KEAP1-NRF2 Interaction in Cancer: Competitive Interactors and Their Role in Carcinogenesis

Oskomić, Marina; Tomić, Antonija; Barbarić, Lea; Matić, Antonia; Kindl, Domagoj Christian; Matovina, Mihaela (2025) KEAP1-NRF2 Interaction in Cancer: Competitive Interactors and Their Role in Carcinogenesis. Cancers, 17 (3). ISSN 2072-6694

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Abstract

The KEAP1−NRF2 signaling pathway is one of the main regulators of the cellular response to oxidative and electrophilic stress. NRF2 is a transcription factor that controls more than 200 cytoprotective genes encoding proteins involved in detoxification, antioxidant protection, carbohydrate metabolism, NADPH regeneration, lipid metabolism, heme and iron metabolism, transcription factors, and the regulation of the proteasome and autophagy. KEAP1 is an inhibitory protein that maintains low levels of NRF2 under basal conditions by targeting it for degradation via the CUL3-RBX1 E3 ubiquitin ligase complex, leading to NRF2 ubiquitination and subsequent proteasomal degradation. Dysregulation of the KEAP1-NRF2 pathway has been observed in various non-communi�cable diseases, including cancer. NRF2 activity has a dual role in cancer: it prevents cancer initiation by protecting the cells from oxidative and electrophilic damage that can lead to genomic instability and DNA damage. However, in later stages of cancer, overactivation of NRF2 promotes cancer progression by protecting cancer cells from the reactive oxygen species (ROS) induced cell death, enabling the detoxification of chemotherapeutics, promoting metabolic reprogramming, and suppressing the immune response by reducing inflammation. One mechanism of NRF2 activation in cancer involves the disruption of the KEAP1-NRF2 interaction through the binding of competitive disruptor proteins to KEAP1. This prevents NRF2 ubiquitination and degradation. This review provides an overview of the most prominent competitive interactors of KEAP1, including SQSTM1, MCM3, PALB2, IKKβ, DPP3, PGAM5, PTMA, FAM129B, and WTX, as well as several less well-characterized KEAP1 interactors, and their potential roles in carcinogenesis.

Item Type:	Article
Uncontrolled Keywords:	KEAP1; NRF2; oxidative stress; protein–protein interactions; cancer development
Subjects:	NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions:	Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type Interakcija dipeptidil peptidaze III s proteinom SH2 domain-containing protein 3C – moguća veza između odgovora na oksidativni stres i stanične migracije-OxMiLink Mihaela Matovina IP-2020-02-6743 HRZZ
Depositing User:	Mihaela Matovina
Date Deposited:	03 Feb 2025 11:07
URI:	http://fulir.irb.hr/id/eprint/9537
DOI:	10.3390/cancers17030447

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