# Regulatory role of E3 ubiquitin ligases in multiple myeloma: from molecular mechanisms to therapeutic strategies

**Authors:** Xiaoran Chen, Jiale Zhou, Xiaoqing Dong, Yan Xu, Bing Chen

PMC · DOI: 10.3389/fcell.2025.1620097 · 2025-07-30

## TL;DR

This review explores how E3 ubiquitin ligases influence multiple myeloma and their potential as therapeutic targets.

## Contribution

The paper provides a comprehensive overview of the emerging roles of E3 ubiquitin ligases in multiple myeloma therapy.

## Key findings

- E3 ubiquitin ligases regulate protein ubiquitination, affecting protein degradation and signaling in MM.
- They contribute to MM progression and drug resistance, making them potential therapeutic targets.
- Understanding their mechanisms could lead to improved treatment strategies for MM patients.

## Abstract

Multiple myeloma (MM) is a hematological tumor characterized by the malignant proliferation of plasma cells in bone marrow (BM). Despite the prolonged survival of MM patients, a significant amount of patients relapse or become drug resistant. This underlines the importance of the development and investigation of novel targets to improve MM therapy. Increasing evidences have shed light on the emerging roles of E3 ubiquitin ligases in MM. E3 ubiquitin ligases play an essential role in protein ubiquitination, which is involved in the regulation of protein degradation, protein-protein interactions and signal transduction. In this comprehensive review, we will summarize the current understanding of E3 ubiquitin ligases in MM and their contribution to MM therapy, which could help explore the molecular mechanisms in MM and provide potential therapeutic targets for the treatment of MM.

## Linked entities

- **Diseases:** multiple myeloma (MONDO:0009693)

