Mechanisms and Therapeutic Potential of GPX4 in Pain Modulation

Abstract

Pain, a complex symptom encompassing both sensory and emotional dimensions, constitutes a significant global public health issue. Oxidative stress is a pivotal factor in the complex pathophysiology of pain, with glutathione peroxidase 4 (GPX4) recognized as a crucial antioxidant enzyme involved in both antioxidant defense mechanisms and ferroptosis pathways. This review systematically explores GPX4’s functions across various pain models, including neuropathic, inflammatory, low back, and cancer-related pain. Specifically, the focus includes GPX4’s physiological roles, antioxidant defense mechanisms, regulation of ferroptosis, involvement in signal transduction pathways, and metabolic regulation. By summarizing current research, we highlight the potential of GPX4-targeted therapies in pain management.

Key Summary Points

The glutathione peroxidase (GPX) family, particularly GPX4, plays a pivotal role in combating oxidative stress and maintaining redox balance. GPX4 has shown potential in inhibiting cellular ferroptosis and alleviating various types pain.

This study focuses on the mechanisms of GPX4 in pain signaling pathways and its therapeutic potential.

GPX4 plays a critical role in pain management, with potential for modulation through antioxidants and nanotechnology to enhance its expression. Future research on GPX4 holds promise for translating these findings into effective clinical therapies for pain treatment.

Introduction

Pain is a fundamental physiological response to potential tissue damage, crucial for self-preservation [1]. It is classified into acute and chronic pain based on its cause and duration. Acute pain, typically responsive to treatment, often resolves within a week [2]. However, inadequate management of postoperative acute pain can hinder recovery and may contribute to the transition from acute to chronic pain [3], resulting in an enormous social, psychological, and economic burden [4]. Chronic pain, defined as pain persisting for more than 3 months [5], affects over 30% of the global population [4, 6]. In the United States alone, chronic pain affected approximately 20.9% of adults, or about 51.6 million people, in 2021 [7]. Despite the availability of various treatment options, chronic pain management remains insufficient, largely due to an incomplete understanding of the underlying mechanisms [8]. To improve pain management, further research is necessary to elucidate these mechanisms, identify new therapeutic targets, and develop integrated, interdisciplinary treatment approaches.

The glutathione peroxidase (GPX) family, consisting of eight members (GPX1–GPX8), plays a critical role in combating oxidative stress and maintaining redox homeostasis [9]. GPX4 represents a critical component of the cellular redox system, influencing numerous cellular processes [10]. Its unique ability to scavenge membrane lipid peroxidation products and prevent oxidative stress distinguishes it from other family members [11]. This distinct function is attributed to GPX4’s specific amino acid sequence and spatial structure [12]. The GPX4 gene, which encodes a 19-kDa monomeric enzyme, is located on chromosome 19p13.3 in the human genome. It spans 2.8 kb and consists of seven exons [13, 14]. Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and endogenous antioxidant defenses, has been implicated in neuronal sensitization and the pathogenesis of chronic pain [15]. Despite the known connection between the GPX family and oxidative stress, the role of GPX in pain modulation has not been extensively studied. Recently, GPX4 has gained attention for its role in pain regulation [16]. Wang et al. demonstrated that upregulating GPX4 expression can inhibit ferroptosis, blocking the activation of neurons and astrocytes in the spinal dorsal horn, thereby alleviating neuropathic pain (NP) caused by chronic constriction injury (CCI) in rats [17]. Similarly, in a spared nerve injury (SNI)-induced NP rat model, reduced GPX4 expression contributed to the onset of ferroptosis. Sirtuin 2 (SIRT2) alleviates chronic NP by suppressing ferroptosis in rats [18]. Research has also shown that the disordered levels of GPX4 and the abnormal mitochondrial morphological changes in the spinal cord and dorsal root ganglion (DRG) tissues of rats with complete Freund’s adjuvant (CFA)-induced inflammatory pain are associated with ferroptosis. Intrathecal delivery of liproxstatin-1 inhibits ferroptosis and attenuates mechanical and thermal hypersensitivity in rats [19]. Therapeutics like ferrostatin-1 (Fer-1), which inhibit iron accumulation and reduce GPX4 levels, have been shown to alleviate lipid peroxidation associated with bone cancer pain (BCP) [20]. The findings highlight oxidative stress as an important therapeutic target for alleviating various types pain and its significance for improving pain management and patient quality of life. In this review, further studies on GPX4 and its relationship to pain will be detailed in the subsequent sections.

This review explores the biological functions of GPX4 in pain modulation, including its antioxidant defense, regulation of ferroptosis, participation in signal transduction pathways, and metabolic regulation. Understanding these mechanisms provides insights into potential GPX4-targeted therapies for alleviating pain. In diseases characterized by oxidative stress, such as neurodegenerative, inflammatory, cardiovascular disorders and neoplasms, inhibiting ferroptosis via GPX4 can indirectly alleviate associated pain [21, 22]. Taken together, these results suggest that GPX4 plays a significant role in pain regulation, with a crucial role in regulating pain models such as NP, arthritic pain, low back pain, and cancer pain (Table 1).

Table 1.

The role of GPX4 in different pain models

Pain type	Models	Location	Conclusions	References
Neuropathic pain (NP)	Chronic constriction injury (CCI) (rat)	Sciatic nerve	Ferroptosis caused by dysregulated levels of glutathione peroxidase 4 (GPX4) and anti-acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) in the spinal cord of rats leads to NP caused by CCI of the sciatic nerve	[23]
NP	Spared nerve injury (SNI) (rat)	Sciatic nerve	The levels of both iron and ACSL4 were significantly increased in the spinal cord after SNI, while the expression of GPX4 was decreased	[18]
Inflammatory pain	Complete Freund’s adjuvant (CFA) (rat)	Subcutaneous intra-plantar of left hind paw	Intrathecal injection of liproxstatin-1 alleviates inflammatory pain by reducing ACSL4 protein levels, increasing GPX4 protein levels, and inhibiting ferroptosis in dorsal root ganglion (DRG) and myelocele cells	[19]
Low back pain	Intervertebral disc degeneration (IDD)(mice)	L4–L5 lumbar vertebrae	The expression of ACSL4 was enhanced while GPX4 was decreased after IDD. Knockdown of Sirt3, increased expression of ACSL4, and decreased expression of GPX4, but overexpression of USP11 could ameliorate ferroptosis events	[24]
Arthritic pain	Osteoarthritis (OA) (mice)	Knee of the medial meniscus	Acetyl zingerone reduced the occurrence of ferroptosis by promoting the expression of GPX4, inhibiting cartilage destruction and osteophyte formation, and alleviating damage to articular cartilage caused by surgical destabilization of the medial meniscus	[25]
Arthritic pain	OA (rat)	Knee of the anterior cruciate ligament	Vitamin K2 (VK2) can inhibit the decreased expression of GPX4 in cells, thereby reducing the degradation of chondrocyte extracellular matrix (ECM) and alleviating knee pain	[26]
Cancer pain	Cancer-induced bone pain (CIBP) (rat)	Right leg	Naringenin reversed the downregulation of the spinal anti-oxidative molecule GPX4 in CIBP rats and alleviated mechanical allodynia in rats	[27]

