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PubMed2025

Anthracyclines attenuate Nrf1-dependent proteolytic pathways and potentiate proteasome inhibitor cytotoxicity.

Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib are FDA-approved treatments for multiple myeloma, but resistance frequently limits their effectiveness. The transcription factor Nrf1 (NFE2L1) upregulates proteasome and autophagy genes upon proteasome inhibition, contributing to adaptive resistance. In this study, we identified anthracyclines, including doxorubicin, as suppressors of the Nrf1-driven transcriptional response. Mechanistically, doxorubicin impaired Nrf1 binding to antioxidant response elements (AREs) within promoter regions of target genes without affecting Nrf1 processing or nuclear localization. Importantly, aclarubicin, a non-DNA-damaging anthracycline, also attenuated Nrf1 transcriptional activity, indicating that DNA damage is not required for this inhibition. Doxorubicin cotreatment delayed proteasome recovery after pulse inhibition and partially restored sensitivity to carfilzomib in bortezomib-resistant U266 myeloma cells, consistent with genetic knockout of Nrf1. These findings identify a DNA-damage-independent mechanism by which anthracyclines directly obstruct Nrf1-mediated transcriptional induction. Thus, anthracyclines serve as chemical tools to probe the molecular control of proteostasis and suggest a strategy to mitigate Nrf1-driven adaptive response to proteasome inhibition.

Humans↗

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↗

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

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

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

Eugenol-Derived Cytoprotective Action Against Dityrosine-Induced Oxidative Stress in Mice Liver via Akt/Nrf2/ARE Signaling Pathway.

Dityrosine (Dityr), a byproduct of protein oxidation in protein-rich food, induces oxidative stress, inflammation, and apoptosis, jeopardizing human health. Eugenol (EUG), a natural compound with antioxidative and anti-inflammatory properties, was investigated for its protective effects against Dityr-induced hepatotoxicity in this work. In this study, in vivo and in vitro analyses demonstrated EUG's protective effects against Dityr-induced hepatotoxicity. EUG significantly attenuated oxidative stress markers, inflammatory infiltration, fibrotic progression, and apoptotic signaling in mice liver tissues. Mechanistically, EUG activated the Akt/NF-E2-related factor 2/antioxidant response element (Akt/Nrf2/ARE) pathway, enhancing cellular antioxidant capacity while suppressing pro-inflammatory cytokine release. In HepG2 cells, EUG treatment effectively counteracted Dityr-induced ROS overproduction and cell death through Nrf2-mediated antioxidant upregulation. In conclusion, our findings indicate that EUG effectively mitigates Dityr-induced oxidative stress via the Akt/Nrf2/ARE pathway, and this antioxidative impact further inhibits inflammation and apoptosis. These effects ultimately ameliorate liver function impairment caused by Dityr.

Animals↗

PubMed2026

Physiological sub-typing of cold and freezing injury in Triticum turgidum subspecies with bioinformatic and expression characterization of glutathione reductase.

BACKGROUND: This study examined how different subspecies of Triticum turgidum (T. durum, T. polonicum, T. turanicum) respond to cold and freezing, assessing their water status, stress responses, and antioxidant system, with particular focus on the structure and function of glutathione reductase (TtGR). METHODS: TtGR genes were first identified from the T. turgidum genome using publicly available genomic resources such as Ensembl Plants. Promoter regions (~2 kb upstream) were analyzed to identify cis-regulatory elements using PlantCARE. Gene classification was performed based on predicted subcellular localization and conserved domain features. Plants were subjected to cold acclimation and freezing treatments, and physiological, biochemical, and enzymatic parameters were measured. RESULTS: Bioinformatics analyses identified four TtGR genes in the T. turgidum genome. The genes in two groups: cytosolic (Class I) and chloroplastic (Class II). Gene structure analysis showed a conserved exon-intron organization, while motif analysis confirmed the presence of Nicotinamide Adenine Dinucleotide Phosphate (NADPH)-binding and redox-active domains across all TtGR proteins. Several regulatory sequences in the promoters are involved in cold (DRE), abscisic acid (ABRE), and stress (STRE) responses, indicating that TtGR genes are dynamically regulated in response to environmental changes. Physiological analyses showed that freezing treatment reduces leaf water content in all genotypes, leading to turgor loss, hydrogen peroxide (H2O2) accumulation, and increased malondealdehyte (MDA) levels. However, tolerance mechanisms addressing water stress and membrane damage differ among genotypes. At the biochemical level, activation of the antioxidant defense system occurs in all genotypes. T. turanicum displays strong defense by significantly increasing enzyme activities, ensuring that the ascorbate-glutathione cycle continues under stress. By contrast, T. polonicum, although showing increased overall enzyme activities, experiences a dramatic drop in glutathione reductase (GR) activity at freezing temperatures, which restricts reduced glutathione (GSH) regeneration and creates a functional bottleneck in the antioxidant cycle. T. durum fails to sustain enzyme activities over the stress period, leading to an intermediate-sensitive response. Thus, whereas T. turanicum effectively maintains antioxidant function during freezing, T. polonicum and T. durum exhibit less efficient stress responses, either through enzymatic bottlenecks or a lack of sustained defense. CONCLUSIONS: One of the most striking findings of this study is the observed dissociation between TtGR gene expression levels and enzyme activities. Low temperature limits the link between transcription and enzyme function. The primary determinant of low-temperature tolerance in T. turgidum subspecies is the sustainability of GR enzyme activity and GSH regeneration under freezing conditions.

