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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↗

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

Targeted Nrf2 activation improves vascular endothelial function with aging and prevents vascular dysfunction following disuse in younger and older adults.

Aging and physical inactivity/disuse contribute to cardiovascular disease, which is attributable, in part, to vascular endothelial dysfunction associated with impaired nuclear-factor erythroid 2-related factor 2 (Nrf2) signaling. However, the ability to augment Nrf2 activation and its effects on age- and disuse-related vascular dysfunction in humans remains limited. In a double-blind, randomized, placebo-controlled study design 20 younger adults (8M/12F, age 27 ± 7 y) and 24 older adults (12M/12F, age 67 ± 8 y) were randomized to receive either placebo or PB125 (200 mg/day, Nrf2 activator) across three visits: baseline, 2 weeks of supplementation, and following either 5 days of bed rest (old) or 2 weeks of limb immobilization (young). Brachial and popliteal artery flow-mediated dilation (FMD), passive leg movement-induced (PLM) leg blood flow (LBF) and vascular conductance (LVC) and serum antioxidant status (superoxide dismutase, SOD) were assessed at each timepoint. Compared to placebo, 2 weeks of PB125 increased brachial (PB125: 2.8 ± 1.5 to 3.8 ± 1.3%, p < 0.0001) and popliteal FMD (PB125: 1.5 ± 1.5 to 2.3 ± 1.4%, p = 0.033) in older, but not younger adults (both, p > 0.27). During bed rest, PB125 preserved brachial (3.8 ± 1.3 to 3.6 ± 1.4%, p = 0.543) and popliteal FMD (2.3 ± 1.4 to 2.7 ± 1.4%, p = 0.269), LVC (1.1 ± 0.8 to 1.1 ± 1.5 AUC, p = 0.530) and circulating SOD concentrations (28.3 ± 7.2 to 28.6 ± 8.6 U/mL, p = 0.888) in older adults compared to placebo (all, p < 0.05). Following limb immobilization, PB125 preserved popliteal FMD (4.4 ± 2.8 to 3.4 ± 1.8%, p = 0.302) in younger adults compared to placebo (p < 0.05). These findings demonstrate targeted Nrf2 activation with PB125 improves age-related vascular endothelial dysfunction while preserving vascular function and antioxidant capacity following periods of disuse.

Humans↗

PubMed2024

The NRF2-CARM1 axis links glucose sensing to transcriptional and epigenetic regulation of the pentose phosphate pathway in gastric cancer.

Cancer cells autonomously alter metabolic pathways in response to dynamic nutrient conditions in the microenvironment to maintain cell survival and proliferation. A better understanding of these adaptive alterations may reveal the vulnerabilities of cancer cells. Here, we demonstrate that coactivator-associated arginine methyltransferase 1 (CARM1) is frequently overexpressed in gastric cancer and predicts poor prognosis of patients with this cancer. Gastric cancer cells sense a reduced extracellular glucose content, leading to activation of nuclear factor erythroid 2-related factor 2 (NRF2). Subsequently, NRF2 mediates the classic antioxidant pathway to eliminate the accumulation of reactive oxygen species induced by low glucose. We found that NRF2 binds to the CARM1 promoter, upregulating its expression and triggering CARM1-mediated hypermethylation of histone H3 methylated at R arginine 17 (H3R17me2) in the glucose-6-phosphate dehydrogenase gene body. The upregulation of this dehydrogenase, driven by the H3R17me2 modification, redirects glucose carbon flux toward the pentose phosphate pathway. This redirection contributes to nucleotide synthesis (yielding nucleotide precursors, such as ribose-5-phosphate) and redox homeostasis and ultimately facilitates cancer cell survival and growth. NRF2 or CARM1 knockdown results in decreased H3R17me2a accompanied by the reduction of glucose-6-phosphate dehydrogenase under low glucose conditions. Collectively, this study reveals a significant role of CARM1 in regulating the tumor metabolic switch and identifies CARM1 as a potential therapeutic target for gastric cancer treatment.

Stomach Neoplasms↗

PubMed2025

Targeting the bile acid receptor TGR5 with Gentiopicroside to activate Nrf2 antioxidant signaling and mitigate Parkinson's disease in an MPTP mouse model.

