Sevoflurane promotes neuronal ferroptosis via upregulation of PLIN4 to modulate the hippo signaling pathway
Abstract
Background Sevoflurane is a widely used inhalation anesthetic associated with neuronal damage, cognitive impairment and neurodegenerative diseases, with iron overload reported to contribute to these adverse effects. However, the mechanisms of iron-dependent cell death (ferroptosis) in sevoflurane-induced neurotoxicity remain poorly understood. Methods The role of PLIN4, a protein associated with neurodegeneration, in sevoflurane-induced neuronal damage was investigated using cultured mouse hippocampal neurons (HT22). PLIN4 knockdown or overexpression was performed through vector transfection, and PLIN4 transcription and expression levels after sevoflurane treatment and knockdown experiments were assessed via RT-qPCR, immunostaining, and western blot to evaluate its impact on ferroptosis. Transmission electron microscopy was used to assess cellular morphology and measure Fe 2+ levels. Results Sevoflurane treatment significantly increased PLIN4 expression in hippocampal neurons and induced ferroptosis. Silencing PLIN4 reduced ferroptosis and partially reversed sevoflurane's inhibition of the Hippo signaling pathway. Specifically, sevoflurane treatment led to a 2.9-fold increase in PLIN4 mRNA levels. Furthermore, higher PLIN4 levels upregulated ferroptosis in hippocampal neurons by inhibiting the Hippo pathway. Conclusion Our study indicates that sevoflurane promotes ferroptosis in neurons by upregulating PLIN4 and modulating the Hippo signaling pathway. These findings provide i…
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Increased PLIN4 expression increases ferroptosis in tumor cells, Leydig cells, and hippocampal neurons.
“emerging data has linked PLIN4 to ferroptosis with increased PLIN4 expression increasing ferroptosis in tumor cells [38], Leydig cells [39], and hippocampal neurons [40].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [40]
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- Authors
- Zeng, F., Zhou, M., Li, Q., Hu, H., & Chen, C.
- Affiliations
- University of Electronic Science and Technology of China (CN)
- Third People's Hospital of Chengdu (CN)
- Wuhan Union Hospital (CN)
- Corresponding author
- Chen, Chen
- Venue
- NeuroToxicology
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 105
- Pages
- 1-9
- ISSN
- 0161-813X (ISSN-L)
- OpenAlex
- W4401853206
- Cited by
- 12
- References
- 36
- Citations by year
- 2026: 8 · 2025: 4
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- NeuroToxicology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Keywords
- sevoflurane, ferroptosis, PLIN4, Hippo signaling pathway, neuronal ferroptosis, iron overload, hippocampal neurons, anesthetic neurotoxicity, cognitive impairment, neurodegeneration
- MeSH terms
- Sevoflurane, Ferroptosis, Hippo Signaling Pathway, Animals, Cell Line, Hippocampus, Neurons, Signal Transduction, Up-Regulation, Protein Serine-Threonine Kinases, Anesthetics, Inhalation, Mice
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