# Nrf3: an emerging player in cancer, inflammation, and cellular homeostasis

**Authors:** Deniz Kilicaslan, Meliha Burcu Irmak-Yazicioglu, Erna Copuroglu

PMC · DOI: 10.1007/s11033-026-11678-1 · Molecular Biology Reports · 2026-03-16

## TL;DR

Nrf3 is a versatile transcription factor involved in cancer, inflammation, and cell balance, with both tumor-promoting and tumor-suppressing roles depending on the context.

## Contribution

The paper reviews Nrf3's dual and context-dependent roles in cancer and inflammation, highlighting its potential as a biomarker and therapeutic target.

## Key findings

- Nrf3 can act as an oncogene in colorectal and pancreatic cancers by promoting tumor growth and survival.
- In breast cancer, Nrf3 may function as a tumor suppressor by increasing stress signals and inhibiting migration.
- Nrf3 regulates cellular stress, redox balance, and inflammation, often influenced by microRNAs and cellular signals.

## Abstract

Nuclear factor erythroid 2-related factor 3 (Nrf3) is a transcription factor of the CNC-bZIP family that plays a critical role in managing cellular stress, redox balance, and internal homeostasis. Initially localized to the endoplasmic reticulum, Nrf3 undergoes a sophisticated activation process to reach the nucleus and regulate gene expression. Emerging evidence identifies Nrf3 as a multifaceted and context-dependent regulator whose biological impact varies significantly across different tissues and disease states. In cancer biology, Nrf3 exhibits a dual role by acting as either an oncogene or a tumor suppressor. In many malignancies, such as colorectal and pancreatic cancers, it promotes tumor growth by driving cell cycle progression, metabolic adaptation, and cancer cell survival. Conversely, in other contexts like breast cancer, Nrf3 can inhibit tumor progression by increasing stress signals and suppressing pathways that lead to cell migration. Beyond its role in oncology, Nrf3 coordinates responses to inflammation and metabolic shifts, often under the control of various cellular signals and microRNAs. This review highlights its importance in maintaining cellular health and underscores its potential as a clinical biomarker and therapeutic target, while calling for further research to fully clarify its diverse biological functions.

## Linked entities

- **Genes:** NFE2L3 (NFE2 like bZIP transcription factor 3) [NCBI Gene 9603]
- **Diseases:** cancer (MONDO:0004992), colorectal cancer (MONDO:0005575), pancreatic cancer (MONDO:0005192), breast cancer (MONDO:0004989)

