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Oxidative Stress and NRF2 in Health and Disease—2nd Edition

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (20 November 2025) | Viewed by 22770

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Dr. Lidija Milković

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Laboratory for Membrane Transport and Signaling, Division of Molecular Medicine, Ruđer Bošković Institute, HR10000 Zagreb, Croatia
Interests: oxidative stress; reactive oxygen species (ROS); lipid peroxidation; cancer; cancer stem cells; cellular and extracellular antioxidants; NRF2; metabolic reprogramming
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Special Issue Information

Dear Colleagues,

I am delighted to announce that the Special Issue “Oxidative Stress and NRF2 in Health and Disease” is continuing with its 2nd edition, following the success of its 1st edition, which featured numerous excellent papers. These papers are freely accessible at: https://www.mdpi.com/journal/antioxidants/special_issues/H7968G1761.

Oxidative stress (OS) has long been considered a cause of various noncommunicable diseases. The term refers to the increased formation of reactive oxygen species (ROS) and other byproducts that can react with cellular macromolecules such as proteins, DNA, and lipids to impair cellular function. Earlier research opinions assumed that OS only leads to various pathologies and referred to it as a harmful process that should be abolished. However, further research revealed that OS byproducts, such as hydrogen peroxide, are also important for redox signaling. Depending on the cue, cells use their signaling abilities, which include turning certain protein targets on and off, to provide signal transduction that regulates their own functions or the functions of neighboring cells. The extent of OS is closely intertwined with metabolic switches and antioxidant machinery. While some ROS, such as hydrogen peroxide, are essential for normal physiology, their increase leads to pathology. The NRF2 pathway is the main pathway activated as a response to OS. The NRF2 pathway is the major signaling pathway activated in response to OS. The transcription factor NRF2 (nuclear factor, erythroid 2 like 2) is mainly regulated by Kelch-like ECH-associated protein 1 (KEAP1), although its regulation/activation is more complex. NRF2 regulates the expression of more than 250 genes, not only antioxidant enzymes but also others involved in autophagy, metabolism, detoxification, protein turnover, etc. Its mode of action is not always beneficial to humans and is not fully understood.

We invite researchers in this field and participants of the COST Action CA20121 and the Bench to Bedside Transition for Pharmacological regulation of NRF2 in non-communicable diseases (BenBedPhar) to submit their latest research to this Special Issue. Potential topics include, but are not limited to, deciphering the role of oxidative stress and NRF2 in physiology and pathology, their linkage to other signaling pathways, the “omics” approach to identify specific targets and key molecules, potential therapeutic strategies, etc.

text

Dr. Lidija Milković
Guest Editor

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Keywords

oxidative stress
redox signaling
NRF2 and its regulation
redox-modifying therapeutic approach
omics approach
physiology
non-communicable diseases
metabolism
aging

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Published Papers (11 papers)

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Research

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21 pages, 11951 KB

Open AccessArticle

Synthetic Oleanane Triterpenoids Reduce Tumor Growth and Promote an Anti-Tumor Immune Response Independent of Cancer KEAP1 Mutational Status

by Christopher J. Occhiuto, Jessica A. Moerland, Karen T. Liby and Ana S. Leal

Antioxidants 2025, 14(12), 1406; https://doi.org/10.3390/antiox14121406 - 26 Nov 2025

Viewed by 316

Abstract

KEAP1 negatively regulates the cytoprotective factor NRF2 and is commonly inactivated in lung cancer cells. Loss-of-function KEAP1 mutations in cancer cells contribute to NRF2 activation and tumor immune evasion through immunosuppression and drug resistance. Counterintuitively, treatment with synthetic oleanane triterpenoids, potent NRF2 activators, reduces the pre-clinical tumor burden. This suggests the functional target of these drugs in cancer models is not the cancer cells but another tumor immune microenvironment (TIME) cell population. The anti-tumor potential of cells within the TIME, particularly macrophages, is potentiated by triterpenoid treatment in cancers with wild-type KEAP1 status. As KEAP1-mutant cancers show reduced tumor immune responses, triterpenoid-mediated immune stimulation may particularly benefit these cases, but this has not been investigated. To characterize the immunomodulatory effects of triterpenoids in KEAP1-mutant lung cancer, we studied tumor-educated bone marrow-derived macrophages (TE-BMDMs) and lung cancer models treated with the triterpenoids CDDO-Me or omaveloxolone. RNA-sequencing of TE-BMDMs cultured in KEAP1 KO compared to WT cancer-conditioned media had enhanced tumor-promoting phenotypes, which reversed with CDDO-Me treatment. Similarly, subcutaneous KEAP1 KO tumors were larger and more immune-suppressed compared to WT tumors. Both CDDO-Me and omaveloxolone reduced the tumor burden and improved immune cell phenotypes within the TIME independent of KEAP1 mutational status. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease—2nd Edition)