INTRODUCTION: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by classical symptoms including bradykinesia, rest tremor and rigidity. Oxidative stress and mitochondrial dysfunction are recognized as pivotal factors in PD progression. Gentiopicroside (GPS), a secoiridoid derived from Gentiana manshurica Kitagawa, exhibits antioxidant and mitophagy induction properties. Nonetheless, the effects and mechanisms by which GPS mitigates neurodegeneration in PD remain to be thoroughly elucidated. OBJECTIVES: The goal of this study was to investigate the neuroprotective effects and mechanisms of GPS in PD models. METHODS: We established the MPTP/MPP+-induced PD models to measure the neuroprotection of GPS. Transcriptomic analysis, oxidative biochemical kits, western blot and cell immunofluorescence were conducted to elucidate the fundamental mechanisms at play. Subsequently, the targeting and activation of the transmembrane G protein-coupled receptor-5 (TGR5) by GPS were measured by molecular docking, cellular thermal shift assay, microscale thermophoresis (MST) and cyclic adenosine monophosphate (cAMP) quantitation. Finally, we verified whether the neuroprotective and antioxidant effects of GPS were dependent on TGR5 by using specific small interfering RNA (siRNA), pharmacological antagonist and knockout mice. RESULTS: GPS significantly attenuated dopaminergic (DAergic) neuron loss and restored motor function in the MPTP-induced PD mouse model. Whole-genome RNA sequencing and subsequent mechanistic investigations revealed that GPS enhanced the expression and facilitated nuclear entry of factor erythroid-related 2-factor 2 (Nrf2), and reduced oxidative stress and mitochondrial dysfunction stimulated by neurotoxin. Additionally, GPS could target TGR5 and prevent its downregulation in PD model. TGR5's silencing or inhibition weakened the neuroprotective effect of GPS and blocked GPS-mediated activation of Nrf2 antioxidant signaling in PD model. Moreover, the therapeutic effect of GPS in mitigating motor deficits and neurodegeneration was also abolished in Tgr5 knockout mice. CONCLUSION: These findings collectively indicated that GPS targeted TGR5 to activate Nrf2 antioxidant signaling and ultimately ameliorated the pathological progression of PD.

Animals↗

PubMed2026

Temporal Transcriptomic Profiling of NMBA-Induced Rat Esophageal Squamous Carcinogenesis Identifies Early Inflammatory Activation and Late NRF2-Associated Oxidative-Stress Remodeling.

Temporal molecular events during early esophageal squamous carcinogenesis remain incompletely defined, in part because human precursor tissues are difficult to obtain sequentially. We used the N-nitrosomethylbenzylamine (NMBA)-induced rat model to characterize stage-associated transcriptional programs during esophageal squamous carcinogenesis. Vehicle-control reference esophageal tissues and NMBA-treated esophageal tissues, collected at weeks 6 and 29, were profiled using Affymetrix Rat Genome 230 2.0 arrays, followed by pathway analysis and qRT-PCR validation of selected genes. Relative to vehicle-control reference tissues, 173 genes were differentially expressed at week 6, whereas 1628 genes were differentially expressed at week 29, indicating marked expansion of transcriptional dysregulation during carcinogenic progression. Sixteen genes were differentially expressed only at week 6, while 157 genes were altered at both time points. Pathway analysis suggested that inflammatory and immunologic processes were prominent during the early response to NMBA exposure, whereas late-stage carcinogenesis was characterized by NRF2-associated oxidative-stress response and dysregulation of multiple glutathione S-transferase family members. A subset of progression-associated genes, including Defb4, Gsta2, Sbsn, Spink5, Plcd4, Hbb, and Hba-a2, showed increasing dysregulation from week 6 to week 29. These findings define temporally distinct molecular programs in NMBA-induced esophageal squamous carcinogenesis and provide a framework for prioritizing candidate pathways and genes relevant to esophageal cancer prevention, early detection, and progression biology.

Animals↗

PubMed2026

Direct targeting of ORAI1 by ginsenoside Rg3 modulates calcium signaling and senescence-associated AMPK-NRF2 activation.

