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Results for “Kelch-Like ECH-Associated Protein 1”

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PubMed2026

Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers.

Metabolic reprogramming is a defining feature of cancer; however, how it contributes to therapeutic resistance remains incompletely understood. Here we show that loss of aldo-ketoreductase 1A1 (AKR1A1) in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) disrupts terminal glycolytic flux and lactate production through S-nitrosylation-mediated inhibition of pyruvate kinase, resulting in the accumulation of methylglyoxal (MGO). In multiple AKR1A1-deficient models, but not in those endogenously expressing the C423/424 A mutant of pyruvate kinase M2, elevated MGO triggers autophagic degradation of Kelch-like ECH-associated protein 1, leading to Nuclear factor erythroid 2-Related Factor 2 (NRF2) activation and transcriptional reprogramming. This NRF2-driven response enhances chemoresistance and promotes tumor cell migration, two hallmarks of aggressive cancer. Therapeutically, we demonstrate that pharmacological inhibition of the glyoxalase system-the major pathway for MGO detoxification-restores drug sensitivity in patient-derived cells and xenograft models, revealing a context-dependent metabolic vulnerability in AKR1A1 loss conditions. These findings identify AKR1A1 as a metabolic tumor suppressor and uncover crosstalk between S-nitrosylation and glycation as a key regulatory axis linking metabolic reprogramming to NRF2-driven therapy resistance, offering glyoxalase inhibition as a potential precision treatment strategy for RCC and HCC.

Humans↗
PubMed2026

KEAP1 loss-of-function suppresses immunogenic ferroptosis and limits PD-1 blockade efficacy through an NRF2-FSP1 pathway.

Loss-of-function mutations in Kelch-like ECH-associated protein 1 (KEAP1) frequently occur in lung adenocarcinoma and are associated with poor prognosis and limited benefit from immunotherapy. However, the mechanisms linking KEAP1 deficiency to immune evasion remain elusive. We combined clinical data analysis, in vivo tumor models, and in vitro co-culture systems to investigate how KEAP1 deficiency shapes dendritic cell (DC) biology and response to PD-1 blockade. Ferroptosis induction assays, damage-associated molecular patterns (DAMPs) quantification, cytokine profiling, and mechanistic interrogation of the FSP1-CoQ10 axis were performed to delineate pathways.KEAP1 mutations correlated with poor response to PD-1 blockade and reduced DC infiltration. In mice, KEAP1-deficient tumors exhibited accelerated growth and reduced DC and CD8+ T-cell infiltration, consistent with an immune-cold phenotype. Mechanistically, KEAP1 loss impaired DC function in vitro, as evidenced by reduced maturation, phagocytosis, and naïve CD8+ T-cell priming capacity. This defect was linked to two mechanisms. First, KEAP1-deficient tumor cells resisted ferroptosis and failed to release immunogenic DAMPs, including extracellular ATP, HMGB1, and calreticulin. Second, KEAP1 deficiency reprogrammed the cytokine secretion profile, with downregulation of CCL2, IL-6, CXCL1, and CXCL2, thereby diminishing DC recruitment and inflammatory signaling. Notably, inhibition of the FSP1-CoQ10 antioxidant axis restored ferroptosis-associated immunogenic cell death. Our study identifies KEAP1 deficiency as a driver of immune-cold tumor microenvironments and resistance to PD-1 blockade, acting through impaired ferroptosis-induced immunogenic cell death and disrupted DC function. Genetic FSP1 deletion restored ferroptosis-associated immunogenicity and DC activation in KEAP1-deficient cells, supporting FSP1 as a potential therapeutic target for further in vivo evaluation.

DAMPs↗
PubMed2026

The potential clinical benefit of routine comprehensive genomic profiling in non-small cell lung cancer for the detection of prognostic co-mutations - A multicenter next generation sequencing study.

INTRODUCTION: Non-driver mutations such as TP53, STK11 and KEAP1 are clinically relevant in determining immunotherapy efficacy in patients with non-small cell lung cancer (NSCLC). The aim of this study is to determine the prevalence and clinical relevance of variations in TP53, STK11 and KEAP1 in patients in the analysis of NSCLC, using targeted next-generation sequencing. METHODS: This real-life prospective multicenter cohort study from July 2022 until October 2023 utilized samples of patients in the analysis of NSCLC. The samples were subjected to a targeted DNA NGS panel and, if indicated, RNA sequencing. The outcome of the molecular diagnostics was retrieved, including driver alterations and more in-depth analysis of TP53, STK11 and KEAP1. RESULTS: In 134 of the 437 samples an actionable genomic alteration (AGA) was detected. Of the remaining samples, 213 carried a mutation in either TP53, STK11 and/or KEAP1, while 90 harbored either variants of unknown significance (VUS) (16) or no variant (74). In-depth analysis showed 77 alterations of STK11, with 56 pathogenic and 21 VUS. Most STK11 variants were identified in exon 1, which is hypothesized to be correlated to an oncogenic isoform. Moreover, variants in KEAP1 were mostly VUS, with 48 VUS and 24 mutations. Lastly, 264 TP53 alterations, of which 249 pathogenic and 15 VUS, occurred, with an even spread in the DNA-binding domain. CONCLUSION: This study demonstrated the broad spectrum of variants in STK11, KEAP1 and TP53 in routine panel-based DNA NGS, with 70.3% of the samples without AGA showing a potential clinically relevant mutation in TP53, STK11 and/or KEAP1.