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21 pages, 2066 KB

Open AccessArticle

Antioxidants Trolox and Methazolamide Protect Microvascular Endothelial Cells from Oxidative Damage Induced by Sporadic and Familial Forms of Oligomeric Amyloid-β

by Maria Luisa Valle, Bitseat Getaneh, Christopher William, Jorge Ghiso and Agueda Rostagno

Antioxidants 2025, 14(11), 1375; https://doi.org/10.3390/antiox14111375 - 19 Nov 2025

Viewed by 476

Abstract

Cerebral amyloid angiopathy (CAA), present in more than 90% of Alzheimer’s disease (AD) cases, associates with focal ischemia and neurovascular dysfunction. Genetic variants at positions 21–23 of amyloid beta (Aβ), among them the Dutch mutation (AβE22Q), are primarily linked to CAA and the development of cerebral hemorrhages. An important contributor to CAA pathogenesis is the dysregulation of mitochondria-mediated pathways with concomitant induction of oxidative stress. Using biochemical assays and immunofluorescence microscopy, this work demonstrates the exacerbated formation of reactive oxygen species (ROS) in human brain microvascular endothelial cells after short exposure to soluble oligomers of synthetic homologues of Aβ1-42 and the Dutch variant, inducing lipid peroxidation and protein carbonylation, both markers of oxidative stress. The heterogeneity of the soluble oligomeric assemblies inducing this oxidative response was highlighted by their reactivity with two conformational antibodies recognizing specific and mutually exclusive epitopes associated with either soluble prefibrillar oligomers or soluble fibrillar oligomers. Treatment with the multitarget antioxidants Trolox and methazolamide significantly attenuated the Aβ-mediated ROS production and reduced oxidative stress markers to basal levels. Our data highlight the damaging role of heterogeneous Aβ oligomers and the preventing effect of antioxidants, suggesting ROS modulation as a complementary therapeutic strategy to preserve neurovascular unit integrity. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease—2nd Edition)

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16 pages, 4613 KB

Open AccessArticle

Inhibitory Effect of S0859 on the Antioxidant Master Switch Nuclear Factor Erythroid 2-Related Factor 2 in Lung Cancer Cells

by Eunsun Lee and Jeong Hee Hong

Antioxidants 2025, 14(10), 1191; https://doi.org/10.3390/antiox14101191 - 28 Sep 2025

Viewed by 813

Abstract

Cancer cells possess endogenous antioxidant systems such as nuclear factor erythroid 2-related factor 2 (NRF2). The electroneutral sodium bicarbonate cotransporter NBCn1, known as a migratory module, is closely associated with cancer metastasis; however, its regulatory signaling in cancer remains unclear. In particular, the regulation of NBCn1 in response to oxidative stress and its relationship with NRF2 need to be elucidated. In the present study, we found that hydrogen peroxide–induced oxidative stress dysregulated NBCn1 via inhibition of NF-κB, thereby suppressing cellular migration in non-small cell lung cancer A549 cells. Phosphorylation of NF-κB was required for maintaining NBCn1 function in A549 cells. Oxidative stress also induced NRF2 nuclear translocation, reduced NBC activity, and activated oxidative stress–responsive gene expression. Treatment with the NBC inhibitor S0859 impaired ERK activation, NRF2 nuclear translocation, and oxidative stress defense gene expression in A549 cells. Furthermore, oxidative stimulation in the presence of S0859 disrupted the NRF2-mediated oxidative stress defense system and cellular migration in A549 lung cancer cells. Collectively, these findings suggest that S0859, as a potential NRF2 inhibitor, may exert anti-cancer properties. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease—2nd Edition)

