fig2

Figure 2. MSC-EV-mediated coordination of antioxidant defence and mitochondrial quality control. Schematic illustrates how MSC-EVs may regulate the coupled oxidative stress-mitochondrial dysfunction module that underlies neuronal vulnerability in neurodegenerative diseases. Following uptake by stressed neurons, MSC-EV cargo promotes nuclear localisation of NRF2, driving antioxidant gene transcription via ARE^[21]. This response is coupled to upregulation of TFAM, supporting mitochondrial biogenesis^[48]. In parallel, MSC-EV-associated miRNAs attenuate ROS amplification and apoptosis by modulating FOXO3- and MAPK-dependent stress signalling^[21]. MSC-EV cargo further restricts mitochondrial accumulation of α-synuclein, preserving respiratory chain function and reducing lipid peroxidation^[49,50]. At the level of organelle quality control, engineered MSC-EVs enhance neuronal mitophagy, facilitating the clearance of damaged mitochondria and reducing mitochondrial damage-associated apoptosis^[32]. Together, these coordinated actions position MSC-EVs as integrative regulators of neuronal stress resilience, acting upstream to decouple oxidative stress from mitochondrial failure and prevent progression toward irreversible bioenergetic collapse. MSC-EV: Mesenchymal stem cell-derived extracellular vesicle; NRF2: nuclear factor erythroid 2-related factor 2; ARE: antioxidant response element; TFAM: mitochondrial transcription factor A; ROS: reactive oxygen species; FOXO3: forkhead box O3; MAPK: mitogen-activated protein kinase; α-syn: alpha-synuclein; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; HIF-1α: hypoxia-inducible factor 1 alpha; KEAP1: Kelch-like ECH-associated protein 1; CREB: cAMP response element-binding protein; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; EGR1: early growth response 1; SIRT3: sirtuin 3; SOD2: superoxide dismutase 2; NLRP3: NOD-like receptor family pyrin domain containing 3; H₂O₂: hydrogen peroxide; NOX4: NADPH oxidase 4; p38 MAPK: p38 mitogen-activated protein kinase; VDAC1: voltage-dependent anion channel 1; PINK1: PTEN-induced kinase 1; OXPHOS: oxidative phosphorylation; AMPK: AMP-activated protein kinase; mTOR: mammalian target of rapamycin; ER: endoplasmic reticulum.