Methods

Search Strategy and Selection Criteria

To identify relevant studies on the mechanisms and therapeutic potential of GPX4 in pain modulation, we conducted a systematic search of electronic databases including PubMed, Scopus, and Web of Science up to August 2024. The search terms included glutathione peroxidase 4, GPX4, glutathione peroxidase, GPX, pain modulation, pain, mechanisms, and applications. Additional records were identified by searching the reference lists of retrieved articles to ensure comprehensive coverage. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Inclusion criteria were as follows: studies must have been published in English; focused on the role and mechanisms of GPX4 in pain modulation; and included human participants. Only peer-reviewed articles were considered.

Exclusion criteria included: studies that did not focus on GPX4’s role in pain modulation; and studies not available in English. Two independent reviewers performed the initial screening of titles and abstracts, followed by a full-text review to confirm eligibility. Any discrepancies were resolved through consensus with a third reviewer.

Biological Functions of GPX4 in the Regulation of Pain

Antioxidant Defense

GPX4 plays a crucial role in regulating oxidative stress by acting as an essential antioxidant enzyme that protects cells. It catalyzes the reduction of lipid hydroperoxides, thereby counteracting lipid peroxidation [22]. Oxidative stress, a common cause of neurodegenerative diseases and nerve damage, often manifests with painful symptoms [28]. GPX4 helps protect sensory neurons, particularly mitochondrial membranes, from oxidative damage, thereby potentially reducing pain associated with nerve injury [29]. Mitochondria, crucial for ROS production and cellular energy generation, highlight GPX4’s significant role in maintaining cellular integrity and reducing NP resulting from mitochondrial dysfunction [30, 31]. Furthermore, research indicates that mitochondrial damage in the gastrocnemius muscle tissue of a rat fibromyalgia model affects mitochondrial biogenesis processes, upregulates the expression of NRF2 and GPX4, and can potentially alleviate fibromyalgia [32]. Additionally, GPX4’s expression is regulated at both the transcriptional and post-translational levels [33, 34]. The transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2, NFE2L2; nuclear factor-erythroid 2-related factor 2, NRF2) induces GPX4 expression, thereby enhancing antioxidant defenses against oxidative stress [35]. The activation of NRF2, which is responsible for antioxidant defense and membrane repair, limits membrane damage [36, 37]. The relevance of NFE2L2 in modulating both acute and chronic neuroinflammation has been reported in several studies [38, 39]. GPX4 has been discovered to be a target gene of NFE2L2, further demonstrating the crucial role of NFE2L2 in antioxidant defense [40, 41]. Li et al. demonstrated that the combination of autophagy and NFE2L2/NRF2 activation represents a treatment approach for NP. Impaired autophagy also reduces the protective effect of astrocytes on neurons against ROS stress due to decreased levels of glutathione (GSH) released by astrocytes, which could be improved by activating the NFE2L2/NRF2 pathway. Research has also demonstrated that simultaneous activation of autophagy and the NFE2L2 pathway further relieves pain compared to activating autophagy alone [42]. In addition to transcriptional regulation, the expression of GPX4 is also regulated at the protein level [43]. Heat shock proteins, such as heat shock protein family A member 5 (HSPA5), have been identified as key regulators of GPX4 protein degradation, further highlighting its role in cellular protection and membrane integrity [44, 45].

A study by Han et al. has shown correlations between oxidative stress biomarkers (e.g., malondialdehyde, MDA; GPX; superoxide dismutase, SOD) and inflammation markers (e.g., interleukin-1, IL-1; interleukin-6, IL-6; C-reactive protein, CRP) in pain modulation post-laryngectomy surgery [46]. GPX4 suppresses oxidative stress, thereby reducing inflammatory mediators like prostaglandins and interleukins, which amplify pain sensation [47]. Additional studies suggest that maintaining sufficient GPX4 activity prevents lipid peroxidation in neurons, facilitates effective repair of lipid oxidation damage, reduces pain-associated neuropathy, and potentially suppresses neuroinflammatory responses, thereby alleviating pain sensation [48, 49].

Consequently, GPX4, as a vital component of the anti-oxidative defense system, mitigates lipid peroxidation and regulates oxidative stress, preserving mitochondrial function and cellular membrane stability, which alleviates neural damage and pain induced by oxidative stress. This mechanism holds potential benefits for treating pain conditions closely linked to oxidative stress, such as neuropathic and inflammatory pain, by suppressing oxidative stress and reducing the production of inflammatory mediators. Research indicates that GPX4 is significant in reducing oxidative stress and lipid peroxidation, making it a promising therapeutic target [50]. Regulating the activity or expression of GPX4 may effectively alleviate pain and pathological conditions associated with oxidative stress, thus having significant value.