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28 pages, 20644 KB

Open AccessArticle

Mechanisms of Cisplatin-Induced Acute Kidney Injury: The Role of NRF2 in Mitochondrial Dysfunction and Metabolic Reprogramming

by Jihan Liu, Yiming Wang, Panshuang Qiao, Yi Ying, Simei Lin, Feng Lu, Cai Gao, Min Li, Baoxue Yang and Hong Zhou

Antioxidants 2025, 14(7), 775; https://doi.org/10.3390/antiox14070775 - 24 Jun 2025

Cited by 2 | Viewed by 3474

Abstract

Cisplatin (Cis) is a widely used chemotherapy drug, but its nephrotoxicity limits its clinical application. Acute kidney injury (AKI) is a common complication, restricting long-term use. This study investigates the mechanisms of cisplatin-induced AKI and explores potential therapeutic targets. C57BL/6J mice were intraperitoneally injected with 20 mg/kg cisplatin to establish an AKI model. Serum creatinine, urea nitrogen, and tubular injury biomarkers (NGAL, KIM-1) progressively increased, indicating kidney dysfunction. Mitochondrial ATP levels significantly decreased, along with reduced mitochondrial fission and fusion, suggesting mitochondrial dysfunction. Increased oxidases and reduced antioxidants indicated redox imbalance, and metabolic reprogramming was observed, with lipid deposition, impaired fatty acid oxidation (FAO), and enhanced glycolysis in proximal tubular epithelial cells (PTECs). Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcriptional regulator of redox homeostasis and mitochondrial function. We found NRF2 levels increased early in AKI, followed by a decrease in vivo and in vitro, suggesting activation in the stress response. Nfe2l2 knockout mice showed aggravated kidney injury, characterized by worsened kidney function and histopathological damage. Mechanistically, Nfe2l2 knockout resulted in redox imbalance, reduced ATP synthesis, mitochondrial dysfunction and metabolic dysregulation. Furthermore, we activated NRF2 using dimethyl fumarate (DMF), observing a reduction in kidney damage and lipid deposition in mice. In conclusion, activating NRF2-dependent antioxidant pathways plays a crucial role in protecting against cisplatin-induced AKI. NRF2 may serve as a potential target for developing therapeutic strategies to prevent cisplatin nephrotoxicity. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease—2nd Edition)

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14 pages, 1023 KB

Open AccessArticle

Evidence for a Functional Link Between the Nrf2 Signalling Pathway and Cytoprotective Effect of S-Petasin in Human Retinal Pigment Epithelium Cells Exposed to Oxidative Stress

by Michela Pizzoferrato, Giacomo Lazzarino, Anna Brancato, Elisabetta Tabolacci, Maria Elisabetta Clementi and Giuseppe Tringali

Antioxidants 2025, 14(2), 180; https://doi.org/10.3390/antiox14020180 - 4 Feb 2025

Cited by 1 | Viewed by 1540

Abstract

The retinal pigment epithelium (RPE) is a highly specialised monolayer epithelium subjected to constant oxidative stress, which, in the long term, favours the development of a complex pathological process that is the underlying cause of macular damage. Therefore, counteracting the overproduction of ROS is the best-researched approach to preserve the functional integrity of the RPE. S-Petasin, a secondary metabolite extracted from the plant Petasites hybridus, has numerous biological effects, which highlight its anti-inflammatory and antioxidative properties. The aim of our study is to investigate whether S-Petasin exerts cytoprotective effects by protecting the RPE from oxidative damage. The effects of pretreatment with S-Petasin were assessed by the determination of the cell viability, intracellular ROS levels, activation of the Nrf2 pathway and the resulting post-transcriptional antioxidant/antiapoptotic response. Our results show that S-Petasin pretreatment (1) reduces intracellular ROS levels, improving cell viability of RPE exposed to oxidative damage; (2) activates the Nrf2 signalling pathway, modulating the post-transcriptional response of its antioxidant chemical biomarkers; (3) reduces the Bax levels, and an increase in those of Bcl-2, with a concomitant downregulation of the Bax/Bc-2 ratio. Overall, our results provide the first evidence that S-Petasin is able to protect the RPE from oxidative damage. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease—2nd Edition)

