Taurochenodeoxycholic acid alleviates MPP⁺/MPTP-induced neurotoxicity in vitro and in vivo by suppressing ferroptosis via TGR5/cGAS/STING signaling pathway.

Authors

Lupeng Wang, Ying Ni, Xuefang Wang, Yanni Ma, Yanli Chang, Ling Chen, Liqin Yu, Zhiyong He, Feifei Li

Published in

IBRO neuroscience reports. Volume 21. Pages 264-274. Epub Jun 30, 2026.

Abstract

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra, with ferroptosis emerging as critical pathogenic mechanisms. Recent evidence suggests that STING activation can induce neuronal ferroptosis through autophagic degradation of GPX4. Taurochenodeoxycholic acid (TCDCA), a naturally occurring bile acid, has demonstrated neuroprotective properties through activation of Takeda G protein-coupled receptor 5 (TGR5). However, whether TCDCA can improve PD by modulating the cGAS-STING-ferroptosis axis remains unexplored. We investigated the effects of TCDCA treatment on motor function, dopaminergic neuronal survival, oxidative stress markers, ferroptosis-related proteins (GPX4, SLC7A11, ACSL4), and cGAS-STING signaling components in the substantia nigra of male mice subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration and in MPP⁺-treated SH-SY5Y cells. Behavioral assessments demonstrated that TCDCA significantly improved motor dysfunction in both open field and pole tests. TCDCA treatment markedly increased tyrosine hydroxylase-positive neurons and reduced oxidative stress markers including malondialdehyde and ferrous iron levels while restoring superoxide dismutase activity and glutathione content in the substantia nigra. Results showed that TCDCA upregulated TGR5 expression and concurrently suppressed cGAS and STING activation in both in vivo and in vitro PD models. Importantly, TCDCA treatment significantly enhanced the expression of anti-ferroptotic proteins GPX4 and SLC7A11 while reducing pro-ferroptotic ACSL4. These neuroprotective effects were associated with TGR5 upregulation and cGAS-STING pathway suppression. Our findings demonstrate that TCDCA alleviates PD-related neurodegeneration by inhibiting cGAS-STING-mediated ferroptosis through TGR5 activation, suggesting that TCDCA holds promise as a candidate drug for the treatment of PD.

PMID:
42437012
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.

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