cells, and MCs), proinflammatory factors (IL-1 family, TNF-α, IL-6, IL-8), chemokines (CXCL5/CXCR2), inflammatory mediators (NGF, PKA/PKC), and TLR4 can activate TRPA1 channels. Activation of TRPA1 channels can increase intracellular Ca²⁺ concentration, which promotes the release of SP, NK-A, and CGRP, affects immune cells (T cells, NK cells), and modulates inflammation-related pathways (PANX1 pathway), thereby enhancing the excitability of DRG neurons and maintaining neuroinflammation and persistent pain. Please click here to view a larger version of this figure.

Chemotherapy-induced neuropathy diagram with TRP channels showing pain pathways, ion exchange, modulation.
Figure 6: TRPA1 modulates ion channels to accelerate pain signaling. TRPA1 and TRPM8 are involved in cold hypersensitivity, and TRPA1 and TRPV1 are involved in mechanical allodynia. In addition, TRPA1 channels with voltage-gated Ca²⁺, Nav1.7, Zn²⁺, Kv 7, and Kir4.1 channels promote the release of inflammatory mediators (e.g., CGRP, GFAP) and proinflammatory factors (e.g., TNF-α, IL-6), triggering the hyperexcitability of DRG neurons, which in turn exerts a synergistic effect in exacerbating neuropathic and inflammatory pain. Please click here to view a larger version of this figure.

TRPA1 pathway in neuropathic pain, diagram with herb influence, Ca2+ ions, neuronal inflammation, CIPN.
Figure 7: Potential of targeting TRPA1 for CIPN treatment. The use of TRPA1 antagonists and natural herbs can inhibit TRPA1 channel activity, thereby reducing Ca²⁺flux and oxidative stress, which, in turn, suppresses neuroinflammatory responses and reduces neuropathic pain, ultimately reducing nerve damage and improving CIPN-related symptoms. Please click here to view a larger version of this figure.

TRPA1 pathway activation diagram; oxidative stress, inflammatory mediators, and cold conditions effects.
Figure 8: Inhibiting TRPA1. A Therapeutic Strategy for CIPN. TRPA1 activation drives inflammation and hypersensitivity in CIPN; its inhibition by antagonists or herbs may reduce neurogenic inflammation, nociceptive sensitization, and CIPN symptoms. Please click here to view a larger version of this figure.

Table 1: Potential mechanisms underlying CIPN. Chemotherapeutic agents contribute to CIPN through multiple pathological pathways, including mitochondrial dysfunction and oxidative stress, immune system abnormalities, ion channel dysregulation, DRG neuronal injury, and disruption of the neuronal cytoskeleton. These mechanisms collectively lead to neuroinflammation, neurotoxicity, and neuropathic pain. Please click here to download this Table.

Table 2: Mechanisms of CIPN associated with TRPA1. TRPA1 contributes to CIPN through multiple pathological processes, including oxidative stress-induced activation, immune modulation and inflammation, ion channel interactions, and DRG neuronal injury. These mechanisms collectively enhance neuronal excitability and promote neuropathic pain and hypersensitivity. Please click here to download this Table.

Table 3: Current development status and clinical indications of representative TRPA1 antagonists. This table summarizes the major TRPA1 antagonists investigated in preclinical and clinical studies, including their mechanisms of action, therapeutic indications, and drug development stages. These agents inhibit TRPA1 channel activity, thereby reducing oxidative stress, inflammation, and neuropathic pain associated with CIPN and other pathological conditions. Please click here to download this Table.

Table 4: Natural herbal sources of TRPA1 ligands and their potential mechanisms in alleviating CIPN. This table summarizes representative natural compounds and herbal extracts that modulate TRPA1 activity, including their sources, chemical types, experimental conditions, and molecular targets. These natural agents exert neuroprotective and anti-inflammatory effects by regulating TRPA1 and related signaling pathways, thereby alleviating oxidative stress, neuroinflammation, and neuronal hyperexcitability associated with CIPN. Please click here to download this Table.

Disclosures

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There are no financial conflicts of interest to disclose.

Acknowledgements

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The authors would like to express their gratitude to all members of Mingzhu Li's group for their support and assistance. This manuscript was supported by the China National Natural Science Foundation (82104838), China Promotion Foundation Spark Program (XH-D001), and Liaoning Provincial Key Research and Development Programme(2024JH2/102500062), which is gratefully acknowledged. Figure 1 and Figure 2 were drawn using FigDraw.

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TRPA1 in Chemotherapy-Induced Peripheral Neuropathy: A Promising Target for Immunomodulation and Anti-Inflammatory Therapy

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