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20 pages, 4339 KB

Open AccessArticle

Therapeutic Potential of Dimethyl Fumarate for the Treatment of High-Fat/High-Sucrose Diet-Induced Obesity

by Helber da Maia Valenca, Evelyn Caribé Mota, Andressa Caetano da Fonseca Andrade Silva, Alexsandro Tavares Figueiredo-Junior, Fernanda Verdini, Bruna Romana-Souza, Mariana Renovato-Martins, Manuella Lanzetti, Samuel dos Santos Valenca and João Alfredo Moraes

Antioxidants 2024, 13(12), 1496; https://doi.org/10.3390/antiox13121496 - 8 Dec 2024

Cited by 2 | Viewed by 2092

Abstract

Obesity is characterized by an imbalance between energy intake and expenditure that triggers abnormal growth of adipose tissues. Dimethyl fumarate (DMF) and its primary active metabolite, monomethyl fumarate (MMF), are Nrf2 activators and have been recognized as strategic antioxidants. This study aimed to evaluate the potential of MMF and DMF to interfere with adipogenesis and obesity, and identify the molecular mechanisms involved. The 3T3-L1 preadipocytes were incubated with differentiation medium (MIX) and simultaneously treated with different concentrations of MMF. In addition, male C57BL/6 mice were fed a standard diet or high-fat/high-sucrose diet (HFHSD) for 16 weeks, during the last 4 of which, they received oral DMF treatment. Exposure to MMF prevented the development of MIX-induced adipogenesis by reducing the expression of transcription factors that drive adipocyte differentiation and by decreasing triglyceride levels. In addition, various antioxidant and anti-inflammatory effects were observed after treatment with MMF as evidenced by the modulation of transcription factor activities and reduction in reactive oxygen species, adipokine, proinflammatory cytokine and resistin levels. In vivo treatment with DMF reduced calorie intake, body weight, and visceral and subcutaneous fat mass in HFHSD mice. Furthermore, DMF administration led to a better glycemic response as well as lower leptin and adiponectin plasma levels in these animals. Our data demonstrate that DMF and its metabolite MMF interfere with adipogenesis and prevent the key features of diet-induced obesity. Considering DMF is already a commercial drug used to treat psoriasis and multiple sclerosis, its pharmacological application for the treatment of obesity and related metabolic disorders holds promise. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease—2nd Edition)

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16 pages, 3292 KB

Open AccessArticle

NRF2 and Thioredoxin Reductase 1 as Modulators of Interactions between Zinc and Selenium

by Alina Löser, Maria Schwarz and Anna Patricia Kipp

Antioxidants 2024, 13(10), 1211; https://doi.org/10.3390/antiox13101211 - 8 Oct 2024

Cited by 2 | Viewed by 2913

Abstract

Background: Selenium and zinc are essential trace elements known to regulate cellular processes including redox homeostasis. During inflammation, circulating selenium and zinc concentrations are reduced in parallel, but underlying mechanisms are unknown. Accordingly, we modulated the zinc and selenium supply of HepG2 cells to study their relationship. Methods: HepG2 cells were supplied with selenite in combination with a short- or long-term zinc treatment to investigate intracellular concentrations of selenium and zinc together with biomarkers describing their status. In addition, the activation of the redox-sensitive transcription factor NRF2 was analyzed. Results: Zinc not only increased the nuclear translocation of NRF2 after 2 to 6 h but also enhanced the intracellular selenium content after 72 h, when the cells were exposed to both trace elements. In parallel, the activity and expression of the selenoprotein thioredoxin reductase 1 (TXNRD1) increased, while the gene expression of other selenoproteins remained unaffected or was even downregulated. The zinc effects on the selenium concentration and TXNRD activity were reduced in cells with stable NRF2 knockdown in comparison to control cells. Conclusions: This indicates a functional role of NRF2 in mediating the zinc/selenium crosstalk and provides an explanation for the observed unidirectional behavior of selenium and zinc. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease—2nd Edition)