Humans↗
PubMed2024

Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer.

The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as KEAP1. Genomic, functional, and clinical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.

Kelch-Like ECH-Associated Protein 1↗
PubMed2026

Obeticholic Acid and Edaravone Protect Against Cisplatin-Induced Hepatotoxicity Through Modulation of Keap1/Nrf2/ARE, TNF-α/NF-κB, and AKT/GSK-3β Pathways.

Hepatotoxicity is one of the most crucial side effects of chemotherapy administration. Obeticholic acid (OCA) is a semisynthetic bile acid and farnesoid X receptor (FXR) agonist derived from chenodeoxycholic acid, with reported antioxidant and anti-inflammatory effects in liver disorders. This study investigated the hepatoprotective effect of OCA against commonly used chemotherapy cisplatin (CP)-induced hepatotoxicity in rats, as well as the modulatory effects of edaravone (EDA), a potent free radical scavenger, on its effects. Rats were divided into five groups: control (received vehicle), CP (7.5 mg/kg), EDA (30 mg/kg) + CP, OCA (30 mg/kg) + CP, and EDA + OCA + CP. The results of the present study demonstrated that both OCA and EDA significantly mitigated liver damage caused by CP, as evidenced by restoring liver enzymes and histological structure, reestablishment of oxidant/antioxidant status, suppression of inflammation, and attenuation of pro-death signaling. The study highlights the role of key molecular pathways, including Keap1/Nrf2/HO-1,HO-1, TNF-α/NF-κB, and AKT/GSK-3β, in the hepatoprotective mechanisms of OCA. Collectively, these findings suggest that OCA and EDA, particularly in combination, attenuate CP-induced hepatotoxicity and are associated with coordinated modulation of oxidative stress, inflammatory signaling, and AKT/GSK-3β-associated pro-survival/pro-death pathways.

Animals↗
PubMed2026

Dictamnine alleviates oxidative stress in rheumatoid arthritis via modulation of the NR1D1-Keap1/Nrf2/ARE axis.

Rheumatoid arthritis (RA) is a persistent systemic disorder of autoimmune origin, with its core pathological manifestation being inflammation of the synovial tissue. The excessive growth of fibroblast-like synoviocytes (FLS) represents a critical pathological mechanism in RA, actively driving the advancement of the condition. Dictamnus dasycarpus Turcz. (D. dasycarpus) exhibits prominent anti-inflammatory effects and shows favorable therapeutic efficacy against RA. Dictamnine (Dic) is a major active component of D. dasycarpus, however, its therapeutic effectiveness and underlying mechanisms in RA have yet to be fully elucidated. This study investigated the effect of Dic on synovial hyperplasia in RA and elucidated the underlying mechanisms. Using a TNF-α-induced human fibroblast-like synoviocyte (HFLS-RA) model and a collagen-induced arthritis (CIA) mouse model, Dic was found to effectively inhibit synovial cell proliferation and pathological hyperplasia. Proteomics analysis was employed to clarify its potential mechanism in ameliorating the disease, and the findings were further validated through hematoxylin and eosin (H&E) staining, immunofluorescence (IF), ROS detection, JC-1 staining, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) analysis, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB). The results suggested that the anti-RA activity of Dic is associated with its interaction with the nuclear receptor NR1D1. Moreover, the NR1D1 antagonist SR8278 reversed Dic's effects on Nrf2 and cytoprotection, confirming that Dic functions through NR1D1. This activation consequently influences the Keap1/Nrf2/ARE cascade, leading to decreased intracellular reactive oxygen species (ROS) accumulation and an improvement in compromised mitochondrial membrane potential. siRNA knockdown experiments further confirmed that NR1D1 is a target of Dic and regulates the downstream Keap1/Nrf2/HO-1 signaling pathway, through which Dic ameliorates RA both in vitro and in vivo by upregulating NR1D1 expression to activate the Keap1/Nrf2/ARE antioxidant pathway, thereby mitigating oxidative stress, inhibiting synovial cell proliferation, and ultimately alleviating pathological synovial hyperplasia.

Arthritis, Rheumatoid↗
PubMed2026

Perm1 enhances Nrf2-driven antioxidant defense through Keap1 oxidation during myocardial ischemia/reperfusion injury.

