ArticleCell death discovery2025
CO confers neuroprotection via activating the PERK-calcineurin pathway and inhibiting necroptosis.
Article in Cell death discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Novel mechanism of neuronal hypoxia response: HIF-1α/STOML2 mediated PINK1-dependent mitophagy activation against neuronal injury.Cell death discovery · 2026Article
- The role of gasotransmitters in Parkinson's disease: Interplay of nitric oxide, carbon monoxide, and hydrogen sulfide.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Systems pharmacology identifies ajugol-mediated NF-κB/caspase-3 inhibition and isoacteoside-driven p62/mTOR-mediated autophagy as key mechanisms of Rehmanniae Radix and its processed form in Alzheimer's treatment.Frontiers in pharmacology · 2025Article
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Authors and funding
12 authors.
Funding
Abstract
Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), are marked by progressive neuronal loss. Regulated cell death programs (i.e., necroptosis) as well as homeostatic mechanisms (i.e., autophagy) can modulate disease pathogenesis. Low-dose carbon monoxide (CO) has been shown to activate cytoprotective responses in various models of tissue injury. Our study investigates the protective roles of CO in neurodegenerative disease through the modulation of necroptosis and autophagy programs. We found that CO activates the Protein kinase RNA (PKR)-like ER kinase (PERK) branch of the unfolded protein response (UPR) and the calcineurin pathway, leading to significant neuroprotective effects in cellular and mouse models of PD. CO-induced PERK activation promotes the nuclear translocation of transcription factor EB (TFEB). Subsequently, TFEB enhances autophagy through increased expression of autophagy-related genes and inhibits necroptosis by suppressing the phosphorylation and oligomerization of Mixed Lineage Kinase Domain-Like Pseudokinase (MLKL), a key necroptosis regulator. Furthermore, CO enhances the expression of Beclin 1, which inhibits necroptosis, independently of its autophagic function, by regulating MLKL oligomerization. Our findings suggest that modulation of the PERK-calcineurin pathway and downstream activation of cellular defense mechanisms by CO may serve as a promising therapeutic approach to mitigate neuronal loss in neurodegenerative diseases.
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