Keap1

Overview

KEAP1 (Kelch-like ECH-associated protein 1) is a cytoplasmic regulatory protein best known for its central role in controlling the cellular antioxidant response through the KEAP1–NRF2 axis. Under basal conditions, KEAP1 contributes to the ubiquitin-mediated degradation of nuclear factor erythroid 2-related factor 2 (NRF2), thereby limiting transcription of antioxidant and cytoprotective genes. When KEAP1 function is altered or inhibited, NRF2 can accumulate and translocate to the nucleus, where it promotes expression of downstream defense genes such as heme oxygenase 1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1).

Because of this regulatory role, KEAP1 is widely studied in oxidative stress biology, inflammation, mitochondrial injury, and disease contexts in which redox imbalance is important. Recent research has continued to examine KEAP1 as both a mechanistic node in disease pathways and a potential therapeutic target, especially in kidney injury, ischemic injury, and other disorders linked to oxidative stress and proinflammatory cytokine signaling.

Role in Recent Research

Recent studies have continued to position KEAP1 as a mechanistic node linking oxidative stress, metabolism, inflammation, and disease progression.

In oncology, KEAP1 was highlighted in the context of tumors harboring co-occurring Kras and KEAP1 mutations, where metabolic reprogramming toward glutamine anaplerosis creates a dependency on glutaminase (GLS)-mediated glutaminolysis for survival and growth. This supports the idea that KEAP1 loss can reshape tumor metabolism and sensitize cancers to glutamine-targeted strategies such as GLS inhibition. In metastatic non-small cell lung cancer, KEAP1 was also examined alongside STK11 and Kras, reflecting the clinical importance of this mutation combination in mNSCLC and its association with distinct tumor biology and outcomes.

Several studies focused on pharmacologic modulation of the KEAP1-NRF2 axis. Omaveloxolone was used to pharmacologically activate NRF2 in SMA type I human fibroblasts, with the study noting previously identified dysregulated NRF2-KEAP1 signaling in SMA mice. In this setting, KEAP1 is relevant as the upstream suppressor whose inhibition or functional antagonism permits NRF2 target protein upregulation. Similarly, 10-shogaol from Zingiber officinale was reported to act as a novel NRF2 activator by inhibiting KEAP1-mediated ubiquitination and proteasome degradation, thereby suppressing proinflammatory cytokines and mitigating tissue damage in mice. These findings reinforce KEAP1 as a druggable regulator of endogenous antioxidant defense.

KEAP1 was also implicated in ischemia-reperfusion and inflammatory injury models. In cerebral ischemia-reperfusion injury, inhibition of endothelial ALOX12 with ML355 was associated with reduced KEAP1 expression, enhanced nuclear NRF2 accumulation, and increased HO-1 expression, consistent with partial restoration of antioxidant signaling. In diabetic nephropathy, inotodiol improved renal histopathology and oxidative stress while decreasing KEAP1, NOX4, and malondialdehyde and increasing superoxide dismutase, catalase, glutathione peroxidase, Nrf2, NQO1, and heme oxygenase-1. Together, these studies suggest that lowering KEAP1 activity or expression can shift tissues toward a more protective redox state.

In cardiovascular and renal cell models, KEAP1 was evaluated in relation to oxidative injury and apoptosis. In doxorubicin-induced cardiac injury, exosomal MALAT1 expression was studied for its potential involvement in Nrf2/Keap1-related signaling, with Nrf2, Keap1, and extracellular vesicle-associated MALAT1 measured by quantitative PCR. In metabolic dysfunction-associated fatty liver disease, serum Keap-1 was significantly increased alongside TNF-α, IL-6, ACSL4, HO-1, and ferritin, while Nrf2 and GPX4 were decreased, linking KEAP1-associated signaling to ferroptosis-related protein changes and systemic inflammatory status.