Ischemia/reperfusion (IR) enhances oxidative stress, leading to myocardial injury. Although Perm1 promotes cytoprotective mechanisms, the underlying mechanisms are poorly understood. Cysteine oxidation of Keap1 alleviates Cul3-mediated ubiquitination/degradation of Nrf2 and promotes antioxidant transcription. Here we show that Perm1 activates Nrf2 through cysteine oxidation of Keap1 and stabilization of Nrf2. Endogenous Perm1 was downregulated during IR, whereas the rescue of Perm1 reduced IR injury. Downregulation of Perm1 exacerbated oxidative stress, whereas upregulation of Perm1 alleviated it, accompanied by downregulation and upregulation of Nrf2-regulated antioxidant genes, respectively. Perm1 promoted oxidation of cysteine residues in Keap1, possibly through thiol-disulfide exchange reactions, which decreases Keap1-Nrf2 interaction and inhibits Cul3-mediated degradation of Nrf2. We identified Cys121 and Cys746 in Perm1 as critical for Keap1 oxidation and cardioprotection. Thus, Perm1 induces cysteine oxidation of Keap1, thereby conferring myocardial resistance to IR injury by inducing Nrf2 stabilization and transcriptional activation of antioxidant genes.

Kelch-Like ECH-Associated Protein 1↗
PubMed2026

JP1 peptide modulates oxidative stress and autophagy via Keap1-Nrf2-ARE in ALS model mice.

BACKGROUND: The simultaneous modulation of oxidative stress and autophagy represents a potential therapeutic strategy for amyotrophic lateral sclerosis (ALS), yet agents capable of coordinately regulating both processes remain scarce. The Keap1‑Nrf2‑ARE pathway serves as a critical hub linking redox homeostasis and autophagic regulation, making it an attractive target for ALS intervention. JWA is a stress‑responsive protein involved in cellular protection against oxidative injury, and its neuroprotective effects have been shown to depend on activation of the MEK/ERK‑Nrf2 axis. JP1 is a functional oligopeptide derived from the JWA protein that has been engineered to cross the blood-brain barrier and specifically target integrin αVβ3. Based on the link between JWA and Nrf2 signaling, we hypothesized that JP1 activates the Keap1‑Nrf2‑ARE pathway to coordinate antioxidant defense and autophagic clearance. Here, we evaluated this hypothesis in the SOD1‑G93A mouse model, a well‑established transgenic model of familial ALS, and elucidated the underlying mechanisms. METHODS: We evaluated the efficacy of JP1 in the SOD1-G93A mice model using behavioral phenotyping and survival analysis. The coordinated mechanism was investigated in spinal cord tissues by profiling the Keap1-Nrf2-ARE pathway and oxidative stress, quantifying autophagic flux (by Western blotting and transmission electron microscopy) and neuronal apoptosis, and evaluating histology (by Nissl staining and immunofluorescence). Integrated transcriptomic and proteomic analyses further elucidated the global molecular landscape underlying the therapeutic effects of JP1. RESULTS: JP1 treatment ameliorated motor deficits and extended survival in SOD1-G93A mice without adversely affecting liver or kidney function. JP1 crossed the blood-brain barrier, targeted motor neurons expressing integrin αVβ3, and activated the ERK pathway. This promoted Keap1/Cul3 degradation and Nrf2 nuclear translocation, thereby activating the Keap1-Nrf2-ARE pathway to alleviate oxidative stress. Concurrently, JP1 restored autophagic flux, increased autophagic activity, attenuated motor neuron injury, suppressed neuronal apoptosis, and preserved neuronal structural integrity. The Nrf2 inhibitor ML385 reversed the protective effects of JP1 on survival, motor function, autophagy, oxidative stress, and neuronal apoptosis, which confirms that JP1 acts via the Nrf2 pathway. CONCLUSIONS: JP1 acts as a promising coordinator of antioxidant and autophagic processes by targeting the Keap1-Nrf2-ARE pathway, thus highlighting its therapeutic potential for ALS.

Animals↗
PubMed2024

Nrf2/Keap1/ARE regulation by plant secondary metabolites: a new horizon in brain tumor management.

Brain cancer is regarded as one of the most life-threatening forms of cancer worldwide. Oxidative stress acts to derange normal brain homeostasis, thus is involved in carcinogenesis in brain. The Nrf2/Keap1/ARE pathway is an important signaling cascade responsible for the maintenance of redox homeostasis, and regulation of anti-inflammatory and anticancer activities by multiple downstream pathways. Interestingly, Nrf2 plays a somewhat, contradictory role in cancers, including brain cancer. Nrf2 has traditionally been regarded as a tumor suppressor since its cytoprotective functions are considered to be the principle cellular defense mechanism against exogenous and endogenous insults, such as xenobiotics and oxidative stress. However, hyperactivation of the Nrf2 pathway supports the survival of normal as well as malignant cells, protecting them against oxidative stress, and therapeutic agents. Plants possess a pool of secondary metabolites with potential chemotherapeutic/chemopreventive actions. Modulation of Nrf2/ARE and downstream activities in a Keap1-dependant manner, with the aid of plant-derived secondary metabolites exhibits promise in the management of brain tumors. Current article highlights the effects of Nrf2/Keap1/ARE cascade on brain tumors, and the potential role of secondary metabolites regarding the management of the same.

Animals↗