BACKGROUND: 20(S)-ginsenoside Rg3 (Rg3(S)), a major saponin derived from red ginseng, exhibits diverse biological activities, including antioxidant and anti-senescence effects. However, the direct molecular targets through which Rg3(S) regulates calcium signaling and its role at membrane contact sites during cellular senescence remain largely unknown. METHODS: Plasma membrane (PM)-endoplasmic reticulum (ER) contacts and related protein interactions were analyzed using proximity ligation assays and co-immunoprecipitation. Direct binding of Rg3(S) to ORAI1 was validated using cellular thermal shift assays and microscale thermophoresis. Molecular docking simulations followed by site-directed mutagenesis were used to define critical binding residues. Cytosolic calcium levels and cellular senescence were assessed using calcium imaging and senescence-associated β-galactosidase staining. RESULTS: Rg3(S) increased cytosolic calcium levels independently of ER calcium depletion and was accompanied by a reduction in PM-ER contacts. Rg3(S) directly bound to ORAI1 in a dose-dependent manner, identifying ORAI1 as a previously unrecognized molecular target of ginsenoside Rg3. Molecular docking revealed LYS204 and ILE229 within the extracellular loop of ORAI1 as key residues maintaining this interaction. Mutation of these residues abolished Rg3(S)-induced calcium influx, leading to impaired activation of the AMPK-NRF2 pathway and attenuation of the anti-senescence effect of Rg3(S). CONCLUSION: These findings identify ORAI1 as a key molecular mediator of ginsenoside Rg3(S)-induced calcium signaling linked to cellular senescence. By modulating PM-ER contact sites and cytosolic calcium dynamics, Rg3(S) attenuates senescence, providing new mechanistic insight into the anti-aging potential of ginseng-derived compounds beyond autophagy-centered pathways.

Calcium signaling↗

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

Hepatitis C Virus Enhances Lysosome-Associated Membrane Protein 2 A Transcription Through Nuclear Factor Erythroid 2-Related Factor 2 to Support Viral Replication.

Hepatitis C virus (HCV) establishes persistent infection by rewiring host stress-response pathways. Chaperone-mediated autophagy (CMA) contributes to HCV replication, but it remains unclear whether HCV regulates lysosome-associated membrane protein 2 A (LAMP-2A), the rate-limiting receptor for CMA. Here, we examined LAMP-2A regulation in HCV-infected Huh-7.5 cells. HCV infection increased LAMP-2A promoter activity, mRNA, and protein abundance, indicating transcriptional upregulation. Among candidate stress-responsive transcription factors, nuclear factor erythroid 2-related factor 2 (NRF2), hypoxia-inducible factor 1α (HIF-1α), and nuclear factor of activated T cells 1 (NFAT1) were elevated in infected cells. However, promoter mutagenesis identified NRF2 as the principal direct regulator. Mutation of the NRF2-responsive antioxidant response element markedly reduced basal and HCV-induced LAMP-2A promoter activity. Chromatin immunoprecipitation assays revealed NRF2 association with the LAMP-2A promoter, and HCV infection increased nuclear accumulation and Ser40 phosphorylation of NRF2. Functionally, shRNA-mediated knockdown of LAMP-2A reduced intracellular HCV RNA and protein levels. These findings identify an NRF2-LAMP-2A regulatory axis engaged during HCV infection and support a model in which HCV upregulates LAMP-2A to establish a cellular environment favorable for viral replication.

Hepacivirus↗

PubMed2026

The KEAP1-NFE2L2/NRF2 Axis in Non-Small Cell Lung Cancer Radioresistance: Redox Homeostasis and Emerging DNA Damage Response Mechanisms.

