# The Analgesic Effects of Nrf2 Activators in Chemotherapy-Induced Neuropathic Pain: Evidence from Animal Studies and Consequences for Translation into Clinical Trials **Authors:** Jimin Kim, Jeongmin Kim, Hee Kee Kim, Salahadin Abdi PMC · DOI: 10.3390/ijms27041748 · 2026-02-11 ## TL;DR This paper reviews how Nrf2 activators reduce chemotherapy-induced neuropathic pain in animals and their potential for clinical use. ## Contribution It summarizes the analgesic effects of multiple Nrf2 activators and their mechanisms in animal models of CINP. ## Key findings - Nrf2 activators like tempol and curcumin showed analgesic effects in CINP animal models. - Curcumin reduced vincristine-induced neuropathy in pediatric leukemia patients. - Alpha-lipoic acid with ipidacrin improved paclitaxel-induced motor neuropathy in breast cancer patients. ## Abstract Chemotherapy-induced neuropathic pain (CINP) can be caused by several chemotherapeutic drugs, including paclitaxel, oxaliplatin, and vincristine, which is difficult to treat with several drugs, including antidepressants and anticonvulsants. The patho-mechanisms of CINP are not completely understood. However, they showed oxidative stress, mitochondrial damage, ion channel damage, and immunological dysfunction. Acting as a key regulator of antioxidant responses, nuclear factor erythroid 2-related factor 2 (Nrf2) decreased oxidative stress and mitochondrial damage. In addition, it plays a role in inhibiting nuclear factor kappa B (NF-κB). A systematic, English-only search of MEDLINE (PubMed) was performed for studies on Nrf2, chemotherapy, and neuropathic pain from database inception through 1 December 2024. Several Nrf2 activators, including tempol, oltipraz, rosiglitazone, pristimerin, cannabidiol, daidzein, bardoxolone methyl, curcumin, resveratrol, and mitoquinone, demonstrated analgesic effects in CINP animal models. Furthermore, in clinical studies, curcumin demonstrated significant efficacy in reducing vincristine-induced neuropathy in pediatric leukemia patients, while the combined administration of alpha-lipoic acid with ipidacrin hydrochloride prevented paclitaxel-induced motor neuropathy and improved axonal function in breast cancer patients. Thus, the purposes of our review article were to summarize the analgesic effects of Nrf2 activators and the patho-mechanisms of Nrf2 in CINP animal, and then the consequences for clinical trials were presented. ## Linked entities - **Genes:** GABPA (GA binding protein transcription factor subunit alpha) [NCBI Gene 2551], NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] - **Chemicals:** paclitaxel (PubChem CID 36314), oxaliplatin (PubChem CID 9887053), vincristine (PubChem CID 5978), tempol (PubChem CID 137994), oltipraz (PubChem CID 47318), rosiglitazone (PubChem CID 77999), pristimerin (PubChem CID 159516), cannabidiol (PubChem CID 644019), daidzein (PubChem CID 5281708), bardoxolone methyl (PubChem CID 400769), curcumin (PubChem CID 969516), resveratrol (PubChem CID 5056), mitoquinone (PubChem CID 11388332), alpha-lipoic acid (PubChem CID 864) - **Diseases:** breast cancer (MONDO:0004989) ## Full-text entities - **Genes:** APP (amyloid beta precursor protein) [NCBI Gene 351] {aka AAA, ABETA, ABPP, AD1, APPI, CTFgamma}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, NQO1 (NAD(P)H quinone dehydrogenase 1) [NCBI Gene 1728] {aka DHQU, DIA4, DTD, NMOR1, NMORI, QR1}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, Nlrp3 (NLR family, pyrin domain containing 3) [NCBI Gene 287362] {aka Cias1}, TRPV1 (transient receptor potential cation channel subfamily V member 1) [NCBI Gene 7442] {aka VR1}, MIR155 (microRNA 155) [NCBI Gene 406947] {aka MIRN155, miRNA155, mir-155}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, COL11A2 (collagen type XI alpha 2 chain) [NCBI Gene 1302] {aka DFNA13, DFNB53, FBCG2, HKE5, OSMEDA, OSMEDB}, Mgll (monoglyceride lipase) [NCBI Gene 23945] {aka Magl, Mgl}, MAF (MAF bZIP transcription factor) [NCBI Gene 4094] {aka AYGRP, CCA4, CTRCT21, c-MAF}, Sod1 (superoxide dismutase 1) [NCBI Gene 24786] {aka CuZnSOD}, TRPV4 (transient receptor potential cation channel subfamily V member 4) [NCBI Gene 59341] {aka BCYM3, CMT2C, HMSN2C, OTRPC4, SMAL, SPSMA}, NFE2 (nuclear factor, erythroid 2) [NCBI Gene 4778] {aka NF-E2, p45}, TRPM8 (transient receptor potential cation channel subfamily M member 8) [NCBI Gene 79054] {aka LTRPC6, LTrpC-6, TRPP8, trp-p8}, BCL2 (BCL2 apoptosis regulator) [NCBI Gene 596] {aka Bcl-2, PPP1R50}, TOP2A (DNA topoisomerase II alpha) [NCBI Gene 7153] {aka TOP2, TOP2alpha, TOPIIA, TP2A}, KEAP1 (kelch like ECH associated protein 1) [NCBI Gene 9817] {aka INrf2, KLHL19}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, Nlrp3 (NLR family, pyrin domain containing 3) [NCBI Gene 216799] {aka