# Eukaryotic initiation factors: central factor associating mRNA translational plasticity during neuropathic pain progression **Authors:** Xinshuo Li, Haibo Zhan, Xindan Zhang, Jiayi Li, Xiangrui Li, Xihua Lu, Changhong Miao, Chunli Zhou, Zhen Zhang PMC · DOI: 10.3389/fneur.2025.1566205 · 2025-07-30 ## TL;DR This paper reviews how eukaryotic initiation factors, especially eIF4E and eIF2α, influence mRNA translation during neuropathic pain and may offer new treatment targets. ## Contribution The paper provides a novel review of eIFs' role in translational plasticity during neuropathic pain and suggests new therapeutic approaches. ## Key findings - Eukaryotic initiation factors like eIF4E and eIF2α are central to mRNA translational plasticity in neuropathic pain. - Phosphorylation of eIFs affects neuropathic pain signal transmission and processing. - Changes in eIF4E and eIF2α activity are closely linked to various neuropathic pain conditions. ## Abstract Neuropathic pain causes plasticity in the nervous system, which is often associated with altered protein synthesis. Proteins are the key executors of cellular functions, and their alteration is closely related to the occurrence of neuropathic pain. Protein synthesis is a finely regulated process involving the interaction of multiple biomolecules. Among them, the eukaryotic translation initiation factors (eIFs) are a group of key regulatory proteins that control the initiation phase of protein translation and thus influence the rate and type of protein synthesis. Recent studies have shown that the eIFs are involved in the regulation of neuropathic pain regulating translation through phosphorylation and affecting the transmission and processing of neuropathic pain signals. Among them, eIF4E and eIF2α, as core initiation factors, changes in their expression and activity are closely associated with various neuropathic pain. This review aims to summarize the evidence for the involvement of the eIFs, especially eIF4E and eIF2α, in pain-associated mRNA translational plasticity, and to propose relevant therapeutic approaches. We hope that this review will provide important ideas for future research on the mechanisms of neuropathic pain and new targets for the treatment of neuropathic pain. ## Linked entities - **Proteins:** EIF4E (eukaryotic translation initiation factor 4E), EIF2A (eukaryotic translation initiation factor 2A) ## Full-text entities - **Genes:** EIF2S2 (eukaryotic translation initiation factor 2 subunit beta) [NCBI Gene 8894] {aka EIF2, EIF2B, EIF2beta, PPP1R67, eIF-2-beta}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 5599] {aka JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, PRKM8}, KCNA2 (potassium voltage-gated channel subfamily A member 2) [NCBI Gene 3737] {aka DEE32, EIEE32, HBK5, HK4, HUKIV, KV1.2}, EIF4G1 (eukaryotic translation initiation factor 4 gamma 1) [NCBI Gene 1981] {aka EIF-4G1, EIF4F, EIF4G, EIF4GI, P220, PARK18}, MKNK1 (MAPK interacting serine/threonine kinase 1) [NCBI Gene 8569] {aka MNK1}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, EIF4A1 (eukaryotic translation initiation factor 4A1) [NCBI Gene 1973] {aka DDX2A, EIF-4A, EIF4A, eIF-4A-I, eIF4A-I}, FKBP1AP4 (FKBP prolyl isomerase 1A pseudogene 4) [NCBI Gene 2285] {aka FKBP12, FKBP1P4}, MAP3K4 (mitogen-activated protein kinase kinase kinase 4) [NCBI Gene 4216] {aka MAPKKK4, MEKK 4, MEKK4, MTK1, PRO0412}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, MKNK2 (MAPK interacting serine/threonine kinase 2) [NCBI Gene 2872] {aka GPRK7, MNK2}, TRPV1 (transient receptor potential cation channel subfamily V member 1) [NCBI Gene 7442] {aka