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20 pages, 1222 KB

Open AccessReview

Melatonin-Mediated Nrf2 Activation as a Potential Therapeutic Strategy in Mutation-Driven Neurodegenerative Diseases

by Lucía Íñigo-Catalina, María Ortiz-Cabello, Elisa Navarro, Noemí Esteras, Lisa Rancan and Sergio D. Paredes

Antioxidants 2025, 14(10), 1190; https://doi.org/10.3390/antiox14101190 - 28 Sep 2025

Viewed by 1791

Abstract

Neurodegeneration is intrinsically linked to aging through processes such as oxidative stress, mitochondrial dysfunction, and chronic inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) emerges as a central transcription factor regulating these molecular events and promoting cytoprotective responses. In neurodegenerative diseases, notably, frontotemporal dementia (FTD) and Parkinson’s disease (PD), genetic mutations—including MAPT, LRRK2, PINK1, PRKN, and SNCA—have been reported to alter Nrf2 signaling, both in vitro and in vivo. Melatonin, a neurohormone widely known for its strong antioxidant and mitochondria-stabilizing properties, has been shown to activate Nrf2 and restore redox balance in several experimental models of neurodegeneration. Its effects include a reduction in tau hyperphosphorylation, α-synuclein aggregation, and neuroinflammation. While most data are derived from sporadic models of Alzheimer’s disease and PD, emerging evidence supports a role for melatonin in familial forms of FTD and PD as well. Thus, targeting Nrf2 through melatonin may offer a promising approach to mitigating neurodegeneration, especially in the context of mutation-driven pathologies. Further investigation is warranted to explore mutation-specific responses and optimize the therapeutic strategies. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease—2nd Edition)

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35 pages, 2019 KB

Open AccessReview

Non-Electrophilic Activation of NRF2 in Neurological Disorders: Therapeutic Promise of Non-Pharmacological Strategies

by Chunyan Li, Keren Powell, Luca Giliberto, Christopher LeDoux, Cristina d’Abramo, Daniel Sciubba and Yousef Al Abed

Antioxidants 2025, 14(9), 1047; https://doi.org/10.3390/antiox14091047 - 25 Aug 2025

Cited by 1 | Viewed by 2904

Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) serves as a master transcriptional regulator of cellular antioxidant responses through orchestration of cytoprotective gene expression, establishing its significance as a therapeutic target in cerebral pathophysiology. Classical electrophilic NRF2 activators, despite potent activation potential, exhibit paradoxically reduced therapeutic efficacy relative to single antioxidants, attributable to concurrent oxidative stress generation, glutathione depletion, mitochondrial impairment, and systemic toxicity. Although emerging non-electrophilic pharmacological activators offer therapeutic potential, their utility remains limited by bioavailability and suboptimal potency, underscoring the imperative for innovative therapeutic strategies to harness this cytoprotective pathway. Non-pharmacological interventions, including neuromodulation, physical exercise, and lifestyle modifications, activate NRF2 through non-canonical, non-electrophilic pathways involving protein–protein interaction inhibition, KEAP1 degradation, post-translational and transcriptional modulation, and protein stabilization, though mechanistic characterization remains incomplete. Such interventions utilize multi-mechanistic approaches that synergistically integrate multiple non-electrophilic NRF2 pathways or judiciously combine electrophilic and non-electrophilic mechanisms while mitigating electrophile-induced toxicity. This strategy confers neuroprotective effects without the contraindications characteristic of classical electrophilic activators. This review comprehensively examines the mechanistic underpinnings of non-pharmacological NRF2 modulation, highlighting non-electrophilic activation pathways that bypass the limitations inherent to electrophilic activators. The evidence presented herein positions non-pharmacological interventions as viable therapeutic approaches for achieving non-electrophilic NRF2 activation in the treatment of cerebrovascular and neurodegenerative pathologies. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease—2nd Edition)

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20 pages, 1516 KB

Open AccessReview

Ferroptosis and Nrf2 Signaling in Head and Neck Cancer: Resistance Mechanisms and Therapeutic Prospects

by Jaewang Lee, Youngin Seo and Jong-Lyel Roh

Antioxidants 2025, 14(8), 993; https://doi.org/10.3390/antiox14080993 - 13 Aug 2025