The Regulation of Ferroptosis

GPX4 acts as a crucial downstream mediator of the amino acid transporter system x_c⁻, playing a vital role in ferroptosis regulation by reducing lipid hydroperoxides in membranes. This reduction prevents harmful lipid oxidation and offers cellular protection against ferroptosis [51, 52]. The direct knockout of GPX4 induces ferroptosis, demonstrating its essential function in this cell death pathway [53]. GPX4’s activity is closely tied to selenium, which enhances GPX4 expression at the transcriptional level, further emphasizing its importance in ferroptosis regulation [54]. Previous studies have indicated that Fer-1 not only suppresses iron accumulation but also diminishes GPX4 levels, thereby alleviating lipid peroxidation associated with BCP [20]. This review synthesizes recent findings that implicate oxidative stress as a significant therapeutic target for alleviating cancer pain. A comprehensive understanding of the molecular mechanisms underlying nociception during cancer progression and treatment is crucial for advancing pain management and improving patients’ quality of life [55]. Seibt et al. suggested that genetic studies in cellular and mouse models have identified GPX4 as a critical regulator of ferroptosis, a specific form of cell death. Beyond these genetic approaches, the development of small molecule inhibitors and inducers specific to ferroptosis has not only advanced our understanding of its molecular mechanisms but also holds promise for therapeutic intervention [56]. Consequently, these molecules could potentially be used to modulate ferroptosis, inhibiting it in the context of degenerative diseases and inducing it in cancer, thereby providing targeted treatments for these conditions. The implication of this research is that cellular susceptibility to ferroptosis markedly increases under conditions of GPX4 activity inhibition or diminished expression. Specifically, intracellular iron accumulation promotes GSH depletion and accelerates lipid peroxidation, which exacerbates oxidative stress, leading to downregulation of GPX4 expression and upregulation of ACSL4 mRNA and protein levels. Excessive iron loading promotes lipid peroxidation and enhanced mitochondrial ROS production, thereby reducing the mitochondrial membrane potential—a phenomenon consistent with the induction of ferroptosis [30]. For instance, Guo et al. suggested that the dysregulation of GPX4 and ACSL4 leading to ferroptosis in the rat spinal cord contributes to NP caused by CCI of the sciatic nerve [23]. This is potentially linked to CCI-induced mitochondrial damage, enhanced membrane lipid peroxidation, and increased oxidative stress, which lower GPX4 levels and elevate ACSL4 levels [17]. Moreover, Zhang et al. reported that in a rat SNI model, elevated iron content and ACSL4 levels alongside reduced expression of GPX4 in the spinal cord resulted in mechanical allodynia, which could be relieved by intrathecal injection of recombinant adenovirus overexpressing SIRT2, decreasing oxidative stress and inhibiting spinal cord ferroptosis [18]. The aforementioned studies highlight the significant role of ferroptosis in NP, with GPX4 being a critical component in this process.

Additionally, recent studies have uncovered a novel mechanism linking copper-induced GPX4 depletion to ferroptosis, providing new insights into the regulation of this form of cell death and its connection to autophagy-dependent cell death. A novel mechanism involving copper-induced GPX4 depletion has been discovered, where exogenous copper directly binds to GPX4 cysteine residues C107 and C148, enhancing GPX4 ubiquitination and aggregate formation. Copper induces ferroptosis in macrophages via autophagy-mediated degradation of GPX4, a process distinct from nucleosome uptake. Tax1 binding protein 1 (TAX1BP1), functioning as an autophagic receptor for GPX4, facilitates this degradation, leading to enhanced lipid peroxidation and subsequent ferroptosis [57]. These findings provide new insights into the connection between mental stress and autophagy-dependent cell death.

Overall, GPX4 plays a significant role in suppressing ferroptosis by reducing lipid peroxidation through GSH consumption, thereby alleviating pain, which suggests that interventions targeting GPX4 may hold promise as novel therapeutic strategies for pain management [51, 58].

Signal Transduction

Multiple studies indicate that GPX4 plays a significant role in the mechanisms of pain signal transduction. Cheng et al. demonstrated that in both animal models and cell cultures, suppression of the SLC7A11 (solute carrier family 7 member 11, SLC7A11)-GPX4 axis by aconitine-induced ferroptosis regulates joint pain [59]. Atorvastatin facilitates mitochondria-driven ferroptosis through modulation of the NRF2-xCT/GPX4 (solute carrier family 7 member 11, xCT) signaling axis [60]. Maresin1 mitigates liver injury initiated by ferroptosis by suppressing ROS production and concurrently stimulating the NRF2/HO-1/GPX4 (heme oxygenase 1, HO-1) pathway [61]. Wan et al. established a destabilization of the medial meniscus (DMM)-induced osteoarthritis (OA) model in 8-week-old wild-type and AMPK (adenosine 5′-monophosphate (AMP)-activated protein kinase, AMPK) α-knockout mice, and conducted an in vitro study using chondrocytes exposed to interleukin-1β (IL-1β) to mimic an OA microenvironment. The study results indicate that baicalein alleviates OA pain by suppressing ferroptosis in mouse chondrocytes via activation of the AMPK/NRF2/HO-1 signaling pathway [62]. Similarly, sappanone A has been found to alleviate osteoarthritic pain by inhibiting chondrocyte ferroptosis through the SIRT1/NRF2 signaling pathway, and it contributes to OA pain relief by upregulating the expression of SLC7A11 and GPX4 proteins [63]. Interestingly, vitamin K2 (VK2) protects against OA by inhibiting the degradation of the extracellular matrix (ECM) in chondrocytes and alleviating knee joint pain through suppression of the GPX4-reduced MAPK/NF-κB (mitogen-activated protein kinase, MAPK; nuclear factor kappa-B, NF-κB) pathway activation. This was demonstrated using both an in vivo rat OA model established via anterior cruciate ligament transection and an in vitro model of chondrocyte oxidative damage induced by tert-butyl hydrogen peroxide [26].

In cancer pain research, GPX4 is involved in multiple signaling pathways that play a role in pain regulation. Naringenin upregulates the anti-oxidative molecule GPX4 in rat spinal cords via the serine/threonine protein kinase AMPK/PGC-1α (peroxisome proliferator-activated receptor-gamma coactivator-1alpha, PGC-1α) signaling pathway, alleviating mechanical allodynia caused by bone cancer in rats. Naringenin promoted spinal microglia M2 polarization in a rat model of cancer-induced bone pain (CIBP) by regulating the AMPK/PGC-1α signaling axis. This study verified that shifting microglial polarization toward the M2 phenotype represents a potential strategy for CIBP treatment [27]. Similarly, the study indicated that bavachin triggers ferroptosis in osteosarcoma cells by engaging the STAT3/p53/SLC7A11 axis, downregulating GPX4 expression in these cells [64]. Dihydroartemisinin sensitizes glioma cells to ferroptosis in vitro and in vivo by inhibiting the PERK-ATF4-HSPA5-GPX4 (protein kinase R-like ER kinase, PERK; activating transcription factor 4, ATF4) pathway, thereby exerting an antitumor effect [45].