Triticum↗

PubMed2026

Genome-wide identification of the Glutathione Peroxidase (GPX) gene family in Taxodium distichum and functional characterization of TdGPX9 in enhancing salt tolerance.

This study systematically identified 10 TdGPX genes in Taxodium distichum, demonstrating that the nucleocytoplasmic-localized TdGPX9 plays a pivotal role in salt stress response. Overexpression of TdGPX9 significantly enhances salt tolerance by strengthening the antioxidant defense system and improving root system plasticity under stress. Taxodium distichum is a premier coniferous species renowned for its exceptional waterlogging and salinity tolerance, serving as a vital forest resource for coastal afforestation and wetland ecological restoration. Within the physiological framework of plant stress resistance, the glutathione peroxidase (GPX) family represents a cornerstone of the antioxidant enzymatic system, playing a critical role in scavenging reactive oxygen species and maintaining cellular redox homeostasis. In this study, 10 TdGPX genes were identified via a comprehensive genome-wide analysis and mapped across eight chromosomes. These genes possess a highly conserved Thioredoxin_like domain, with structural and motif analyses revealing a well-maintained arrangement of conserved motifs within each subgroup. The promoter analysis identified a sophisticated regulatory network enriched with cis-acting elements responsive to light, phytohormones, and abiotic stresses, suggesting their integration into diverse signaling pathways. Expression profiling across various tissues and embryonic developmental stages further highlighted the versatile roles of TdGPX members in plant growth and organogenesis. Notably, qRT-PCR analysis identified the nucleocytoplasmic-localized TdGPX9 as a primary respondent to salinity. Functional validation demonstrated that TdGPX9 overexpression significantly enhances salt tolerance in transgenic Arabidopsis and T. distichum callus by strengthening the antioxidant defense system. Furthermore, TdGPX9 promoted root system plasticity under stress, as evidenced by increased lateral root density. These findings provide a systematic basis for understanding the redox-regulatory mechanisms in baldcypress and offer vital genetic resources for improving forest resilience in coastal wetland ecosystems.

Salt Tolerance↗

PubMed2026

The R2R3-MYB transcription factor ScMYB20 negatively regulates drought and salt tolerance through a dual-repression of ScCHALCONE SYNTHASE-1 (ScCHS1)-mediated flavonoid biosynthesis in the desert moss Syntrichia caninervis.

The desert moss Syntrichia caninervis is one of the most desiccation-tolerant land plants known and provides a powerful system for dissecting the molecular foundations of extreme stress adaptation in early-diverging land lineages. The MYB transcription factor superfamily orchestrates secondary metabolism and stress signaling across plants, yet its lineage-specific evolution and mechanistic deployment in bryophytes remain poorly understood. Here, we identified 65 ScMYB genes in the S. caninervis genome and showed that the family expanded predominantly through dispersed duplication, with no detectable synteny to vascular-plant MYBs, indicating bryophyte-specific neo-functionalization. Integrating phylogenetic clustering, cis-element architecture and stress-responsive expression profiling, we pinpointed ScMYB20, a nuclear-localized, S13-subgroup R2R3-MYB that is rapidly and strongly induced by dehydration and salinity. Heterologous overexpression in Arabidopsis, together with overexpression and RNAi in S. caninervis, demonstrated that ScMYB20 negatively regulates drought and salt tolerance by suppressing antioxidant capacity, osmotic adjustment and photosynthetic performance, while concomitantly elevating ROS and MDA accumulation. Mechanistically, ScMYB20 directly binds a TAACCA motif in the ScCHS1 promoter to repress its transcription, and simultaneously sequesters the WD40 protein ScTTG1, a positive transcriptional activator of ScCHS1, thereby antagonising ScTTG1-mediated activation. Transient ScCHS1 overexpression restored flavonoid accumulation, antioxidant capacity and stress tolerance. Together, our findings define a dual-repression module (ScMYB20-ScTTG1-ScCHS1) that fine-tunes flavonoid flux under abiotic stress, and provide evolutionary and mechanistic insights into how R2R3-MYB repressors evolved to balance metabolic investment and stress survival in land plants.

Syntrichia caninervis↗

PubMed2026

Functional Characterization of the Oat (Avena sativa L.) TCP Transcription Factor AsTCP38 Reveals Its Role in Low-Nitrogen Stress Tolerance.