Radioresistance and local recurrence remain major barriers to effective radiotherapy in non-small cell lung cancer (NSCLC). Loss-of-function KEAP1 alterations or activating NFE2L2 alterations can stabilize NRF2, but do not alone establish sustained transcriptional activity or functional dependency. This focused narrative review evaluates clinical radiotherapy studies and mechanistically informative preclinical studies linking the KEAP1-NFE2L2/NRF2 axis to NSCLC radioresistance. We prioritized clinical studies reporting radiotherapy-specific outcomes and preclinical studies coupling NRF2-related molecular status or perturbation with radiation-response endpoints; contextual studies informed metabolic, DNA damage response (DDR), immune and normal-lung effects. Evidence most consistently supports NRF2-mediated redox protection through glutathione-dependent defense, cellular reducing capacity and antioxidant enzymes, limiting radiation-induced reactive oxygen species (ROS) accumulation and oxidative injury. Limited studies further suggest that NRF2 may affect DNA-damage signaling, checkpoint control and repair. The detailed RPA32-TOPBP1-ATR-CHK1 model is therefore considered proposed rather than established in NRF2-active NSCLC. Retrospective clinical studies associate pathogenic KEAP1/NFE2L2 alterations with impaired local control in some radiotherapy-treated cohorts, but do not justify treating genomic status, protein abundance, transcriptional activity and functional dependency as equivalent measures or demonstrate treatment-predictive value. NRF2-mediated normal-lung protection also constrains systemic inhibition. Prospective studies integrating molecular classification, radiation-response endpoints, local control and normal-tissue toxicity are required before biomarker-guided radiosensitization can be considered.

DNA damage response↗

PubMed2025

Validation of breast cancer as a risk factor for anxiety and depression: Insights from Mendelian randomization analysis.

This study employed Mendelian randomization (MR) analysis to confirm the association between breast cancer and the risk of anxiety and depression, and to explore the molecular mechanisms by which lipid nanoparticles of ketamine (LNP@Ket) modulate these behaviors in a mouse model of breast cancer. Through single-cell transcriptomic analysis, the study aimed to clarify nuclear factor erythroid 2-related factor 2 (Nrf2)'s role in the development of anxiety and depression in these mice. Analysis of patient data from genome-wide association study (GWAS) databases supported the link between breast cancer, anxiety, and depression. In vivo experiments demonstrated that treating breast cancer mice with LNP@Ket significantly reduced anxiety and depression behaviors. The synthesis of LNP@Ket and its subsequent analysis highlighted its inhibitory effects on these behaviors. Single-cell transcriptomic sequencing identified key cells and genes affected by LNP@Ket treatment, particularly emphasizing Nrf2. Upregulation of Nrf2 in astrocytes increased the expression of antioxidant enzymes and reduced pro-inflammatory cytokines, alleviating anxiety and depression symptoms by inhibiting neuroinflammation and neurodegeneration. This comprehensive study highlights the pivotal role of Nrf2 in the therapeutic efficacy of LNP@Ket for treating anxiety and depression in breast cancer mice.

Anxiety and depression behaviors↗

PubMed2026

Mechanism of Shaofu Zhuyu decoction in improving diabetic mellitus erectile dysfunction inhibition of ferroptosis based on network pharmacology and experimental validation.

OBJECTIVE: To explore the medication patterns and mechanisms of action of Shaofu Zhuyu decoction (, SFZYD) in inhibiting ferroptosis through the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/glutathione peroxidase 4 (GPX4) pathway to improve diabetes mellitus-induced erectile dysfunction (DMED). METHODS: Firstly, data mining was employed to identify the medication patterns of Traditional Chinese Medicine (TCM) in treating DMED. Secondly, network pharmacology combined with a ferroptosis database was used to predict the targets. Subsequently, cell counting kit-8, 4',6-diamidino-2-phenylindole staining, reverse transcription-polymerase chain reaction (RT-PCR), and reagent kits were utilized to assess the repair effects of SFZYD on corpus cavernosum endothelial cells (CCECs) induced by high glucose (HG). Metabolic indicators, hematoxylin-eosin staining, and Masson staining were performed to observe the restorative effects of SFZYD on erectile function and penile tissue in diabetic rats. Finally, using Nrf2 inhibitors, the expression of related proteins and mRNAs was detected through Western blotting and RT-PCR. Reactive oxygen species levels and mitochondrial membrane potential were detected by flow cytometry. RESULTS: Data mining revealed that the prescription rules for blood stasis-type DMED coincide with the treatment principles of SFZYD. Network pharmacology identified 48 ferroptosis-related targets, primarily heme oxygenase 1 (HMOX1) and GPX4. Kyoto Encyclopedia of Genes and Genomes enrichment analysis associated these targets with the ferroptosis pathway. SFZYD repaired HG-induced CCECs damage and restored HMOX1 and GPX4 mRNA levels. in vivo, SFZYD effectively alleviated erectile dysfunction and repaired blood sinuses and fibrosis in diabetic rats. Following Nrf2 inhibition, the expression of Nrf2, HMOX1, and GPX4 decreased, while SFZYD intervention reversed these effects, improving ferroptosis and oxidative stress indicators. CONCLUSION: This study explored the potential mechanisms and efficacy of the TCM prescription SFZYD in treating DMED through data mining, network pharmacology analysis, cellular experiments, and animal experiments. It verified its effectiveness in repairing HG-induced CCECs damage, improving the pathological state of penile tissue in diabetic rats, and restoring erectile function by regulating the Nrf2/HO-1/GPX4 signaling pathway. This provides new insights and scientific evidence for treating DMED with TCM.