Across these publications, KEAP1 also appeared in drug-discovery and computational contexts. Molecular docking studies included KEAP1 among key biological targets, indicating ongoing interest in identifying small molecules that may interact with or modulate KEAP1-related pathways. Overall, the recent literature portrays KEAP1 as a central regulator of antioxidant defense whose dysregulation contributes to cancer metabolism, ischemic injury, diabetic complications, ferroptosis-associated pathology, and inflammatory tissue damage.

Key Publications

Jul Design, synthesis and biological evaluation of symmetric thiadiazole carboxamide derivative as glutaminase inhibitor. (Bioorganic & medicinal chemistry letters, 2026, PMID 41730394): "Metabolic reprogramming toward glutamine anaplerosis is a well-established vulnerability in tumors harboring co-occurring KRAS and KEAP1 mutations, creating a dependency on glutaminase (GLS)-mediated glutaminolysis for survival and growth."
Jul Inhibition of endothelial ALOX12 mitigates cerebral ischemia-reperfusion injury by suppressing 12-HETE. (Free radical biology & medicine, 2026, PMID 41887376): "At the signaling level, ML355 was associated with reduced KEAP1 expression, enhanced nuclear NRF2 accumulation, and increased HO-1 expression, consistent with partial restoration of antioxidant signaling."
Jun Exosomal MALAT1 expression associated with the cardioprotective effects of carvacrol in acute doxorubicin-induced cardiac injury: Potential involvement of Nrf2/Keap1-related signaling. (Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2026, PMID 42259137): "Nrf2, Keap1, and extracellular vesicle-associated MALAT1 expression levels were evaluated using quantitative PCR."
Jun Clinical Outcomes Associated with Single STK11 Mutations and Those Co-occurring with KEAP1 and KRAS Mutations in Metastatic Non-Small Cell Lung Cancer. (Advances in therapy, 2026, PMID 42377736): "Tumors with STK11 mutations and those co-occurring with KEAP1 and KRAS mutations commonly occur in patients with metastatic non-small cell lung cancer (mNSCLC)."
Jun Pharmacological Activation of NRF2 by Omaveloxolone Upregulates NRF2-Target Proteins in SMA Type I Human Fibroblasts. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42301137): "Recently, we identified dysregulated NRF2-KEAP1 signaling in SMA mice."
Jun Inotodiol ameliorates oxidative stress and apoptosis by regulating PI3K/Akt/GSK-3β signaling pathways in diabetic nephropathy. (Renal failure, 2026, PMID 42367005): "It ameliorated renal histopathology and oxidative stress, as evidenced by decreased KEAP1, NOX4, and malondialdehyde, along with increased superoxide dismutase, catalase, glutathione peroxidase, Nrf2, NQO1, and heme oxygenase-1."
Jun Discovery of 10-Shogaol from Zingiber officinale with Broad Antiviral and Anti-inflammatory Activity against Dengue and Zika Viruses Using Activity-Guided Molecular Networking. (Journal of agricultural and food chemistry, 2026, PMID 42270434): "Additionally, 10-shogaol suppressed proinflammatory cytokines and mitigated tissue damage in mice by acting as a novel Nrf2 activator by inhibiting Keap1-mediated ubiquitination and proteasome degradation."
May Chemical Profiling and Scaffold-Based Drug-Discovery Analysis of Bioactive Compounds from Ceratonia siliqua L. with Computational and Biological Validation. (Journal of chemical information and modeling, 2026, PMID 42206975): "To further bridge the gap between the identified scaffolds and their corresponding biological activity, molecular docking was performed against key biological targets, including KEAP1, Staphylococcus aureus DHFR, and EGFR."
Jun Association of Serum Angiopoietin-Like Protein 7 With Ferroptosis-Related Proteins in Patients With Metabolic Dysfunction-Associated Fatty Liver Disease. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42247282): "Serum levels of ANGPTL7, TNF-α, IL-6, ACSL4, Keap-1, HO-1, and ferritin were significantly increased, while IL-10, GPX4, and Nrf2 levels were decreased in MAFLD patients when compared with the Con group (MAFLD vs. Con, all p < 0.001)."