Nitrogen limitation restricts plant growth, development, and yield in crops and forage species. Although TCP transcription factors are implicated in diverse abiotic-stress responses, the functions of most TCP genes in oat remain unclear. Here, we cloned and characterized the AsTCP38 gene, which is 1215 bp long and encodes a 405-amino-acid protein. The predicted protein contains a conserved TCP domain and shares its highest sequence similarity with Arabidopsis thaliana (A. thaliana) AtTCP15. The AsTCP38 protein localized to the nucleus, and promoter analysis identified cis-elements associated with light, hormone, and stress responses. We generated AsTCP38-overexpressing A. thaliana and wheat plants and screened an oat leaf yeast cDNA library for candidate interacting proteins. In these heterologous overexpression lines, AsTCP38 overexpression was associated with greater abscisic acid (ABA) sensitivity and improved seedling growth under low-nitrogen conditions. Changes in antioxidant-enzyme activities, nitrogen-metabolism-related enzyme activities, and endogenous hormone contents were also observed. Together, these findings suggest that AsTCP38 may participate in low-nitrogen responses and provide a basis for further functional studies in oat. Direct regulatory targets and the contribution of AsTCP38 to low-nitrogen adaptation in oat remain to be established.

Avena↗

PubMed2026

Contrasting redox-related physiological responses associated with HaGATA23 and HaGATA36 during Orobanche cumana parasitism in sunflower (Helianthus annuus L.).

Helianthus annuus is an economically important Asteraceae species used for seed oil production and ornamental purposes, but its production is seriously affected by the root-parasitic plant Orobanche cumana. GATA transcription factors are zinc-finger DNA-binding regulators involved in plant development and stress adaptation. However, the molecular characteristics of GATA transcription factors in Helianthus annuus and their contribution to Helianthus annuus -Orobanche cumana interaction remain poorly understood. Here, 36 HaGATA members were retrieved from the Helianthus annuus genome and classified into four phylogenetic clades. Chromosomal placement, collinearity, gene structure, motif composition, and promoter elements varied among the 36 HaGATA members, indicating evolutionary conservation coupled with functional diversification. Expression analysis and RT-qPCR analyses revealed differential expression patterns among HaGATA genes under O. cumana stress, with HaGATA23 markedly downregulated and HaGATA36 strongly upregulated. Overexpression of HaGATA23 was associated with increased malondialdehyde (MDA) accumulation and unfavorable changes in antioxidant enzyme activities, whereas its silencing showed the opposite physiological tendency. In contrast, overexpression of HaGATA36 reduced malondialdehyde accumulation, increased peroxidase (POD), catalase (CAT), and superoxide dismutase (SOD) activities, while its silencing showed the reverse tendency. These results indicate that HaGATA23 and HaGATA36 are candidate genes associated with contrasting redox-related physiological responses during O. cumana stress. This work provides evidence that GATA transcription factors are associated with redox-related physiological responses in sunflower under O. cumana treatment and identifies HaGATA23 and HaGATA36 as functionally divergent candidate genes for further validation.

Helianthus↗

PubMed2026

Genome-Wide Characterization of the ScLOR Gene Family in Wild Tomato Solanum lycopersicoides Reveals ScLOR16 as a Negative Regulator of Cold-and Drought-Stress Tolerance.

The LOR (LURP-one related) gene family encodes proteins containing conserved LOR domains; however, its functions in plant abiotic stress responses remain largely unexplored. In this study, we systematically identified and characterized the LOR gene family in the stress-tolerant wild tomato Solanum lycopersicoides using comprehensive bioinformatic analyses and conducted functional validation of the candidate gene ScLOR16. A total of 19 ScLOR members were identified and classified into eight phylogenetic subgroups. Numerous cis-acting elements associated with responses to abscisic acid (ABA), cold, and drought, including ABRE, LTR, and MBS, were detected in the promoter regions, suggesting that the ScLOR family may be broadly involved in ABA-mediated stress signaling pathways. RT-qPCR analysis revealed that ScLOR16 expression was significantly induced by both cold and drought treatments. Subcellular localization assays demonstrated that ScLOR16 is localized in both the nucleus and cytoplasm. Virus-induced gene silencing (VIGS) was subsequently employed to generate ScLOR16-silenced plants. Following 24 h of cold treatment at 4 °C and four days of drought stress, ScLOR16-silenced seedlings exhibited significantly less severe wilting symptoms than empty-vector controls. Physiological analyses showed that silenced plants exhibited enhanced superoxide dismutase (SOD) and peroxidase (POD) activities, increased proline accumulation, and decreased thiobarbituric acid-reactive substances (TBARS) content. Collectively, these results indicate that reduced ScLOR16 transcript levels are associated with enhanced cold and drought tolerance, accompanied by alterations in antioxidant defense and osmoprotection-related physiological markers. This study yields new insights into the evolution and stress-related functions of the ScLOR family.

LOR gene family↗