Additionally, GPX4 is involved in the ferroptotic pathway [65]. Notably, Fer-1 ameliorates cardiac dysfunction resulting from sepsis by targeting the TLR4/NF-κB (toll-like receptor 4, TLR4) signaling pathway [66]. An intraperitoneal injection of lipopolysaccharide (LPS) was performed to induce a rat cardiac dysfunction model. Astragaloside IV alleviated PM2.5-induced lung injury in mice by regulating the iron-dependent apoptotic signaling pathway through the NRF2/SLC7A11/GPX4 axis [67]. In vivo, a streptozotocin (STZ)-induced diabetes mellitus model was established using a high-fat diet and STZ. 6-Gingerol upregulated the anti-ferroptotic protein GPX4 via the NRF2/HO-1 pathway, effectively reducing ferroptosis and inflammation in diabetic cardiomyopathy [68]. Chen et al. demonstrated that GPX4 is essential for motor neuron health and survival in vivo; conditional ablation of GPX4 in adult mouse neurons leads to rapid paralysis and death due to the degeneration of motor neurons in the spinal cord, without evident degeneration in the cerebral cortex. Multiple compounds can directly or indirectly modulate GPX4 activity through the MAPK pathway, with the ERK (extracellular signal-regulated kinases, ERK) pathway being particularly implicated in neuronal ferroptosis [48].

While GPX4’s role in modulating pain signaling pathways is not fully elucidated, its involvement in maintaining intracellular redox homeostasis suggests it may indirectly influence pain signaling pathways. Collectively, GPX4 participates in the regulation of specific signaling pathways, influencing gene expression and determining cellular outcomes.

Metabolic Regulation

GPX4 is integral to cellular metabolic regulation, influencing lipid metabolism balance and energy homeostasis, thus underscoring its multifaceted role in both physiological and pathological processes [29, 69]. Dysfunctional amino acid metabolism related to iron deficiency is primarily associated with abnormalities in GSH metabolism [70]. GPX4, the Xc-system, sulfur transfer pathways, and a series of genes and regulators involved in GSH biosynthesis and degradation participate in ferroptosis. GSH, composed of cysteine, glutamate, and glycine, is the most abundant intracellular antioxidant and a primary detoxifier, with cystine being reduced to cysteine for GSH synthesis. This tripeptide plays a central role in amino acid metabolism within the context of ferroptosis [71, 72].

GPX4, as a pivotal enzyme utilizing GSH to clear lipid peroxyl radicals, suppresses ROS production and lipid peroxidation when overexpressed [73]. Conversely, diminished GPX4 activity or expression leads to the accumulation of intracellular lipid hydroperoxides, triggering ferroptosis [74]. Upon activation, GPX4 catalyzes the conversion of reduced GSH into its oxidized form, glutathione disulfide (GSSG), concurrently reducing cytotoxic lipid hydroperoxides (L-OOH) into benign lipid alcohols (L-OH). This process underscores the critical role of GSH as a protective metabolite in combating ferroptosis, highlighting its indispensable function in cellular defense mechanisms [75].

GPX4 plays a crucial role in metabolic regulation, as evidenced by its involvement in multiple pain studies. Tang et al. suggested that aberrant lipid peroxidation, iron metabolism, and GPX4 expression facilitate ferroptosis, indicating that downregulation of GPX4 may correlate with increased pain sensitivity in a rat model of CCI [76, 77]. In inflammatory pain, research implicates redox imbalance and abnormal iron and lipid metabolism as pivotal factors in the molecular mechanisms of ferroptosis [78, 79]. Similarly, increased lipid peroxidation (ROS and MDA) in a rat model of chronic prostatitis/chronic pelvic pain syndrome is closely linked to ferroptosis mediated by the downregulated system Xc-/GPX4 axis, and inhibiting ferroptosis alleviates inflammatory pain [80]. Therefore, GPX4, through its involvement in iron metabolism, GSH metabolism, proteasomal function, and metabolic homeostasis regulation, may exert analgesic effects.

Mechanisms

GPX4 Could Regulate Pain via Inflammatory and Oxidative Stress Mechanisms

Chronic NP is intimately linked to increased oxidative stress levels caused by mitochondrial dysfunction [18, 19]. Oxidative stress can initiate or exacerbate inflammatory responses, with accumulating evidence demonstrating a close association between peripheral and central nervous system inflammation and chronic pain [81–83]. During inflammatory processes, cells generate large amounts of ROS and reactive nitrogen species, which not only directly harm tissues but also activate inflammatory signaling pathways, enhancing the sensitivity of pain receptors and intensifying pain perception. GPX4, by suppressing oxidative stress, reduces the production of inflammatory mediators such as prostaglandins and interleukins, which play crucial roles in pain sensation and amplification [47]. It is well known that OA is the most common type of arthritis [84, 85]. Ma et al. suggested that ferroptosis is a key factor in reduced chondrocyte viability in OA, with GPX4 downregulated in both OA cartilage and synovium in vivo [79, 86]. Miao et al. found that the expression of GPX4 was significantly lower in OA cartilage from 55 patients compared to undamaged cartilage. Fer-1 and deferoxamine (DFO) protected against OA progression in a necroptosis-independent manner, suggesting the presence of ferroptosis in OA. In order to further investigate the role of GPX4 in OA, 10-week-old male wild-type C57BL/6 mice underwent anterior cruciate ligament transection surgery of the right knee to induce mechanical instability and establish an experimental OA model. Remarkably, the study revealed a dual function of GPX4 in OA, regulating ferroptosis and oxidative stress and modulating ECM degradation through the MAPK/NF-κB signaling pathway [87]. To sum up, chronic NP, closely linked to increased oxidative stress and mitochondrial dysfunction, involves GPX4 in reducing oxidative stress and inflammatory mediators.

In intervertebral disc degeneration (IDD)-related low back pain (LBP), RNA-sequencing datasets indicate that ferroptosis occurs in IDD, suggesting that ferroptosis may contribute to IDD progression by triggering immune infiltration. Treatment with IL-1β decreases the expression of GPX4 protein, while the protein expression levels of NCOA4 (nuclear receptor coactivator 4) and PCBP1 (poly(rC)-binding protein 1) are elevated in nucleus pulposus cells [88]. This work was conducted to further understand IDD pathogenesis and identify new treatment strategies. Furthermore, recent studies have demonstrated that increased intracellular levels of oxidative stress upregulate the expression of pro-inflammatory mediators, including IL-1β, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Concurrently, this condition leads to a decrease in the levels of GPX4 and SLC7A11, and an increase in ACSL4 [89]. In future research, further mechanistic investigations are necessary to validate the therapeutic potential of ferroptosis inhibitors and GPX4 inducers in chronic pain. GPX4 mitigates inflammation and potentially manages inflammatory pain by reducing lipid peroxidation and managing oxidative stress. Increasing GPX4 activity has been theoretically found to alleviate pain induced by inflammation in various inflammatory pain models.