Cited by 3 | Viewed by 2593

Abstract

Ferroptosis is an iron-dependent form of regulated cell death marked by lipid peroxidation in polyunsaturated phospholipids. In head and neck cancer (HNC), where resistance to chemotherapy and immunotherapy is common, ferroptosis offers a mechanistically distinct strategy to overcome therapeutic failure. However, cancer cells often evade ferroptosis via activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant and iron-regulatory genes. HNC remains therapeutically challenging due to therapy resistance driven by redox adaptation. This review highlights the ferroptosis pathway—a form of regulated necrosis driven by iron and lipid peroxidation—and its regulation by Nrf2, a master antioxidant transcription factor. We detail how Nrf2 contributes to ferroptosis evasion in HNC and summarize emerging preclinical studies targeting this axis. The review aims to synthesize molecular insights and propose therapeutic perspectives for overcoming resistance in HNC by modulating Nrf2–ferroptosis signaling. We conducted a structured narrative review of the literature using PubMed databases. Relevant studies from 2015 to 2025 focusing on ferroptosis, Nrf2 signaling, and head and neck cancer were selected based on their experimental design, novelty, and relevance to clinical resistance mechanisms. In HNC, Nrf2 mediates resistance through transcriptional upregulation of GPX4 and SLC7A11, epigenetic stabilization by PRMT4 and ALKBH5, and activation by FGF5 and platelet-derived extracellular vesicles. Epstein–Barr virus (EBV) infection also enhances Nrf2 signaling in nasopharyngeal carcinoma. More recently, loss-of-function KEAP1 mutations have been linked to persistent Nrf2 activation and upregulation of NQO1, which confer resistance to both ferroptosis and immune checkpoint therapy. Targeting NQO1 in KEAP1-deficient models restores ferroptosis and reactivates antitumor immunity. Additionally, the natural alkaloid trigonelline has shown promise in reversing Nrf2-mediated ferroptosis resistance in cisplatin-refractory tumors. Pharmacologic agents such as auranofin, fucoxanthin, carnosic acid, and disulfiram/copper complexes have demonstrated efficacy in sensitizing HNC to ferroptosis by disrupting the Nrf2 axis. This review summarizes emerging mechanisms of ferroptosis evasion and highlights therapeutic strategies targeting the Nrf2–ferroptosis network. Integrating ferroptosis inducers with immune and chemotherapeutic approaches may provide new opportunities for overcoming resistance in head and neck malignancies. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease—2nd Edition)

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17 pages, 1841 KB

Open AccessReview

An Update on Role of Ionizing Radiation to Enhance Proliferation and Differentiation of Normal Stem Cells via Activation of NRF2 Pathway: Review

by Kave Moloudi and Siamak Haghdoost

Antioxidants 2025, 14(8), 986; https://doi.org/10.3390/antiox14080986 - 11 Aug 2025

Cited by 1 | Viewed by 2317

Abstract

Ionizing radiation (IR) as a stress inducer has a significant impact on various normal stem cells differentiation through activation of various signaling pathways. Low levels of oxidative stress of IR may preserve or even enhance cell differentiation. In response to IR, reactive oxygen species (ROS) can activate various signaling pathways that promote cell differentiation, notably through the involvement of nuclear factor erythroid 2–related factor 2 (NRF2). NRF2 interacts with multiple pathways, including Wnt/β-catenin (osteogenesis), PPARγ (adipogenesis), and BDNF/TrkB (neurogenesis). This response is dose-dependent: low doses of IR activate NRF2 and support differentiation, while high doses can overwhelm the antioxidant system, resulting in cell death. However, the quality of various types of IR, such as proton and carbon ion radiation, may have a varied impact on stem cells (SCs) differentiation compared to X-rays. Hence, activation of the NRF2 signaling pathway in SCs and cell differentiation depends on the level of stress and the quality and quantity of IR. This review is an update to explore how IR modulates SCs fate toward osteogenic, adipogenic, and neurogenic lineages through the NRF2 signaling pathway. We highlight mechanistic insights, dose-dependent effects, and therapeutic implications, bridging gaps between experimental models and clinical translation. Full article

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Health and Disease—2nd Edition)

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