Activation of Nrf2 with natural flavonoids and mesenchymal stromal/stem cells: mechanisms and therapeutic potential for inflammatory diseases

Redox balance is crucial for maintaining normal physiological functions. Its disruption by oxidative stress can trigger or exacerbate a series of pathological cascades, ultimately contributing to various chronic diseases, particularly inflammatory disorders. Inhibiting oxidative stress and its associated pathological cascades may alleviate these diseases, a process often linked to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Initially characterized as a redox-sensitive transcription factor, Nrf2 is now recognized as a pivotal regulator of an extensive network of antioxidant genes, effectively counteracting oxidative stress and its detrimental effects. Consequently, advances in understanding Nrf2 activators and their regulatory mechanisms have accelerated the development of Nrf2-targeted therapies, demonstrating significant potential for preventing and treating chronic inflammation diseases. Many natural phytochemicals, particularly flavonoids, have been identified as Nrf2 activators that can ameliorate inflammatory responses. Furthermore, therapy with mesenchymal stromal/stem cells (MSCs) is a highly researched treatment approach with the potential to confer immunomodulatory, anti-inflammatory, anti-apoptotic and antimicrobial effects. Owing to their superior safety profile compared to conventional therapeutics, MSCs are gaining prominence as sustainable long-term treatment options, although their precise molecular mechanisms remain to be fully elucidated. This review focuses on the activation mechanisms of Nrf2 and its clinical and preclinical inducers, with particular emphasis on the mechanistic insights and therapeutic applications of natural flavonoids and MSCs in the prevention or treatment of inflammatory diseases. More importantly, it summarizes the profound role of flavonoid-MSCs combinatorial therapy in the intervention of inflammatory diseases, pointing out novel therapeutic strategies and future prospects for modulating the Nrf2 signaling pathway in the treatment of inflammatory disorders.