GPX4 May Impact Pain via Oxidative Stress and Ferroptosis Mechanisms

The close relationship of oxidative stress and ferroptosis has been studied in various of pain conditions. Wang et al. suggested that ferroptosis triggered by imbalances in GPX4 and ACSL4 levels in the rat spinal cord contributes to NP induced by CCI of the sciatic nerve [17]. Similarly, the mechanism involves CCI-induced mitochondrial damage, resulting in lowered GPX4 levels, increased ACSL4, enhanced lipid peroxidation, and heightened oxidative stress, which collectively promote the development of chronic pain [23]. In the SNI model, increased iron content and ACSL4 levels, coupled with decreased expression of GPX4 in the spinal cord, lead to mechanical allodynia. Intrathecal administration of a recombinant adeno-associated virus overexpressing SIRT2 decreases oxidative stress levels and alleviates mechanical allodynia [18]. In brief, involving imbalances in GPX4 and ACSL4 levels contributes to NP in models like CCI and SNI by inducing mitochondrial damage, increasing lipid peroxidation, and promoting mechanical allodynia, which can be alleviated by decreasing oxidative stress levels.

In addition to NP, conditions such as LBP, cancer pain, and inflammatory pain have also been studied. Zhu et al. suggested that Circ-STC2 (circular RNA derived from stanniocalcin 2) and transferrin receptor 2 (TFR2) expression was upregulated in IDD tissues, whereas miR-486-3p expression was downregulated. Knockdown of circ-STC2 promoted the viability of nucleus pulposus cells and inhibited their ferroptosis, thereby improving pain-related behavioral scores by decreasing oxidative stress-induced ferroptosis. Research on ferroptosis induced by oxidative stress regulation has revealed that aberrant GPX4 regulation exacerbates lumbar pain and worsens pain-related behavioral scores in a mouse IDD model [24, 90]. Similarly, exploring the role of circ-STC2 in the pathogenesis of IDD, following circ-STC2 knockdown, the levels of GSH, GPX4, and SLC7A11 protein were increased, while the levels of lactate dehydrogenase (LDH), MDA, Fe²⁺, and ACSL4 protein were decreased [91].

In cancer pain research, intraperitoneal injection of the ferroptosis inhibitor Fer-1 suppresses spinal ferroptosis in BCP mice, effectively reducing their nociceptive hypersensitivity and spontaneous pain. Furthermore, Fer-1 inhibited the pain-associated activation of ERK1/2 and the expression of COX-2, and prevented the loss of GABA (gamma-aminobutyric acid)-ergic interneurons [20, 92]. The results suggest that ferroptosis is a potential therapeutic target in patients suffering from BCP and possibly other types of pain.

In order to explore whether ferroptosis in the spinal cord and DRG contributes to CFA-induced painful behaviors in rats, Zhang et al. utilized intrathecal administration of the ferroptosis inhibitor liproxstatin-1 to alleviate mechanical and thermal hyperalgesia in rats with CFA-induced inflammatory pain. This approach reduced ACSL4 protein levels, upregulated GPX4 levels, and inhibited ferroptosis in DRG and spinal cord cells, effectively alleviating inflammatory pain symptoms [19]. Similarly, interstitial cystitis/bladder pain syndrome (IC/BPS) is a bladder syndrome of unknown etiology. Fang et al. found that NRF2 expression is upregulated and GPX4 expression is downregulated in patients with IC/BPS. The experiment involved collecting bladder tissue samples and cells from patients with IC/BPS, as well as using an LPS-induced rat model of IC/BPS, to explore the role and mechanisms of ROS-induced ferroptosis in IC/BPS. The study provided the first evidence that oxidative stress-induced ferroptosis plays a significant role in the pathology of IC/BPS. Mechanistically, Wnt/β-catenin signaling inhibits ROS-induced ferroptosis by downregulating NF-κB, thereby ameliorating bladder damage in IC/BPS [93].

Through the above studies, it is evident that the intricate relationship between oxidative stress and ferroptosis has emerged as a critical factor in the development and progression of various pain conditions. From NP to inflammatory pain, and even in cancer pain and LBP, the dysregulation of ferroptosis through mechanisms such as altered GPX4 and ACSL4 levels exacerbates pain symptoms. These findings highlight the potential for targeting ferroptosis as a therapeutic strategy. Future research should focus on further elucidating the molecular mechanisms underlying these relationships and developing specific inhibitors or modulators of ferroptosis to manage different types of pain more effectively.

The Role of Genetic Regulation of GPX4 in Pain Mechanisms

The genetic regulation of GPX4 expression reveals its potential impact on pain modulation [94, 95]. This section explores the mechanisms of genetic regulation of GPX4 and their effects on pain in detail.

The transcription factor NRF2 is a significant regulator of GPX4 expression. As a key transcription factor in the antioxidant response, NRF2 upregulates GPX4 expression by binding to the antioxidant response element (ARE) in the promoter region of the GPX4 gene [96]. Under normal conditions, NRF2 is bound to Keap1 (Kelch-like ECH-associated protein 1) and subsequently degraded. However, under oxidative stress conditions, NRF2 dissociates from Keap1, translocates into the nucleus, forms a heterodimer with small Maf proteins, and binds to the ARE in the GPX4 promoter region, thereby activating GPX4 transcription [97–99]. Furthermore, electroacupuncture (EA) increased the immunofluorescence co-staining of GPX4 in neuronal cells of the spinal cord in CCI rats. Mechanistic analysis revealed that inhibition of the antioxidant pathway of the NRF2 signaling pathway via its specific inhibitor, ML385, significantly counteracted EA’s protective effect against neuronal ferroptosis in NP rats while marginally diminishing its analgesic effect. These findings suggest that EA treatment at acupoints ST36 and GV20 may protect against NP by inhibiting neuronal ferroptosis in the spinal cord, partially through the activation of NRF2 signaling [100]. Similarly, research has indicated that the overexpression of methyltransferase-like 3 (METTL3) promoted N6-methyladenosine (m6A) methylation of high-mobility group box 1 (HMGB1). Overexpression of HMGB1 reversed the effects of sh-METTL3 on chondrocytes treated with IL-1β. The study examined the impact of METTL3 on ferroptosis and pain relief in in vitro and in vivo models of knee osteoarthritis (KOA). Specifically, chondrocytes were treated with 10 ng/mL IL-1β or 5 μM estrogen (a ferroptosis inducer), and a KOA rat model was established by injecting sodium iodoacetate into the joints. Results showed that treatment with IL-1β or estrogen inhibited cell viability and glutathione levels; increased the production of Fe2 + , lipid ROS, and MDA; and decreased the levels of GPX4 and SLC7A11. Depletion of METTL3 inhibited ferroptosis and inflammatory responses and improved cartilage damage and knee pain during the progression of KOA by regulating HMGB1 [101].

