Fig. 1

Schematic representation of effects of stem cells-derived exosomes on the Nrf2 pathway. miR-24-3p, miR-141- 3p, miR-125b-5p and miR-200a are transferred by stem cell-exosomes into recipient cells where they target Keap-1, thereby promoting Nrf2 activation. circHIPK3 released from exosomes acts as a ceRNA to bind to miR-20b-5p, which directly inhibits miR-20b-5p and upregulates Nrf2 or/and VEGFA expression, promoting angiogenesis. miR-200a-3p leads to the downregulation of Keap1, nuclear translocation of Nrf2 and promotion of SOD2 expression, resulting in high ATP production and protection against mitochondrial fragmentation. Exosomal miR-23b and miR-21 can alleviate oxidative stress, leading to a reduction in neuroinflammation and providing neuroprotective effects by PTEN/PI3K/AKT/Nrf2 pathway. ADSCs-exosomes could attenuate inflammation and oxidative stress induced by high glucose in podocytes through the upregulation of FAM129B and reactivation of the Nrf2-HO-1 pathway, FAM129B competes with Nrf2 and binds to Keap1, leading to reduced Nrf2 ubiquitination and thereby activation of the Nrf2 pathway. MSCs-exosomes are able to protect against acute liver injury through activation of the P62-Keap1-Nrf2 pathway. P62 serves as an important regulator located upstream of the Keap1-Nrf2 pathway. In response to oxidative stress, P62 competitively interacts with the Nrf2-binding site of Keap1 and inhibits the Nrf2 ubiquitination. It has been demonstrated that miR-100-5p-enriched exosomes have capability to decrease oxidative stress through the regulation of the Nox4-ROS-Nrf2 axis. miR-130a-3p suppresses Nrf2 methylation and upregulates Nrf2 expression through DNMT1 inhibition to activate HIF1α/ACTA1 axis, thereby improving angiogenesis. In addition, exosomes are able to upregulate the expression level of SIRT1 which its restoration results in an increase in Nrf2 and HO-1. Exosomal circ-ITCH suppresses ferroptosis and enhances the angiogenesis by the Nrf2 activation. circ_0072464 shuttled by BMSC-derived EVs can reduce ferroptosis through miR-431 inhibition and the subsequent increase in miR-431-mediated Nrf2 expression. Exosomes loaded with miR-194 alleviate damage caused by ischemia by increasing the Nrf2/HO-1 activation, leading to the downregulation of ferroptosis. Exosome-circAkap7 lessens oxidative stress against ischemic damage via increasing nuclear transcription of Nrf2 by absorbing miR-155-5p. ACTA1, Skeletal muscle actin alpha 1; ceRNAs, competing endogenous RNAs; DNMT1, DNA methyltransferase 1; DPN, Diabetic peripheral neuropathy; HIF1α, Hypoxia inducible factor 1 subunit alpha; HO-1, heme oxygenase-1; KEAP1, Kelch-like ECH-associated protein 1; MSCs, mesenchymal stem cells; Nox4, NADPH oxidase 4; Nrf2, factor nuclear factor-erythroid 2-related factor 2; PI3K, The phosphoinositide 3-kinase; PTEN, Phosphatase and tensin homolog deleted on chromosome 10; SIRT1, silent information regulator 1; SOD; Superoxide dismutase, VEGFA, vascular endothelial growth factor-A