VR1}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, SCN10A (sodium voltage-gated channel alpha subunit 10) [NCBI Gene 6336] {aka FEPS2, Nav1.8, PN3, SNS}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, EIF6 (eukaryotic translation initiation factor 6) [NCBI Gene 3692] {aka CAB, EIF3A, ITGB4BP, b(2)gcn, eIF-6, p27(BBP)}, CACNA1C (calcium voltage-gated channel subunit alpha1 C) [NCBI Gene 775] {aka CACH2, CACN2, CACNA1C-IT2, CACNL1A1, CCHL1A1, CaV1.2}, MYC (MYC proto-oncogene, bHLH transcription factor) [NCBI Gene 4609] {aka MRTL, MYCC, bHLHe39, c-Myc}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, EIF3D (eukaryotic translation initiation factor 3 subunit D) [NCBI Gene 8664] {aka EIF3S7, eIF3-p66, eIF3-zeta}, ATF4 (activating transcription factor 4) [NCBI Gene 468] {aka CREB-2, CREB2, TAXREB67, TXREB}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, SIGMAR1 (sigma non-opioid intracellular receptor 1) [NCBI Gene 10280] {aka ALS16, DSMA2, HMNR2, OPRS1, SIG-1R, SR-BP}, FGFR1 (fibroblast growth factor receptor 1) [NCBI Gene 2260] {aka BFGFR, CD331, CEK, ECCL, FGFBR, FGFR-1}, EIF4B (eukaryotic translation initiation factor 4B) [NCBI Gene 1975] {aka EIF-4B, PRO1843}, RPS6KB1 (ribosomal protein S6 kinase B1) [NCBI Gene 6198] {aka PS6K, S6K, S6K-beta-1, S6K1, STK14A, p70 S6KA}, EIF2AK2 (eukaryotic translation initiation factor 2 alpha kinase 2) [NCBI Gene 5610] {aka PKR, PPP1R83, PRKR}, Eif4e (eukaryotic translation initiation factor 4E) [NCBI Gene 13684] {aka EG668879, Eif4e-ps, If4e, eIF-4E}, NTRK1 (neurotrophic receptor tyrosine kinase 1) [NCBI Gene 4914] {aka MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA}, SOX4 (SRY-box transcription factor 4) [NCBI Gene 6659] {aka CSS10, EVI16, IDDSDF}, NTRK2 (neurotrophic receptor tyrosine kinase 2) [NCBI Gene 4915] {aka DEE58, EIEE58, GP145-TrkB, OBHD, TRKB, trk-B}, IL1A (interleukin 1 alpha) [NCBI Gene 3552] {aka IL-1 alpha, IL-1A, IL1, IL1-ALPHA, IL1F1}, EIF2A (eukaryotic translation initiation factor 2A) [NCBI Gene 83939] {aka CDA02, EIF-2A, MST089, MSTP004, MSTP089}, EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3) [NCBI Gene 9451] {aka PEK, PERK, WRS}, CX3CL1 (C-X3-C motif chemokine ligand 1) [NCBI Gene 6376] {aka ABCD-3, C3Xkine, CXC3, CXC3C, NTN, NTT}, NGF (nerve growth factor) [NCBI Gene 4803] {aka Beta-NGF, HSAN5, NGFB}, EIF4EBP1 (eukaryotic translation initiation factor 4E binding protein 1) [NCBI Gene 1978] {aka 4E-BP1, 4EBP1, BP-1, PHAS-I}, EIF2AK4 (eukaryotic translation initiation factor 2 alpha kinase 4) [NCBI Gene 440275] {aka GCN2, PVOD2}, EIF5B (eukaryotic translation initiation factor 5B) [NCBI Gene 9669] {aka IF2}, EIF5 (eukaryotic translation initiation factor 5) [NCBI Gene 1983] {aka EIF-5, EIF-5A}, EIF2AK1 (eukaryotic translation initiation factor 2 alpha kinase 1) [NCBI Gene 27102] {aka HCR, HRI, hHRI}, EIF3E (eukaryotic translation initiation factor 3 subunit E) [NCBI Gene 3646] {aka EIF3-P48, EIF3S6, INT6, eIF3-p46}, DDIT3 (DNA damage inducible transcript 3) [NCBI Gene 1649] {aka AltDDIT3, C/EBPzeta, CEBPZ, CHOP, CHOP-10, CHOP10}, ATP7A (ATPase copper transporting alpha) [NCBI Gene 538] {aka DSMAX, HMNX, MK, MNK, SMAX3}, PRKAA2 (protein kinase AMP-activated catalytic subunit alpha 2) [NCBI Gene 5563] {aka AMPK, AMPK2, AMPKa2, PRKAA}, MTG1 (mitochondrial ribosome associated GTPase 1) [NCBI Gene 92170] {aka GTP, GTPBP7}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, RPS6 (ribosomal protein S6) [NCBI Gene 6194] {aka S6, eS6}, CXCR4 (C-X-C motif chemokine receptor 4) [NCBI Gene 7852] {aka CD184, D2S201E, FB22, HM89, HSY3RR, LCR1}, Bdnf (brain derived neurotrophic factor) [NCBI Gene 12064], INSR (insulin receptor) [NCBI Gene 3643] {aka CD220, HHF5}, Eif2a (eukaryotic translation initiation factor 2A) [NCBI Gene 229317] {aka D030048D22, D3Ertd194e}, HMGB1 (high mobility group box 1) [NCBI Gene 3146] {aka HMG-1, HMG1, HMG3, SBP-1}, Grm7 (glutamate receptor, metabotropic 7) [NCBI Gene 108073] {aka 6330570A01Rik, C030018L03, E130018M02Rik, Gpr1g, Gprc1g, SMN2}, EIF4G2 (eukaryotic translation initiation factor 4 gamma 2) [NCBI Gene 1982] {aka AAG1, DAP5, NAT1, P97}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, CXCL12 (C-X-C motif chemokine ligand 12) [NCBI Gene 6387] {aka IRH, PBSF, SCYB12, SDF1, TLSF, TPAR1}, MOK (MOK protein kinase) [NCBI Gene 5891] {aka RAGE, RAGE-1, RAGE1, STK30}, MAPK14 (mitogen-activated protein kinase 14) [NCBI Gene 1432] {aka CSBP, CSBP1, CSBP2, CSPB1, EXIP, Mxi2}, IGF1R (insulin like growth factor 1 receptor) [NCBI Gene 3480] {aka CD221, IGFIR, IGFR, JTK13} - **Diseases:** obesity (MESH:D009765), Neuropathic pain (MESH:D009437), injury (MESH:D014947), insulin resistance (MESH:D007333), neurological disorders (MESH:D009461), Parkinson's disease (MESH:D010300), Dysfunction of voltage-gated calcium channels (MESH:D002128), metastasis (MESH:D009362), viral infections (MESH:D014777), diabetes (MESH:D003920), cancer (MESH:D009369), carcinogenesis (MESH:D063646), Nerve tissue damage (MESH:D009380), peripheral nerve injuries (MESH:D059348), nerve injury (MESH:D000080902), inflammatory pain (MESH:D010146), central nervous system injuries (MESH:D002493), neuroinflammation (MESH:D000090862), autism (MESH:D001321), neurological diseases (MESH:D020271), multiple myeloma (MESH:D009101), acid deficiencies (MESH:D015223), T-cell dependent tumors (MESH:D005935), Alzheimer's disease (MESH:D000544), rheumatoid arthritis (MESH:D001172), NAFLD (MESH:D065626), polyneuropathy (MESH:D011115), analgesia (MESH:D000699), SMA (MESH:D009134), nociceptive pain (MESH:D059226), T (MESH:D001260), hATTR) amyloidosis (MESH:C567782), metabolic diseases (MESH:D008659), leukemia (MESH:D007938), ISR (MESH:D000079225), neuronal damage (MESH:D009410), immunodeficiencies (MESH:D007153), type 2 diabetes mellitus (MESH:D003924), hypersensitivity (MESH:D004342), bone destruction (MESH:D001847), chronic pain (MESH:D059350), hypoxia (MESH:D000860), Inflammation (MESH:D007249), diabetic neuropathy (MESH:D003929), spinal cord injury (MESH:D013119), inflammatory bowel disease (MESH:D015212), CCI (MESH:D020208), glucose (MESH:D018149), acute to chronic pain (MESH:D059787), neurodegeneration (MESH:D019636) - **Chemicals:** PatA (MESH:C421324), RocA (MESH:C107772), BAY 1143269 (MESH:C000622122), inorganic phosphate (MESH:D010710), CCI-779 (-), GSK2606414 (MESH:C576403), Rapamycin (MESH:D020123), oxygen (MESH:D010100), ALN (MESH:C052045), Everolimus (MESH:D000068338), paclitaxel (MESH:D017239), guanosine 5'-triphosphate (MESH:D006160), XL388 (MESH:C000626295), cercosporamide (MESH:C085452), carboplatin (MESH:D016190), excitatory amino acids (MESH:D018846), resveratrol (MESH:D000077185), Quercetin (MESH:D011794), calcium (MESH:D002118), CGP57380 (MESH:C466997), Hipp (MESH:C510125), eFT 508 (MESH:C000630785), ROS (MESH:D017382), 4E1RCat (MESH:C000722871), guanine nucleotide (MESH:D006150), Temsirolimus (MESH:C401859), GDP (MESH:D006153), Nusinersen (MESH:C000590926), amino acids (MESH:D000596), Pi (MESH:D010716), ATP (MESH:D000255) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116] - **Mutations:** H1047R, serine/threonine - **Cell lines:** 4E2RCat — Mus musculus (Mouse), Hybridoma (CVCL_B6PD), 4E1RCat — Mus musculus (Mouse), Hybridoma (CVCL_WZ96) ## Figures 2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12351134/full.md --- Source: https://tomesphere.com/paper/PMC12351134