MicroRNAs (miRNAs) regulate GPX4 expression by binding to the 3′UTR region of GPX4 mRNA, inhibiting its translation or promoting its degradation. Various miRNAs including miR-185, miR-503, and miR-127 have been found to regulate GPX4 expression in different types of cancer cells [102]. Experimental data indicate that Tsc22d3 gene-associated miRNAs were mmu-miR-196b-5p and mmu-miR-196a-5p. Compared to the non-morphine-tolerant group, Tsc22d3 expression was significantly upregulated in the morphine-tolerant group. In the morphine-tolerant + Tsc22d3 overexpression group, Tsc22d3 expression was upregulated, and the expression of HIF-1α, GSH, and GPX4 in the GPX4 ferroptosis-related pathway showed a more pronounced decrease [103]. According to reports, miR-185-5p contributes to various diseases. Huang et al. reported that miR-185-5p mitigates CCI-induced NP and neuroinflammation by targeting MyD88 and CXCR4, suggesting that miR-185-5p is an underlying therapeutic target for NP [104, 105].

Epigenetic regulation is another important mechanism controlling GPX4 expression [106]. In liver cancer cells, high methylation of the GPX4 gene promoter region is associated with its downregulation. DNA methylation and histone modifications can influence GPX4 gene expression [107]. Epigenetic modifications, including DNA methylation and histone acetylation, influence the DNA damage response (DDR). In this study, the role of these modifications in DDR in cells exposed to acute or chronic oxidative stress was explored [108].

The above studies demonstrate that the transcription factor NRF2 regulates GPX4 expression by binding to the ARE in its promoter region, and EA activates NRF2 signaling to protect against neuronal ferroptosis in NP. MiRNAs such as miR-185-5p regulate GPX4 expression and mitigate NP by targeting MyD88 and CXCR4. Epigenetic modifications, including DNA methylation and histone acetylation, influence GPX4 expression and the DNA damage response under oxidative stress conditions, playing critical roles in regulating GPX4 expression and ferroptosis in various disease contexts.

Modulating GPX4 in the Management of Pain

The modulation of GPX4 expression represents a promising therapeutic strategy for the management of various pain conditions, including inflammatory, neuropathic, cancer, and arthritis pain. Agents such as gastrodin, naringenin, methyl ferulic acid, liproxstatin-1, Fer-1, and DFO have shown efficacy in alleviating pain symptoms by upregulating GPX4 expression and reducing oxidative stress and ferroptosis. These agents act through multiple mechanisms, including the inhibition of NADPH oxidase 4 (Nox4), enhancement of NRF2/GPX4 antioxidant responses, and modulation of pain signaling pathways. Additionally, alternative methods such as EA have been found to reverse the ferroptosis phenotype and alleviate pain hypersensitivity in NP models. Collectively, these findings underscore the potential of GPX4-targeted therapies in alleviating chronic pain syndromes and provide part of the research foundation for the development of novel therapeutic strategies (Table 2).

Table 2.

The use of related drugs in pain by regulating GPX4

Pain type	Agents	Models	Conclusions	References
Inflammatory pain	Gastrodin	CFA (mice)	GPX4 mRNA expression, in a dose-dependent manner, regulates ferroptosis and exerts analgesic and anti-anxiety effects on jejunal microbiota	[109]
Cancer pain	Naringenin	CIBP (rat)	Naringenin alleviates the pain of bone cancer by regulating GPX4 levels in the spinal cord of rats	[27]
Neuropathic pain (NP)	Methyl ferulic acid (MFA)	SNI (rat)	MFA reduces NP associated with ferroptosis by inhibiting the expression of NADPH oxidase 4 protein in the dorsal root ganglion (DRG) of rats, increasing GPX4 expression and reducing reactive oxygen species, iron content, and abnormal mitochondrial count	[110]
NP	Liproxstatin-1	CCI (rat)	Liproxstatin-1 (a ferroptosis inhibitor) restored dysregulation of GPX4 and anti-acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) levels, reduced iron levels, reduced lipid peroxidation in the spinal cord, and prevented changes in mitochondrial morphology caused by CCI, thereby alleviating hyperalgesia	[23]
Inflammatory pain	Liproxstatin-1	CFA (rat)	Intrathecal injection of liproxstatin-1 reduced the level of ACSL4 protein and increased the level of GPX4 protein, which alleviated mechanical and thermal hypersensitivity in rats	[19]
Arthritis pain	Ferrostatin-1 (Fer-1)/ Deferoxamine(DFO)	OA (mice/humans)	Expression of GPX4 was significantly lower in OA cartilage from 55 patients compared to undamaged cartilage. Fer-1 and DFO protected against OA progression in a necroptosis independent manner, suggesting the presence of ferroptosis in OA	[87]

Antioxidants Could Enhance the Expression of GPX4

Despite advances in medical science, neuropathic and inflammatory pain remain challenging to treat effectively. Recent studies suggest that ROS scavengers may offer a promising therapeutic approach for managing these chronic pain conditions [111]. For instance, methyl ferulic acid has shown efficacy in alleviating ferroptosis-associated NP in a rat model of SNI. This compound upregulates GPX4, reduces ROS levels, decreases iron content, and mitigates mitochondrial abnormalities by inhibiting Nox4 [110]. Similarly, acetyl zingerone has been found to enhance GPX4 expression in mouse chondrocytes, thereby mitigating OA-related cartilage degradation and osteophyte formation by inhibiting ferroptosis [25]. Moreover, in a mouse model of chronic inflammatory pain induced by CFA, gastrodin increased GPX4 mRNA levels in a dose-dependent manner, modulating ferroptosis and intestinal microbiota to provide analgesic and anxiolytic effects [109]. Curcumin, another promising compound, inhibits NLR family pyrin domain-containing 3 (NLRP3) inflammasome-mediated spinal inflammation, enhances NRF2/GPX4 antioxidant responses, and reduces mitochondrial ROS production. This combined action alleviates oxaliplatin-induced NP, including mechanical allodynia, spontaneous pain, thermal hyperalgesia, and motor dysfunction [112, 113]. Additionally, naringenin, a natural flavonoid with antioxidant, anti-inflammatory, and neuroprotective properties, mitigates BCP in rats by increasing spinal GPX4 levels via the AMPK/PGC-1α pathway [27].

