Nrf2–Keap1 Signaling in Arthritis: Therapeutic Potential of Nanoparticle-Based Approaches with Special Reference to Silver Nanoparticles
8 affiliations
- 1Clinical Pharmacology Unit, Department of Basic Medical Sciences, College of Medicine, Al Maarefa University, Diriyah 13713, Riyadh, Saudi Arabia
- 2Department of Clinical Medicine, College of Medicine, Almaarefa University, 11597 Riyadh, Kingdom of Saudi Arabia
- 3Department of Internal Medicine, Prince Mohammed bin Abdulaziz Hospital, Riyadh, Saudi Arabia
- 4Northern Border Regional Lab, Northern Border University, Arar, Saudi Arabia
- 5Consultant Pediatrician, Shendi University, Sudan
- 6Alpha College, Pakistan
- 7Liaquat College of Medicine and Dentistry, Dar Ul Sehat Campus, Jinnah University, Pakistan, Jinnah University, Pakistan
- 8Department of Radiology, College of Medicine, AlMaarefa University, Kingdom of Saudi Arabia
Abstract
Arthritis represents a heterogeneous group of inflammatory and degenerative joint disorders characterized by persistent inflammation, oxidative stress, cartilage degradation, synovial dysfunction and progressive impairment of joint integrity. Rheumatoid Arthritis (RA) and Osteoarthritis (OA), although distinct in etiology, share several pathological mechanisms involving excessive production of Reactive Oxygen Species (ROS), mitochondrial dysfunction, inflammatory cytokine activation and dysregulation of redox-sensitive signaling pathways [1, 2, 3, 4]. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is a major endogenous defense mechanism responsible for maintaining cellular redox homeostasis. Under basal conditions, Keap1 promotes Nrf2 degradation; however, oxidative or electrophilic stress disrupts this interaction, allowing Nrf2 to accumulate and translocate into the nucleus, where it activates antioxidant response element (ARE)-dependent genes, including heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and glutathione-related enzymes [5, 6]. Increasing evidence indicates that impaired or insufficient Nrf2 activity contributes to persistent oxidative stress and inflammation in arthritic joints [1, 7]. Nrf2 also interacts with major inflammatory pathways, particularly nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and NLRP3 inflammasome signaling [8]. Nanotechnology offers an opportunity to improve the delivery, stability, bioavailability and tissue targeting of therapeutic agents capable of modulating redox and inflammatory pathways. Among different nanomaterials, silver nanoparticles (AgNPs) have attracted considerable interest because of their antimicrobial, anti-inflammatory, antioxidant and immunomodulatory properties [9, 10, 11]. Experimental studies have demonstrated that AgNPs can reduce inflammatory cytokines, regulate NF-κB and MAPK signaling, influence macrophage polarization and alleviate inflammatory tissue injury [9, 10]. In experimental RA, targeted folic-acid-modified AgNPs have demonstrated the ability to interact with inflammatory macrophages, promote macrophage apoptosis and repolarization and reduce disease severity [12]. Nevertheless, the relationship between AgNP exposure, oxidative signaling and Nrf2-Keap1 activation is complex and excessive nanoparticle-induced oxidative stress may also produce adverse biological effects. This review examines the role of the Nrf2-Keap1 pathway in arthritis, evaluates nanoparticle-based strategies for modulating redox and inflammatory mechanisms and critically discusses the therapeutic potential and safety considerations of AgNPs. Particular emphasis is placed on the potential intersection between AgNP-mediated redox regulation, Nrf2-Keap1 signaling, NF-κB inhibition, macrophage polarization and joint protection.
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BibTeX
@article{suliman2026nrf2keap1,
title = {{Nrf2–Keap1 Signaling in Arthritis: Therapeutic Potential of Nanoparticle-Based Approaches with Special Reference to Silver Nanoparticles}},
author = {Muhab Suliman and Isra Omar and Ali Mukhtar Mahgoub and Ahmed Sahoud R. Al-Sultany and Mohammed Abdelrazig Ahmed Elrofaie and Muhammad Harmain Maqsood and Madiha Mahmood and Yassir Musa},
journal = {International Journal of Clinical and Medical Research},
year = {2026},
month = jun,
doi = {10.66590/ijcmr2026030105},
url = {https://doi.org/10.66590/ijcmr2026030105},
note = {CC BY},
}
RIS
TY - JOUR
TI - Nrf2–Keap1 Signaling in Arthritis: Therapeutic Potential of Nanoparticle-Based Approaches with Special Reference to Silver Nanoparticles
AU - Muhab Suliman
AU - Isra Omar
AU - Ali Mukhtar Mahgoub
AU - Ahmed Sahoud R. Al-Sultany
AU - Mohammed Abdelrazig Ahmed Elrofaie
AU - Muhammad Harmain Maqsood
AU - Madiha Mahmood
AU - Yassir Musa
PY - 2026
DA - 2026/06/01
JO - International Journal of Clinical and Medical Research
DO - 10.66590/ijcmr2026030105
UR - https://doi.org/10.66590/ijcmr2026030105
AB - Arthritis represents a heterogeneous group of inflammatory and degenerative joint disorders characterized by persistent inflammation, oxidative stress, cartilage degradation, synovial dysfunction and progressive impairment of joint integrity. Rheumatoid Arthritis (RA) and Osteoarthritis (OA), although distinct in etiology, share several pathological mechanisms involving excessive production of Reactive Oxygen Species (ROS), mitochondrial dysfunction, inflammatory cytokine activation and dysregulation of redox-sensitive signaling pathways [1, 2, 3, 4]. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is a major endogenous defense mechanism responsible for maintaining cellular redox homeostasis. Under basal conditions, Keap1 promotes Nrf2 degradation; however, oxidative or electrophilic stress disrupts this interaction, allowing Nrf2 to accumulate and translocate into the nucleus, where it activates antioxidant response element (ARE)-dependent genes, including heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and glutathione-related enzymes [5, 6]. Increasing evidence indicates that impaired or insufficient Nrf2 activity contributes to persistent oxidative stress and inflammation in arthritic joints [1, 7]. Nrf2 also interacts with major inflammatory pathways, particularly nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and NLRP3 inflammasome signaling [8]. Nanotechnology offers an opportunity to improve the delivery, stability, bioavailability and tissue targeting of therapeutic agents capable of modulating redox and inflammatory pathways. Among different nanomaterials, silver nanoparticles (AgNPs) have attracted considerable interest because of their antimicrobial, anti-inflammatory, antioxidant and immunomodulatory properties [9, 10, 11]. Experimental studies have demonstrated that AgNPs can reduce inflammatory cytokines, regulate NF-κB and MAPK signaling, influence macrophage polarization and alleviate inflammatory tissue injury [9, 10]. In experimental RA, targeted folic-acid-modified AgNPs have demonstrated the ability to interact with inflammatory macrophages, promote macrophage apoptosis and repolarization and reduce disease severity [12]. Nevertheless, the relationship between AgNP exposure, oxidative signaling and Nrf2-Keap1 activation is complex and excessive nanoparticle-induced oxidative stress may also produce adverse biological effects. This review examines the role of the Nrf2-Keap1 pathway in arthritis, evaluates nanoparticle-based strategies for modulating redox and inflammatory mechanisms and critically discusses the therapeutic potential and safety considerations of AgNPs. Particular emphasis is placed on the potential intersection between AgNP-mediated redox regulation, Nrf2-Keap1 signaling, NF-κB inhibition, macrophage polarization and joint protection.
SN - 3134-8831
ER -