Neural Regen Res. 2026 Oct 29. doi: 10.4103/NRR.NRRONLINE-D-26-00780. Online ahead of print.
ABSTRACT
Ferroptosis is recognized as a critical driver of dopaminergic neuronal injury. Emerging evidence suggests that the neuroprotective effects of bone marrow mesenchymal stem cells are partially mediated through signal transducer and activator of transcription 6 (STAT6) signaling. However, few studies have investigated whether bone marrow mesenchymal stem cells can modulate ferroptosis in dopaminergic neurons, and the specific regulatory role of STAT6 in neuronal ferroptosis remains poorly understood. We established an in vitro model of Parkinson's disease using SH-SY5Y cells treated with 1-methyl-4-phenyl-pyridinium and an in vivo model of Parkinson's disease using mice exposed to 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine. Bone marrow mesenchymal stem cells were administered via Transwell coculture in vitro and stereotactic brain injection in vivo. Western blotting, immunohistochemistry, transmission electron microscopy, and behavioral tests were used to evaluate neuronal protection and motor function recovery. We assessed phosphorylated STAT6 (p-STAT6), the active form of STAT6, as well as markers related to ferroptosis, iron metabolism, and oxidative stress. Interventions with interleukin-4, AS1517499, and Cas9-mediated STAT6 knockout were performed to verify the regulatory role of the STAT6/p-STAT6 signaling pathway. Laser confocal microscopy was used to analyze the subcellular distribution of p-STAT6 and further elucidate the molecular mechanisms underlying bone marrow mesenchymal stem cells-mediated neuroprotection in Parkinson's disease. Bone marrow mesenchymal stem cells increased tyrosine hydroxylase expression in dopaminergic neurons and alleviated motor dysfunction in a mouse model of Parkinson's disease. Bone marrow mesenchymal stem cells promoted p-STAT6 phosphorylation at Tyr641. Nuclear-cytoplasmic fractionation assays showed that bone marrow mesenchymal stem cells restored nuclear p-STAT6 levels, while confocal microscopy confirmed the nuclear translocation of p-STAT6. Activated p-STAT6 stimulated the SLC7A11-GPX4 antioxidant pathway and restored reduced glutathione levels. Meanwhile, bone marrow mesenchymal stem cells downregulated DMT1 expression, thereby reducing intracellular iron accumulation, reactive oxygen species production, and lipid peroxidation. Interleukin-4 recapitulated the anti-ferroptotic effects of bone marrow mesenchymal stem cells, whereas AS1517499 abolished their neuroprotective effects. STAT6 knockout eliminated the ability of bone marrow mesenchymal stem cells to inhibit neuronal ferroptosis. This study demonstrates that bone marrow mesenchymal stem cells induce p-STAT6 phosphorylation at Tyr641 and facilitate its nuclear translocation. Activated p-STAT6 alleviates iron overload and lipid peroxidation by regulating SLC7A11-GPX4 and DMT1. Bone marrow mesenchymal stem cells activate the STAT6 pathway to inhibit neuronal ferroptosis, increase tyrosine hydroxylase expression, and improve Parkinson's disease-related pathological changes and motor deficits.
PMID:42955878 | DOI:10.4103/NRR.NRRONLINE-D-26-00780