Collectively, these findings underscore the role of enhanced GPX4 activity in boosting peroxide detoxification capacity and alleviating oxidative stress-related neuropathic and inflammatory pain. Thus, therapeutic strategies targeting oxidative stress and GPX4 activity may offer effective relief for various pain syndromes.

Alternative Drugs or Methods to Increase the Expression of GPX4

Liproxstatin-1, an inhibitor of iron-dependent cell death, has demonstrated potential in enhancing GPX4 expression. In a rat model of CCI, liproxstatin-1 restored dysregulated levels of GPX4 and ACSL4, reduced iron content, diminished spinal cord lipid peroxidation, and prevented mitochondrial changes [23]. These effects collectively alleviated pain hypersensitivity induced by CCI. Additionally, intrathecal administration of liproxstatin-1 has been shown to decrease ACSL4 protein levels while increasing GPX4 protein levels, effectively reducing mechanical and thermal hyperalgesia in inflammatory pain models, highlighting its potential as a therapeutic strategy for inflammatory pain [19]. Further research has revealed that ferroptosis, associated with GPX4 in the spinal cord or DRG, contributes to morphine tolerance [103, 114]. Valproic acid, a histone deacetylase inhibitor, significantly increased the levels of GPX4 in the DRG of a cauda equina syndrome model. This finding opens avenues for novel drug development and clinical intervention strategies [115]. EA has also been effective in reversing the ferroptosis phenotype induced by oxidative stress. By upregulating GPX4 and downregulating ACSL4, EA mitigates pain hypersensitivity caused by CCI and reduces neuronal injury in the spinal cords of NP rats [100, 116]. In brief, GPX4’s antioxidant and anti-inflammatory properties, along with its role in preserving cellular function, underscore its potential in pain management. Modulating GPX4 activity through various agents and methods holds promise for developing effective therapeutic strategies. Future research should focus on elucidating the specific mechanisms by which GPX4 regulates pain to lay a theoretical foundation for novel treatments.

The Application of Nanotechnology in the Management of Pain: Modulating the Activity of GPX4 and GPX

Currently, pain management in clinical settings remains inadequate, presenting significant challenges for effective pain therapy [4, 117]. Research has indicated that treatments for joint pain caused by inflammatory arthritis typically include a variety of anti-inflammatory medications—administered orally, topically, or intra-articularly—along with surgical options and physical rehabilitation. However, the overall effectiveness of these treatments has often been limited. The complex interplay between redox imbalance, exacerbated by abnormal levels of ROS, and inflammatory arthritis suggests that ROS may trigger therapeutic responses in arthritic conditions. Given the general nonspecific cytotoxicity and limited bioavailability of systemic drug treatments, there is growing interest in using stimulus-responsive drug delivery systems that incorporate nanomaterials with specialized biomedical applications [118].

Recent studies have demonstrated promising results with such systems. For example, in the context of IDD and LBP, polydopamine nanoparticles (PDA NPs) have been shown to effectively address disc degeneration induced by puncture in vivo. They achieve this by targeting ferroptosis and inhibiting GPX4 ubiquitination, thereby enhancing antioxidant pathways. PDA NPs localize with GPX4 near mitochondria, helping to protect against damage by transforming and clearing phospholipid hydroperoxides. This provides new insights into therapeutic mechanisms and strategies for managing LBP [119]. Moreover, Yu et al. demonstrated the supramolecular self-assembly of an epigallocatechin gallate (EGCG)-selenomethionine nanomedicine, which is directed towards the treatment of OA and the alleviation of associated pain. The results indicate that the nano-drug based on EGCG (ES NDs) can effectively reduce GPX4 inactivation caused by oxidative stress, thereby ameliorating metabolic disorders in chondrocytes [120]. Therefore, the intra-articular delivery of ES NDs as a treatment for OA and other joint inflammatory diseases holds promise as a potentially effective therapeutic method. Furthermore, a promising photosensitizer promotes lipid peroxidation and decreases the expression of GPX4, reversing hypoxia-induced ferroptosis resistance in cancer cells, effectively killing tumor cells and alleviating pain caused by cancer cells [121].

Pentazocine (PTZ) is an antagonist analgesic widely employed in managing initial cancerous or postsurgical pain. Its low oral bioavailability due to substantial first-pass hepatic metabolism results in large dose waste. Nevertheless, solid lipid nanoparticles loaded with PTZ significantly alleviate hyperalgesia and inflammation following carrageenan-induced inflammatory pain by suppressing oxidative stress and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) [122]. Similarly, nanoemulsions alleviate osteoarthritic pain by enhancing SOD and GPX activity in rat synovial tissue, reducing MDA, boosting antioxidant capacity, and improving histopathological features of the rat knee joint [123]. Furthermore, in vitro and in vivo studies, Li et al. confirmed that selenium nanoparticles alleviate pain associated with OA by suppressing the production of ROS in IL-1β-stimulated cells and enhancing GPX activity, which in turn inhibits the NF-κB p65 and p38/MAPK signaling pathways [124]. Therefore, nanoformulations, including solid lipid nanoparticles and nanoemulsions, alleviate pain and inflammation in conditions such as inflammatory pain and OA by suppressing oxidative stress, enhancing antioxidant enzymes like SOD and GPX, and modulating pro-inflammatory pathways.

Looking ahead, the application of nanotechnology in targeting GPX and GPX4-related therapeutic strategies holds great promise. By enabling precise drug delivery, improving bioavailability, prolonging drug action, and targeting specific tissues, these advancements enhance therapeutic efficacy and minimize collateral damage to healthy tissues. As nanotechnology continues to evolve, it is expected to foster the development of innovative therapies for personalized medicine and the management of complex diseases. Future possibilities include the use of nanoparticles loaded with analgesics, such as morphine or local anesthetics, engineered to release drugs in response to specific stimuli such as near-infrared irradiation [125], pH response [126], or external magnetic fields [127], offering more effective and targeted pain relief.

Future Prospects of GPX4 Research: Translational Potential of GPX4 in Clinical Therapy

GPX4 holds significant therapeutic potential in oncology, particularly through its role in inducing ferroptosis in neoplastic cells that are resistant to traditional treatments. Inhibitors of GPX4 effectively trigger iron and lipid peroxidation-dependent cell death, demonstrating considerable antineoplastic effects across various cancers, including nasopharyngeal carcinoma [128], non-small cell lung carcinoma (NSCLC) [129, 130], pancreatic adenocarcinoma [131], and melanoma [132]. Moreover, these inhibitors not only target drug-resistant neoplastic cells but also enhance radiosensitivity. For instance, Deng et al. identified the miR-324-3p-GPX4 signaling axis as a potential target for overcoming cisplatin resistance in human NSCLC, showing that the GPX4 inhibitor RAS-selective lethal small molecule (RSL3) can mimic miR-324-3p upregulation, thereby increasing drug sensitivity in resistant cells [133].