Male↗

PubMed2026

p62/SQSTM1-KEAP1 complex prevents clearance of ubiquitinated Z alpha-1 antitrypsin and aggravates liver proteotoxicity.

Liver disease in Alpha-1 antitrypsin deficiency (AATD) is caused by the toxic accumulation of mutant Z alpha-1 antitrypsin (Z-AAT) within the endoplasmic reticulum (ER) of hepatocytes. Livers from PiZ transgenic mice expressing the human Z-AAT and AATD patients who are homozygotes for the allele expressing Z-AAT were found to have increased p62/SQSTM1, a multifunctional protein involved in protein homeostasis. The goal of this study was to elucidate the involvement of p62/SQSTM1 in the formation of Z-AAT globules that are responsible for liver injury in AATD. In the present study, we found that p62/SQSTM1 decorated ubiquitin-positive, Periodic-Acid Shiff-diastase-resistant Z-AAT globules and interacted with Z-AAT at the ER-cytosol interface. Genetic ablation of p62/SQSTM1 in PiZ mice (PiZ;p62-/-) led to marked reduction in hepatic Z-AAT globules and polymers, and decreased serum Z-AAT, highlighting a central role for p62/SQSTM1 in disease pathogenesis. Moreover, hepatocyte-specific somatic deletion of the ubiquitin-association (UBA) domain of p62/SQSTM1 reduced Z-AAT aggregation. Furthermore, KEAP1 was identified as a binding partner of p62/SQSTM1-Z-AAT complex, leading to nuclear translocation and activation of NRF2. Inhibition of KEAP1-p62/SQSTM1 interaction reduced the abundance of p62 and phosphorylated p62, decreased intracellular Z-AAT, and redistributed NRF2 to the cytoplasm. In conclusion, this study identifies p62/SQSTM1 as a regulator of Z-AAT proteostasis and link Z-AAT/p62 accumulation to KEAP1 sequestration and NRF2 pathway activation in liver disease due to Z-AAT.

AATD↗

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↗

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

Reduced R-loop abundance at proinflammatory loci: a shared epigenetic mechanism in inflammatory and metabolic diseases.

