Advances and challenges in therapeutic targeting of NRF2

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(3), P. 137 - 149

Published: Jan. 9, 2023

Activation of the transcription factor nuclear erythroid 2-related 2 (NRF2) is emerging as an attractive therapeutic approach to counteract oxidative stress, inflammation, and metabolic imbalances. These processes underpin many chronic pathologies with unmet needs, including neurodegenerative disorders diseases. As NRF2 field transitions into clinical phase its evolution, need for understanding factors influencing pharmacology has never been greater. In this opinion article we describe rationale targeting NRF2, summarise recent advances in drug development modulators, reflect on remaining challenges realising full potential a target.

Language: Английский

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Drug resistance mechanisms and treatment strategies mediated by Ubiquitin-Specific Proteases (USPs) in cancers: new directions and therapeutic options

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 3, 2024

Abstract Drug resistance represents a significant obstacle in cancer treatment, underscoring the need for discovery of novel therapeutic targets. Ubiquitin-specific proteases (USPs), subclass deubiquitinating enzymes, play pivotal role protein deubiquitination. As scientific research advances, USPs have been recognized as key regulators drug across spectrum treatment modalities, including chemotherapy, targeted therapy, immunotherapy, and radiotherapy. This comprehensive review examines complex relationship between mechanisms, focusing on specific strategies highlighting influence DNA damage repair, apoptosis, characteristics stem cells, immune evasion, other crucial biological functions. Additionally, highlights potential clinical significance USP inhibitors means to counter treatment. By inhibiting particular USP, cells can become more susceptible variety anti-cancer drugs. The integration with current therapies offers promising strategy circumvent resistance. Therefore, this emphasizes importance viable targets insight into fruitful directions future development. Targeting presents an effective method combat various types, leading enhanced better patient outcomes.

Language: Английский

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Molecular mechanisms of ROS-modulated cancer chemoresistance and therapeutic strategies

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 165, P. 115036 - 115036

Published: June 23, 2023

Drug resistance is the main obstacle to achieving a cure in many cancer patients. Reactive oxygen species (ROS) are master regulators of development that act through complex mechanisms. Remarkably, ROS levels and antioxidant content typically higher drug-resistant cells than non-resistant normal cells, have been shown play central role modulating drug resistance. Therefore, determining underlying functions modulation will contribute develop therapies sensitize resistant by leveraging modulation. In this review, we summarize notable literature on sources regulation production highlight roles chemoresistance, encompassing transcription factor-mediated maintenance stem their impact tumor microenvironment. We also discuss potential ROS-targeted overcoming therapeutic

Language: Английский

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Natural Nrf2 Inhibitors: A Review of Their Potential for Cancer Treatment

International Journal of Biological Sciences, Journal Year: 2023, Volume and Issue: 19(10), P. 3029 - 3041

Published: Jan. 1, 2023

Nuclear factor erythroid 2-related 2 (Nrf2), a transcription that regulates redox homeostasis, plays pivotal role in several cellular processes such as cell proliferation and survival, has been found to be aberrantly activated many cancers.As one of the key oncogenes, Nrf2 represents an important therapeutic target for cancer treatment.Research unraveled main mechanisms underlying pathway regulation promoting tumorigenesis.Many efforts have made develop potent inhibitors, clinical trials are being conducted on some these inhibitors.Natural products well-recognized valuable source development novel therapeutics cancer.So far, number natural compounds identified apigenin, luteolin, quassinoids including brusatol brucein D. These inhibitors mediate oxidant response display effects different types human cancers.In this article, we reviewed structure function Nrf2/Keap1 system with emphasis their biological cancer.The current status regarding potential treatment was also summarized.It is hoped review will stimulate research naturally occurring candidates treatment.

Language: Английский

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An insight into role of amino acids as antioxidants via NRF2 activation

Amino Acids, Journal Year: 2024, Volume and Issue: 56(1)

Published: March 20, 2024

Oxidative stress can affect the protein, lipids, and DNA of cells thus, play a crucial role in several pathophysiological conditions. It has already been established that oxidative close association with inflammation via nuclear factor erythroid 2-related 2 (NRF2) signaling pathway. Amino acids are notably building block proteins constitute major class nitrogen-containing natural products medicinal importance. They exhibit broad spectrum biological activities, including ability to activate NRF2, transcription regulates endogenous antioxidant responses. Moreover, amino may act as synergistic antioxidants part our dietary supplementations. This aroused research interest NRF2-inducing activity acids. Interestingly, acids' activation NRF2-Kelch-like ECH-associated protein 1 (KEAP1) pathway exerts therapeutic effects diseases. Therefore, present review will discuss relationship between different NRF2-KEAP1 pinning their anti-inflammatory properties. We also discussed formulations applications therapeutics. broaden prospect myriad stress-related provide an insight for designing developing new chemical entities NRF2 activators.