A growing body of research has demonstrated the potential of inhibiting ferroptosis in the management of pain [19, 47, 100]. For example, ferroptosis has been found to act as a regulatory mechanism for NP, and inhibiting ferroptosis could relieve NP. Commonly used inhibitors of ferroptosis such as Fer-1, liproxstatin-1, and small molecule compounds like VK2 inhibit ferroptosis primarily by scavenging lipid peroxides. The ferroptosis inhibitors discovered so far are not designed to take effect by specifically activating the enzyme activity of ferroptosis regulator GPX4 and accelerating the reduction of hydroperoxyl-eicosatetraenoic acids to hydroxyeicosatetraenoic acids. As a key regulatory enzyme of ferroptosis, the association of GPX4 with pain is also gradually being explored. Downregulation of GPX4 in the spinal cord could lead to the development of NP induced by CCI and SNI models, as well as inflammatory pain induced by CFA. Downregulation of GPX4 could also play a role in LBP and arthritic pain. Oxidative stress and inflammatory response have become a bridge between GPX4 and various pains. Therefore, activation of GPX4 and thus inhibition of ferroptosis is expected to be a novel strategy for the treatment of pain. Unlike inhibitors of GPX4, activators of GPX4 usually act through allosteric regulation, and the allosteric binding sites of most proteins are unknown. Li et al. identified a potential allosteric site in GPX4 and used a novel computational strategy and experimental studies to successfully find eight GPX4 activators [134]. These activators could increase the activity of GPX4 and may be further developed as cytoprotective and anti-inflammatory agents, providing a viable strategy for future development of drugs targeting the activation of GPX4. In addition, Li et al. identified a novel compound that can activate the enzymatic activity of GPX4 more than twofold using a combined computational and experimental screen [135]. Additionally, in vitro experiments revealed that selenomethionine (SeMet), an activator of GPX4, significantly reduced levels of polyunsaturated fatty acids (PUFAs) and oxidized lipids [136]. Baruah et al. identified a natural polyphenol, tannic acid (TA), that can act as a GPX4 activator to ameliorate Aβ42-induced ferroptosis [137]. 2-Amino-5-chloro-N,3-dimethylbenzamide (CDDO) is a triterpenoid that has been shown to inhibit the degradation of GPX4 and protect cells from ferroptosis [138]. Compound 102 is a specific GPX4 activator that reduces the production of inflammatory agents and promotes the resolution of inflammation [135].

Overall, activation of GPX4 or inhibition of GPX4 degradation is an important factor in counteracting ferroptosis, and activation of GPX4 or inhibition of GPX4 degradation may be critical in modulating pain therapies related to oxidative stress. Although GPX4 is a central regulator of ferroptosis [51], and GPX4 activators can inhibit the onset of ferroptosis, GPX4 agonists are far less well studied. In addition, synthesis of GPX4 is energy-demanding and inefficient. The GPX4 activators that have been reported so far usually act indirectly through metabolic regulation. There are also no GPX4 activators in clinical trials. These are challenges for the future development of targeted GPX4 agonists. Reported activators of GPX4, such as 1d4, SeMet, and CDDO, or inhibitors of GPX4 degradation are promising for pain relief, which may be related to the inhibition of inflammation and oxidative stress. Combinations of GPX4 activators with other anti-inflammatory compounds may be promising strategies for inflammatory intervention. Given the irreplaceable role of GPX4 in reducing lipid hydroperoxides within biological membranes, GPX4 activators have therapeutic potential for lipid peroxidation-associated pain. Further optimization and development of GPX4 activators are expected to provide novel solutions for pain relief.

Conclusions

GPX4 plays a crucial role in regulating pain pathophysiology, with significant connections to oxidative stress, inflammation, and neuronal excitability. Targeting GPX4 therapeutically offers a promising approach for pain management, especially in cases characterized by pronounced oxidative stress. However, research in this area is still in its early stages, highlighting the need for further studies to determine the specific mechanisms, optimal dosages, and long-term safety of GPX4-targeted therapies. Advancements in this field could revolutionize pain management, providing more effective and precise treatment options for individuals experiencing pain.

This review presents a comprehensive overview of GPX4’s biological mechanisms related to pain (see Fig. 1). It starts by discussing GPX4’s roles in antioxidant defense, regulation of ferroptosis, signal transduction, and  metabolic regulation. The review then explores GPX4’s involvement in various pain models, including NP, arthritic pain, LBP, and cancer-induced pain. Lastly, the potential and application of GPX4 as a therapeutic target for pain management are considered. Given its central role in pain pathophysiology, GPX4 is identified as a promising target for therapeutic intervention, particularly in conditions related to oxidative stress. While research is still preliminary, it is evident that further investigation is needed to elucidate GPX4’s precise influence and advance therapeutic strategies.

Fig. 1.

The figure illustrates the intricate biological mechanisms of glutathione peroxidase 4 (GPX4) in modulating pain under various conditions. It details GPX4’s antioxidant defense, regulation of ferroptosis, involvement in signal transduction pathways, metabolic regulation, and genetic regulation, emphasizing its multifaceted contributions to pain modulation. The figure also highlights the potential use of certain drugs in managing pain by targeting these mechanisms. ↓, promote; ⊥, inhibit; ↑, upregulation

Author Contributions

Shiwen Fan and Kaixin Wang performed the literature review, wrote the initial draft of the manuscript, and created the tables and figures. Tianhao Zhang proofread the manuscript and conducted language checks. Daling Deng edited the manuscript and provided feedback on the overall design and format. Jiwei Shen contributed to data analysis and interpretation. Bowen Zhao provided technical support and additional data. Daan Fu and Xiangdong Chen supervised the project and provided critical revisions to the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 82471251, 82303765), the Open Foundation of Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research (Grant No. 2022zsyx008), and the Scientific Research Project of Shehezi University (No. ZZZC2023061). The Rapid Service Fee was funded by the authors.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Shiwen Fan, Kaixin Wang, Tianhao Zhang, Daling Deng, Jiwei Shen, Bowen Zhao, Daan Fu, Xiangdong Chen. The authors declare that there are no conflicts of interest.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.