AGTAVPRL, AII/AVP, Cias1, FCAS, FCU, MWS}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, SOD1 (superoxide dismutase 1) [NCBI Gene 6647] {aka ALS, ALS1, HEL-S-44, IPOA, SOD, STAHP}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, CAT (catalase) [NCBI Gene 847], GPX4 (glutathione peroxidase 4) [NCBI Gene 2879] {aka GPx-4, GSHPx-4, MCSP, PHGPx, SMDS, snGPx}, PPARG (peroxisome proliferator activated receptor gamma) [NCBI Gene 5468] {aka CIMT1, FPLD3, GLM1, NR1C3, PPARG1, PPARG2}, HMOX1 (heme oxygenase 1) [NCBI Gene 3162] {aka HMOX1D, HO-1, HSP32, bK286B10}, GSTK1 (glutathione S-transferase kappa 1) [NCBI Gene 373156] {aka GST, GST 13-13, GST13, GST13-13, GSTK1-1, hGSTK1}, Gstm1 (glutathione S-transferase mu 1) [NCBI Gene 24423] {aka GSTA3}, FPR2 (formyl peptide receptor 2) [NCBI Gene 2358] {aka ALX, ALXR, FMLP-R-II, FMLPX, FPR2A, FPRH1}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, Nfe2l2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 83619], Trpa1 (transient receptor potential cation channel, subfamily A, member 1) [NCBI Gene 277328] {aka Anktm1, TRPA1b} - **Diseases:** Pain (MESH:D010146), mitochondrial damage (MESH:D028361), injury to (MESH:D014947), neurological conditions (MESH:D019636), inflammation (MESH:D007249), gastrointestinal symptoms (MESH:D012817), headache (MESH:D006261), abdominal pain (MESH:D015746), flatulence (MESH:D005414), anorexia (MESH:D000855), anxiety (MESH:D001007), eosinophilia (MESH:D004802), neuroinflammation (MESH:D000090862), neurotoxic (MESH:D020258), myelinopathy (MESH:D011115), weakness (MESH:D018908), sensory dysfunction (MESH:D012678), diabetes (MESH:D003920), cancer (MESH:D009369), fatigue (MESH:D005221), stroke (MESH:D020521), diarrhea (MESH:D003967), nausea (MESH:D009325), pruritus (MESH:D011537), disorders (MESH:D009358), Friedreich's ataxia (MESH:D005621), visceral injury (MESH:D007418), vomiting (MESH:D014839), metabolic diseases (MESH:D008659), chronic constriction injury (MESH:D020208), spinal cord injury (MESH:D013119), VINP (MESH:C564945), nerve damage (MESH:D000080902), leukemia (MESH:D007938), nerve abnormalities (MESH:D005155), flushing (MESH:D005483), numbness (MESH:D006987), toxicities (MESH:D064420), dizziness (MESH:D004244), gastrointestinal adverse events (MESH:D002318), diabetic neuropathy (MESH:D003929), infections (MESH:D007239), immunological dysfunction (MESH:D007154), gastrointestinal complications (MESH:D005767), lymphoblastic leukemia (MESH:D054198), Peripheral neuropathy (MESH:D010523), nasopharyngitis (MESH:D009304), constipation (MESH:D003248), liver transaminase (MESH:D017093), hypersensitivity (MESH:D004342), neuronal damage (MESH:D009410), dry mouth (MESH:D014987), ion channel damage (MESH:D020513), CINP (MESH:D009437), abdominal discomfort (MESH:D000007), depressive (MESH:D003866), breast cancer (MESH:D001943), chronic pain (MESH:D059350), neuronal apoptosis (MESH:D065703), neuropathy (MESH:D009422) - **Chemicals:** Omaveloxolone (MESH:C000589490), GKT137831 (MESH:C576694), Ajugarin-I (MESH:C092328), Platinum (MESH:D010984), CAPE (MESH:C055494), Sulforaphane (MESH:C016766), alpha-lipoic acid (MESH:D008063), Commiphora myrrha extract (MESH:C587573), RvD1 (MESH:C518399), Paclitaxel (MESH:D017239), Vincristine (MESH:D014750), N (MESH:D009584), Quercetin (MESH:D011794), vitamin E. (MESH:D014810), bortezomib (MESH:D000069286), Mitoquinone (MESH:C429014), curcuminoids (MESH:D036381), water (MESH:D014867), cobalt protoporphyrin IX (MESH:C007095), Oxaliplatin (MESH:D000077150), nitric oxide (MESH:D009569), Resveratrol (MESH:D000077185), vitamin C (MESH:D001205), glutamate (MESH:D018698), thalidomide (MESH:D013792), 4-hydroxynonenal (MESH:C027576), doxorubicin (MESH:D004317), Rosiglitazone (MESH:D000077154), cisplatin (MESH:D002945), hydrogen peroxide (MESH:D006861), superoxide anions (MESH:D013481), CoPP (-), epirubicin (MESH:D015251), Puerarin (MESH:C033607), S (MESH:D013455), Curcumin (MESH:D003474), triterpenes (MESH:D014315), vinca alkaloids (MESH:D014748), DZ (MESH:C004742), BM (MESH:C445068), lenalidomide (MESH:D000077269), reactive nitrogen species (MESH:D026361), soy isoflavone (MESH:D007529), cysteine (MESH:D003545), lipid (MESH:D008055), taxanes (MESH:D043823), Pristimerin (MESH:C000718427), DMF (MESH:D000069462), docetaxel (MESH:D000077143), CBD (MESH:D002185), reactive oxygen species (MESH:D017382), calcium (MESH:D002118), berberine (MESH:D001599), monomethyl fumarate (MESH:C509058), alcohol (MESH:D000438), Oltipraz (MESH:C026209), tempol (MESH:C001803), Hydrogen (MESH:D006859), gabapentin (MESH:D000077206) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], Ajuga bracteosa (species) [taxon 1585251] ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12940216/full.md --- Source: https://tomesphere.com/paper/PMC12940216