## Full-text entities

- **Genes:** H3P16 (H3 histone pseudogene 16) [NCBI Gene 644914] {aka H3.6, H3F3AP6, p21}, ATG5 (autophagy related 5) [NCBI Gene 9474] {aka APG5, APG5-LIKE, APG5L, ASP, SCAR25, hAPG5}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, NUAK1 (NUAK family kinase 1) [NCBI Gene 9891] {aka ARK5}, CRTC2 (CREB regulated transcription coactivator 2) [NCBI Gene 200186] {aka TORC-2, TORC2}, MAF (MAF bZIP transcription factor) [NCBI Gene 4094] {aka AYGRP, CCA4, CTRCT21, c-MAF}, CCR1 (C-C motif chemokine receptor 1) [NCBI Gene 1230] {aka CD191, CKR-1, CKR1, CMKBR1, HM145, MIP1aR}, NEDD4L (NEDD4 like E3 ubiquitin protein ligase) [NCBI Gene 23327] {aka NEDD4-2, NEDD4.2, PVNH7, RSP5, hNEDD4-2}, COL11A2 (collagen type XI alpha 2 chain) [NCBI Gene 1302] {aka DFNA13, DFNB53, FBCG2, HKE5, OSMEDA, OSMEDB}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, IKZF1 (IKAROS family zinc finger 1) [NCBI Gene 10320] {aka CVID13, Hs.54452, IK1, IKAROS, LYF1, LyF-1}, RCHY1 (ring finger and CHY zinc finger domain containing 1) [NCBI Gene 25898] {aka ARNIP, CHIMP, PIRH2, PRO1996, RNF199, ZCHY}, TRIM33 (tripartite motif containing 33) [NCBI Gene 51592] {aka DDH4, ECTO, PTC7, RFG7, TF1G, TIF1G}, IRS1 (insulin receptor substrate 1) [NCBI Gene 3667] {aka HIRS-1}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, IKZF3 (IKAROS family zinc finger 3) [NCBI Gene 22806] {aka AIO, AIOLOS, IMD84, ZNFN1A3}, BAK1 (BCL2 antagonist/killer 1) [NCBI Gene 578] {aka BAK, BAK-LIKE, BCL2L7, CDN1}, SALL4 (spalt like transcription factor 4) [NCBI Gene 57167] {aka DRRS, HSAL4, IVIC, ZNF797}, PTEN (phosphatase and tensin homolog) [NCBI Gene 5728] {aka 10q23del, BZS, CWS1, DEC, GLM2, MHAM}, DNER (delta/notch like EGF repeat containing) [NCBI Gene 92737] {aka UNQ26, bet}, RITA1 (RBPJ interacting and tubulin associated 1) [NCBI Gene 84934] {aka C12orf52, RITA}, CCND2 (cyclin D2) [NCBI Gene 894] {aka KIAK0002, MPPH3}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, CASP8 (caspase 8) [NCBI Gene 841] {aka ALPS2B, CAP4, Casp-8, FLICE, MACH, MCH5}, FGF2 (fibroblast growth factor 2) [NCBI Gene 2247] {aka BFGF, FGF-2, FGFB, HBGF-2}, IGF1 (insulin like growth factor 1) [NCBI Gene 3479] {aka IGF, IGF-I, IGFI, MGF}, TRAT1 (T cell receptor associated transmembrane adaptor 1) [NCBI Gene 50852] {aka HSPC062, TCRIM, TRIM, pp29/30}, MYCN (MYCN proto-oncogene, bHLH transcription factor) [NCBI Gene 4613] {aka FGLDS1, MODED, MPAPA, MYCNsORF, MYCNsPEP, N-myc}, IL17RB (interleukin 17 receptor B) [NCBI Gene 55540] {aka CRL4, EVI27, IL17BR, IL17RH1}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, HERC4 (HECT and RLD domain containing E3 ubiquitin protein ligase 4) [NCBI Gene 26091], RIPK1 (receptor interacting serine/threonine kinase 1) [NCBI Gene 8737] {aka AIEFL, IMD57, RIP, RIP-1, RIP1}, FBXW7 (F-box and WD repeat domain containing 7) [NCBI Gene 55294] {aka AGO, CDC4, DEDHIL, FBW6, FBW7, FBX30}, CRBN (cereblon) [NCBI Gene 51185] {aka MRT2, MRT2A}, WWP2 (WW domain containing E3 ubiquitin protein ligase 2) [NCBI Gene 11060] {aka AIP2, WWp2-like}, OAS3 (2'-5'-oligoadenylate synthetase 3) [NCBI Gene 4940] {aka p100, p100OAS}, CUL1 (cullin 1) [NCBI Gene 8454], MUL1 (mitochondrial E3 ubiquitin protein ligase 1) [NCBI Gene 79594] {aka C1orf166, GIDE, MAPL, MULAN, RNF218}, CDKN1B (cyclin dependent kinase inhibitor 1B) [NCBI Gene 1027] {aka CDKN4, KIP1, MEN1B, MEN4, P27KIP1}, NFKBIA (NFKB inhibitor alpha) [NCBI Gene 4792] {aka EDAID2, IKBA, MAD-3, NFKBI}, XIAP (X-linked inhibitor of apoptosis) [NCBI Gene 331] {aka API3, BIRC4, IAP-3, ILP1, MIHA, XLP2}, TLR3 (toll like receptor 3) [NCBI Gene 7098] {aka CD283, IIAE2, IMD83}, NRAS (NRAS proto-oncogene, GTPase) [NCBI Gene 4893] {aka ALPS4, CMNS, N-ras, NCMS, NRAS1, NS6}, PMAIP1 (phorbol-12-myristate-13-acetate-induced protein 1) [NCBI Gene 5366] {aka APR, NOXA}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, ARID2 (AT-rich interaction domain 2) [NCBI Gene 196528] {aka BAF200, CSS6, SMARCF3, ZIPZAP, p200}, ITGB7 (integrin subunit beta 7) [NCBI Gene 3695], MCL1 (MCL1 apoptosis regulator, BCL2 family member) [NCBI Gene 4170] {aka BCL2L3, EAT, MCL1-ES, MCL1L, MCL1S, Mcl-1}, BIRC8 (baculoviral IAP repeat containing 8) [NCBI Gene 112401] {aka ILP-2, ILP2, RNF136, hILP2}, ZBTB16 (zinc finger and BTB domain containing 16) [NCBI Gene 7704] {aka PLZF, ZNF145}, KITLG (KIT ligand) [NCBI Gene 4254] {aka DCUA, DFNA69, FPH2, FPHH, KL-1, Kitl}, FBXO9 (F-box protein 9) [NCBI Gene 26268] {aka FBX9, NY-REN-57, VCIA1, dJ341E18.2}, DKK1 (dickkopf Wnt signaling pathway inhibitor 1) [NCBI Gene 22943] {aka DKK-1, SK}, MAGT1 (magnesium transporter 1) [NCBI Gene 84061] {aka CDG1CC, IAP, MRX95, OST3B, PRO0756, SLC58A1}, TRIM21 (tripartite motif containing 21) [NCBI Gene 6737] {aka RNF81, RO52, Ro/SSA, SSA, SSA1, TRIM21/Ro52}, JUN (Jun proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 3725] {aka AP-1, AP1, c-Jun, cJUN, p39}, SKP2 (S-phase kinase associated protein 2) [NCBI Gene 6502] {aka FBL1, FBXL1, FLB1, p45}, BBC3 (BCL2 binding component 3) [NCBI Gene 27113] {aka JFY-1, JFY1, PUMA}, MAFA (MAF bZIP transcription factor A) [NCBI Gene 389692] {aka INSDM, RIPE3b1, hMafA}, COP1 (COP1 E3 ubiquitin ligase) [NCBI Gene 64326] {aka CFAP78, FAP78, RFWD2, RNF200}
- **Diseases:** inflammation (MESH:D007249), hepatic injury (MESH:D056486), peripheral neuropathy (MESH:D010523), lung cancer (MESH:D008175), AML (MESH:D015470), HCC (MESH:D006528), bone pain (MESH:D010146), immune dysfunction (MESH:D007154), hematologic malignancy (MESH:D019337), SCID (MESH:D053632), MM (MESH:D009101), tumorigenic (MESH:D002471), malignancies (MESH:D009369), hematological carcinogenesis (MESH:D063646), bone marrow failure (MESH:D000080983), pancreatic cancer (MESH:D010190), cytotoxicity (MESH:D064420), metastasis (MESH:D009362), kidney damage (MESH:D007674)
- **Chemicals:** thalidomide (MESH:D013792), lactate (MESH:D019344), ARV-825 (MESH:C000606252), A-1210477 (MESH:C000611392), C1 (MESH:C400149), OTX015 (MESH:C000605331), birinapant (MESH:C582429), Nutlin-3 (MESH:C482205), LCL161 (MESH:C574246), E2 (MESH:D004958), trametinib (MESH:C560077), CELMoD (-), Iberdomide (MESH:C000624220), bortezomib (MESH:D000069286), Pomalidomide (MESH:C467566), Lenalidomide (MESH:D000077269), dexamethasone (MESH:D003907)
- **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090]

## Figures

5 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12343653/full.md

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Source: https://tomesphere.com/paper/PMC12343653