The Impact of Microbial Toxins on NRF2 Signaling, Focusing on Stem Cells: Mechanisms and Therapeutic Potential.

Abstract

Introduction: NF-E2-related factor 2 (NRF2) is a key transcription factor that regulates antioxidant response element (ARE)-driven genes, protecting cells from oxidative damage. Microbial toxins, through mechanisms, such as oxidative stress induction, can activate or inhibit NRF2 signaling. In stem cells, which are highly sensitive to redox imbalance, NRF2 maintains cellular homeostasis while regulating proliferation, differentiation, and metabolism. However, persistent or dysregulated NRF2 activation by toxins may impair differentiation and promote pathological metabolic reprogramming. This review examines how microbial toxins modulate NRF2 signaling, with a focus on stem cells and therapeutic perspectives.

Methods: A structured literature review was performed using predefined search terms across major biomedical databases to identify studies investigating microbial toxin- mediated modulation of NRF2 signaling in stem cells. Study selection followed explicit inclusion and exclusion criteria based on stem cell subtype, toxin origin and exposure model, and NRF2-related mechanistic outcomes, including redox regulation. Eligible studies were screened to minimize selection bias and evaluated for methodological quality and relevance, with evidence systematically synthesized to justify stem cell- specific conclusions and therapeutic implications.

Results: The protective effects of NRF2 in stem cell biology, while essential for maintaining redox homeostasis and genomic integrity under physiological stress, are highly context-dependent and may shift toward pathological outcomes under chronic or dysregulated activation. NRF2 activation can increase antioxidant defenses, improve bacterial clearance, and promote the resolution of inflammation.

Discussion: The NRF2-activating consequences can provide avenues for adjunctive therapy in microbial infections. Moreover, the therapeutic potential of stem cell-based strategies combined with NRF2-targeted interventions is considerable for mitigating microbial toxin-induced damage and enhancing tissue regeneration.

Conclusions: Modulating NRF2 activity under microbial toxin exposure is essential to restore redox balance and preserve stem cell function. Future studies should clarify the molecular mechanisms underlying NRF2-targeted interventions to mitigate toxininduced stem cell dysfunction.