## Full-text entities

- **Genes:** TCF4 (transcription factor 4) [NCBI Gene 6925] {aka CDG2T, E2-2, FCD2, FECD3, ITF-2, ITF2}, CDKN1B (cyclin dependent kinase inhibitor 1B) [NCBI Gene 1027] {aka CDKN4, KIP1, MEN1B, MEN4, P27KIP1}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, NGLY1 (N-glycanase 1) [NCBI Gene 55768] {aka CDDG, CDG1V, PNG-1, PNG1, PNGase}, DUX4 (double homeobox 4) [NCBI Gene 100288687] {aka DUX4L}, SLC2A1 (solute carrier family 2 member 1) [NCBI Gene 6513] {aka CSE, DYT17, DYT18, DYT9, EIG12, GLUT}, HMGCS1 (3-hydroxy-3-methylglutaryl-CoA synthase 1) [NCBI Gene 3157] {aka CMYO28, HMGCS}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, BACH1 (BTB domain and CNC homolog 1) [NCBI Gene 571] {aka BACH-1, BTBD24}, NOX4 (NADPH oxidase 4) [NCBI Gene 50507] {aka KOX, KOX-1, RENOX}, RAB5A (RAB5A, member RAS oncogene family) [NCBI Gene 5868] {aka RAB5}, HSPA5 (heat shock protein family A (Hsp70) member 5) [NCBI Gene 3309] {aka BIP, GRP78, HEL-S-89n}, Il1b (interleukin 1 beta) [NCBI Gene 16176] {aka IL-1beta, Il-1b}, KEAP1 (kelch like ECH associated protein 1) [NCBI Gene 9817] {aka INrf2, KLHL19}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, DDI2 (DDI proteasomal shuttling factor 2) [NCBI Gene 84301] {aka RSC1A1}, RB1 (RB transcriptional corepressor 1) [NCBI Gene 5925] {aka OSRC, PPP1R130, RB, p105-Rb, p110-RB1, pRb}, CDK1 (cyclin dependent kinase 1) [NCBI Gene 983] {aka CDC2, CDC28A, P34CDC2}, RELA (RELA proto-oncogene, NF-kB subunit) [NCBI Gene 5970] {aka AIF3BL3, CMCU, NFKB3, p65}, VCP (valosin containing protein) [NCBI Gene 7415] {aka CDC48, FTDALS6, TERA, p97}, PRDX6 (peroxiredoxin 6) [NCBI Gene 9588] {aka 1-Cys, AOP2, HEL-S-128m, LPCAT-5, NSGPx, PRX}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, Fgf7 (fibroblast growth factor 7) [NCBI Gene 14178] {aka Fgf5b, Kgf}, UHMK1 (U2AF homology motif kinase 1) [NCBI Gene 127933] {aka KIS, KIST, P-CIP2}, NFE2L3 (NFE2 like bZIP transcription factor 3) [NCBI Gene 9603] {aka NRF3}, MAF (MAF bZIP transcription factor) [NCBI Gene 4094] {aka AYGRP, CCA4, CTRCT21, c-MAF}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, HMGB1 (high mobility group box 1) [NCBI Gene 3146] {aka HMG-1, HMG1, HMG3, SBP-1}, GGPS1 (geranylgeranyl diphosphate synthase 1) [NCBI Gene 9453] {aka GGPPS, GGPPS1, MDHLO, MUDHLOV}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, NFE2L1 (NFE2 like bZIP transcription factor 1) [NCBI Gene 4779] {aka LCR-F1, NRF-1, NRF1, TCF11}, NFE2 (nuclear factor, erythroid 2) [NCBI Gene 4778] {aka NF-E2, p45}, MYOCD (myocardin) [NCBI Gene 93649] {aka MGBL, MYCD}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, CUL1 (cullin 1) [NCBI Gene 8454], Cd4 (CD4 antigen) [NCBI Gene 12504] {aka L3T4, Ly-4}, EREG (epiregulin) [NCBI Gene 2069] {aka EPR, ER, Ep}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 5599] {aka JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, PRKM8}, FBXW7 (F-box and WD repeat domain containing 7) [NCBI Gene 55294] {aka AGO, CDC4, DEDHIL, FBW6, FBW7, FBX30}, SREBF2 (sterol regulatory element binding transcription factor 2) [NCBI Gene 6721] {aka SREBP-2, SREBP2, bHLHd2}, SYVN1 (synoviolin 1) [NCBI Gene 84447] {aka DER3, HRD1}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, Nrf1 (nuclear respiratory factor 1) [NCBI Gene 18181] {aka D6Ertd415e}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, NQO1 (NAD(P)H quinone dehydrogenase 1) [NCBI Gene 1728] {aka DHQU, DIA4, DTD, NMOR1, NMORI, QR1}, NRF1 (nuclear respiratory factor 1) [NCBI Gene 4899] {aka ALPHA-PAL}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, PRKAR1A (protein kinase cAMP-dependent type I regulatory subunit alpha) [NCBI Gene 5573] {aka ACRDYS1, ADOHR, CAR, CNC, CNC1, PKR1}, SREBF1 (sterol regulatory element binding transcription factor 1) [NCBI Gene 6720] {aka HMD, IFAP2, SREBP1, bHLHd1}, POMP (proteasome maturation protein) [NCBI Gene 51371] {aka C13orf12, HSPC014, PNAS-110, PRAAS2, UMP1}, CDH1 (cadherin 1) [NCBI Gene 999] {aka Arc-1, BCDS1, CD324, CDHE, ECAD, LCAM}, PRB1 (proline rich protein BstNI subfamily 1) [NCBI Gene 5542] {aka PM, PMF, PMS, PRB1L, PRB1M}, Nfe2l3 (nuclear factor, erythroid derived 2, like 3) [NCBI Gene 18025] {aka Nrf3}, BACH2 (BACH transcriptional regulator 2) [NCBI Gene 60468] {aka BTBD25, IMD60}, MIR1246 (microRNA 1246) [NCBI Gene 100302142] {aka MIRN1246, hsa-mir-1246}, BTRC (beta-transducin repeat containing E3 ubiquitin protein ligase) [NCBI Gene 8945] {aka BETA-TRCP, FBW1A, FBXW1, FBXW1A, FWD1, bTrCP}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, MIR26A1 (microRNA 26a-1) [NCBI Gene 407015] {aka MIR26A, MIRN26A1, mir-26a-1}
- **Diseases:** infections (MESH:D007239), trauma (MESH:D014947), Burkitt's lymphoma (MESH:D002051), skin cancer (MESH:D012878), multiple myeloma (MESH:D009101), PDAC (MESH:D021441), obesity (MESH:D009765), TNBC (MESH:D064726), carcinogenesis (MESH:D063646), lung cancer (MESH:D008175), metastasis (MESH:D009362), actinic keratosis (MESH:D055623), hepatocellular carcinoma (MESH:D006528), breast and gastric cancers (MESH:D013274), pancreatic (MESH:D010195), neurodegenerative disorders (MESH:D019636), basal cell carcinoma (MESH:D002280), colon, thyroid, and pancreatic cancer (MESH:D010190), colon cancer (MESH:D015179), thymic lymphomas (MESH:D013953), deficient (MESH:D007153), choriocarcinoma (MESH:D002822), thyroid cancer (MESH:D013964), Cancer (MESH:D009369), tissue injury (MESH:D017695), metabolic syndromes (MESH:D024821), hyperoxia (MESH:D018496), kidney renal clear cell carcinoma (MESH:D002292), colon adenocarcinoma (MESH:D003110), breast and squamous cell carcinoma (MESH:D001943), hypoxic (MESH:D002534), Inflammation (MESH:D007249), morphological abnormalities (MESH:D000013), SCC (MESH:D002294), HNSC (MESH:D000077195)
- **Chemicals:** t-BHQ (MESH:C018855), cholesterol (MESH:D002784), heavy metal (MESH:D019216), oxygen (MESH:D010100), benzo[a]pyrene (MESH:D001564), lactate (MESH:D019344), fatty acid (MESH:D005227), mevalonate (MESH:D008798), lanosterol (MESH:D007810), Lipids (MESH:D008055), tunicamycin (MESH:D014415), GGPP (MESH:C002963), ROS (MESH:D017382), H2O2 (MESH:D006861), thapsigargin (MESH:D019284), brefeldin A (MESH:D020126), carbohydrates (MESH:D002241), acetyl-CoA (MESH:D000105), farnesyl pyrophosphate (MESH:C004808), glucose (MESH:D005947)
- **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], lymphocytic choriomeningitis virus [taxon 11623]
- **Cell lines:** COS-1 — Chlorocebus aethiops (Green monkey), Transformed cell line (CVCL_0223), JAR — Homo sapiens (Human), Gestational choriocarcinoma, Cancer cell line (CVCL_0360), SCC13 — Homo sapiens (Human), Skin squamous cell carcinoma, Cancer cell line (CVCL_4029), HCT116 — Homo sapiens (Human), Colon carcinoma, Cancer cell line (CVCL_0291), H1299 — Homo sapiens (Human), Lung large cell carcinoma, Cancer cell line (CVCL_0060)

## Full text

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## Figures

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## References

2 references — full list in the complete paper: https://tomesphere.com/paper/PMC12992410/full.md

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Source: https://tomesphere.com/paper/PMC12992410