Language: Английский

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Health position paper and redox perspectives – Bench to Bedside Transition for Pharmacological Regulation of NRF2 in Noncommunicable Diseases

Redox Biology, Journal Year: 2025, Volume and Issue: unknown, P. 103569 - 103569

Published: March 1, 2025

Nuclear factor erythroid 2-related 2 (NRF2) is a redox-activated transcription regulating cellular defense against oxidative stress, thereby playing pivotal role in maintaining homeostasis. Its dysregulation implicated the progression of wide array human diseases, making NRF2 compelling target for therapeutic interventions. However, challenges persist drug discovery and safe targeting NRF2, as unresolved questions remain especially regarding its context-specific diseases off-target effects. This comprehensive review discusses dualistic disease pathophysiology, covering protective and/or destructive roles autoimmune, respiratory, cardiovascular, metabolic well digestive system cancer. Additionally, we also development drugs that either activate or inhibit discuss main barriers translating NRF2-based therapies from bench to bedside, consider ways monitor activation vivo.

Language: Английский

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The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

Molecules and Cells, Journal Year: 2023, Volume and Issue: 46(3), P. 176 - 186

Published: March 1, 2023

The oxidative balance of a cell is maintained by the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related 2 (NRF2) pathway.This cytoprotective pathway detoxifies reactive oxygen species and xenobiotics.The role KEAP1/NRF2 as pro-tumorigenic or anti-tumorigenic throughout stages carcinogenesis (including initiation, promotion, progression, metastasis) complex.This mini review focuses on key studies describing how affects cancer at different phases.The data compiled suggest that roles KEAP1/ NRF2 in are highly dependent context; specifically, model used (carcinogen-induced vs genetic), tumor type, stage cancer.Moreover, emerging suggests also important for regulating microenvironment its effects amplified either epigenetics response to co-occurring mutations.Further elucidation complexity this needed order develop novel pharmacological tools drugs improve patient outcomes.

Language: Английский

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The novel β-TrCP protein isoform hidden in circular RNA confers trastuzumab resistance in HER2-positive breast cancer

Redox Biology, Journal Year: 2023, Volume and Issue: 67, P. 102896 - 102896

Published: Sept. 28, 2023

Trastuzumab notably improves the outcome of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, however, resistance to trastuzumab remains a major hurdle clinical treatment. In present study, we identify circular RNA intimately linked resistance. circ-β-TrCP, derived from back-splicing β-TrCP exon 7 and 13, confers by regulating NRF2-mediated antioxidant pathway in KEAP1-independent manner. Concretely, circ-β-TrCP encodes novel truncated 343-amino acid peptide located nucleus, referred as β-TrCP-343aa, which competitively binds NRF2, blocks SCFβ-TrCP-mediated NRF2 proteasomal degradation, this protective effect β-TrCP-343aa on protein requires GSK3 activity. Subsequently, elevated transcriptionally upregulates cohort genes, giving rise Moreover, translation ability is inhibited eIF3j under both basal oxidative stress conditions, repressed thus forming positive feedback circuit between expediting Collectively, our data demonstrate that circ-β-TrCP-encoded isoform drives HER2-targeted therapy NRF2-dependent manner, provides potential therapeutic targets for overcoming

Language: Английский

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Alkaloids as Natural NRF2 Inhibitors: Chemoprevention and Cytotoxic Action in Cancer

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(6), P. 850 - 850

Published: June 7, 2023

Being a controller of cytoprotective actions, inflammation, and mitochondrial function through participating in the regulation multiple genes response to stress-inducing endogenous or exogenous stressors, transcription factor Nuclear Factor Erythroid 2-Related 2 (NRF2) is considered main cellular defense mechanism maintain redox balance at tissue level. While transient activation NRF2 protects normal cells under oxidative stress, hyperactivation cancer may help them survive adapt stress. This can be detrimental related progression chemotherapy resistance. Therefore, inhibition activity an effective approach for sensitizing anticancer therapy. In this review, we examine alkaloids as inhibitors from natural origin, their effects on therapy, and/or sensitizers chemotherapeutics, potential clinical applications. Alkaloids, inhibitor NRF2/KEAP1 signaling pathway, have direct (berberine, evodiamine, diterpenic aconitine types alkaloids) indirect (trigonelline) therapeutic/preventive effects. The network linking alkaloid action with stress modulation result increased synthesis, nuclear translocation, well downstream impact synthesis antioxidants, strongly presumed inducing cell death promoting sensitivity chemotherapeutic agents. regard, identification additional targeting pathway desirable information arising trials will reveal these compounds promising target

Language: Английский

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Targeting Nrf2 by bioactive peptides alleviate inflammation: expanding the role of gut microbiota and metabolites

Critical Reviews in Food Science and Nutrition, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 20

Published: June 17, 2024

Inflammation is a complex process that usually refers to the general response of body harmful stimuli various pathogens, tissue damage, or exogenous pollutants. Nuclear factor erythroid 2-related 2 (Nrf2) transcription regulates cellular defense against oxidative damage and toxicity by expressing genes related stress drug detoxification. In addition its antioxidant properties, Nrf2 involved in many other important physiological processes, including inflammation metabolism. can bind promoters upregulates their expressions, which alleviate oxidation-induced inflammation. has been shown upregulate heme oxygenase-1 expression, promotes NF-κB activation closely with Nrf2, as key response, expressions pro-inflammatory factors, pathway cell Bioactive peptides come from wide range sources have biological functions. Increasing evidence indicates bioactive potential anti-inflammatory activities. This article summarized sources, absorption utilization role alleviating via pathway. also regulate gut microbiota alter metabolites, through novel supplement mechanisms peptides. review provides reference for further study on effect development functional foods.

Language: Английский

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