INTRODUCTION: R-loops, RNA-DNA hybrid structures with a displaced single-stranded DNA loop, are key regulators of transcriptional control, chromatin architecture, and genome stability and have emerging roles in inflammatory signaling. However, the relationship between R-loop abundance and strongly modulated inflammatory effector genes in metabolic inflammation and influenza virus infection remains underexplored. METHODS: We performed a locus-centric integrative analysis combining robust differentially expressed genes (DEGs) from multiple inflammatory and infection-related murine and human transcriptomic disease models with experimentally validated multi-cell R-loop annotations from the reference atlas RLoopBase. Our correlation framework evaluated the directional relationship between R-loop abundance and inflammatory gene expression rather than assuming disease-sample-matched R-loop measurements. We further analyzed R-loop regulatory proteins, NRF2-associated R-loop regulators, and overlaps between R-loop regulators and CRISPRi-identified mitochondrial and cellular reactive oxygen species (ROS) regulators. RESULTS: In angiotensin II-infused apolipoprotein E-deficient (ApoE-/-) mice, a model of abdominal aortic aneurysm (AAA), genomic regions encoding the top significantly upregulated genes exhibited significantly fewer R-loops than those encoding downregulated genes at days 14 and 28. Similarly, in atherosclerotic ApoE-/- mice fed a high-fat diet for 32 and 78 weeks, upregulated genes were associated with fewer R-loops than downregulated genes. Reduced R-loop abundance was also observed in genomic regions encoding the top significantly upregulated genes in liver tissues from patients with non-alcoholic steatohepatitis (NASH), as well as in monosodium urate (MSU)-stimulated lymphatic endothelial cells (LECs) and influenza virus-infected human umbilical vein endothelial cells (HUVECs). R-loop regulatory proteins upregulated during metabolic inflammation were enriched in immune and inflammatory pathways. NRF2 was identified as a regulator of 27 R-loop regulatory proteins, including 10 positively and 17 negatively regulated proteins. Furthermore, 54 R-loop regulatory proteins overlapped with CRISPRi-identified mitochondrial and cellular ROS regulators, suggesting potential reciprocal regulation between R-loop homeostasis and ROS signaling. Disease-associated changes in pro-ROS and anti-ROS R-loop regulatory proteins further linked R-loop regulation to inflammatory and oxidative stress pathways. DISCUSSION: These findings identify reduced R-loop abundance at genomic regions encoding strongly upregulated inflammatory genes as a shared feature across multiple models of metabolic inflammation and influenza virus infection. The results further suggest that immune-associated R-loop regulatory proteins and the NRF2-ROS axis may contribute to R-loop remodeling during inflammatory disease. This integrative framework provides new insight into the potential role of R-loops and ROS-sensitive R-loop regulators in inflammatory and metabolic diseases and identifies candidate pathways for future mechanistic investigation and therapeutic targeting.

R-loop regulatory proteins↗

PubMed2026

Integrated dual transcriptome sequencing and experimental validation reveal potential mechanisms of baicalin against pneumocystis pneumonia in immunosuppressed rats.

BACKGROUND: Pneumocystis pneumonia (PCP) remains a major cause of morbidity and mortality in immunocompromised individuals. Although baicalin (Ba), a natural bioactive flavonoid, has demonstrated protective and therapeutic effects against PCP, its molecular mechanisms remain undefined. We employed dual RNA sequencing (dual RNA-seq) to characterize host and pathogen transcriptional responses to Ba treatment in an immunosuppressed rat model of PCP. METHODS: Comparative transcriptomic analyses identified differentially expressed genes in both the host and Pneumocystis, followed by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analyses. Candidate targets were further investigated using network pharmacology, protein-protein interaction analysis, molecular docking, and molecular dynamics simulations. Key findings were validated by immunohistochemistry, enzyme-linked immunosorbent assay, and quantitative PCR. RESULTS: Ba markedly remodeled host and pathogen transcriptomes. Host transcriptomic analyses showed that Ba attenuated inflammatory and oxidative stress responses by modulating immune-related pathways, including Toll-like receptor, NF-κB, cytokine-cytokine receptor interaction, chemokine signaling, Th17 cell differentiation, and antigen processing and presentation. Experimental validation demonstrated that Ba reduced pulmonary expression of indoleamine 2,3-dioxygenase 1 (IDO1), Toll-like receptor 2 (TLR2), and TLR4 while increasing nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant enzyme heme oxygenase-1 (HO-1). Pathogen transcriptomic analysis identified Pneumocystis Rtt109 (PcRtt109), a fungal histone acetyltransferase, as a potential pathogen-specific target that was significantly downregulated after Ba treatment. Molecular docking and molecular dynamics simulations supported stable interactions between Ba and IDO1, Nrf2, TLR2, TLR4, and PcRtt109, with the strongest predicted binding observed for PcRtt109. CONCLUSION: Dual RNA-seq revealed that Ba exerts anti-PCP activity through coordinated modulation of host and pathogen molecular networks. Its therapeutic effects are associated with suppression of inflammatory signaling, enhancement of antioxidant defenses, and inhibition of a fungal virulence-associated target. These findings provide mechanistic insights into host-pathogen interactions during PCP and support Ba as a potential therapeutic candidate for PCP.

Nrf2↗

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↗