ArticleBrain and behavior2023
Acetaminophen impairs ferroptosis in the hippocampus of septic mice by regulating glutathione peroxidase 4 and ferroptosis suppressor protein 1 pathways.
Article in Brain and behavior, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 16 citations in OpenAlex.
- Encephalopathy: Cause, Pathogenesis, and Treatment.MedComm · 2026Review
- Metabolomics and Network Pharmacology-Based Screening of Candidate Hepatoprotective Metabolites in FermentedCurrent issues in molecular biology · 2026Article
- Non-apoptotic Regulated Cell Death Mechanisms in Sepsis and their Therapeutic Potential.Inflammation · 2026Review
- Ferroptosis suppressor protein 1-mediated ferroptosis suppression in sepsis: non-canonical antioxidant pathways, inflammatory regulation, and therapeutic perspectives.Frontiers in immunology · 2026Review
- Early acetaminophen use is associated with the reduced mortality risk in patients with sepsis-associated encephalopathy: a retrospective study.European journal of medical research · 2025Article
- Glutathione metabolism as a key regulator of oxidative hippocampal injury in sepsis-associated encephalopathy: an integrated proteomics and metabolomics study.Frontiers in neuroscience · 2025Article
- SIRT5-mediated HOXA5 desuccinylation inhibits ferroptosis to alleviate sepsis induced-lung injury.The Kaohsiung journal of medical sciences · 2025Article
- Circulatory Indicators of Lipid Peroxidation, the Driver of Ferroptosis, Reflect Differences between Relapsing-Remitting and Progressive Multiple Sclerosis.International journal of molecular sciences · 2024Article
- PEG300 Protects Mitochondrial Function By Upregulating PGC-1α to Delay Central Nervous System Oxygen Toxicity in Mice.Neurotoxicity research · 2024Article
- NHH promotes Sepsis-associated Encephalopathy with the expression of AQP4 in astrocytes through the gut-brain Axis.Journal of neuroinflammation · 2024Article
- Cellular preconditioning and mesenchymal stem cell ferroptosis.World journal of stem cells · 2024Article
- Gandouling Regulates Ferroptosis and Improves Neuroinflammation in Wilson's Disease Through the LCN2/NLRP3 Signaling Pathway.Journal of inflammation research · 2024Article
- Association between acetaminophen administration and clinical outcomes in patients with sepsis admitted to the ICU: a retrospective cohort study.Frontiers in medicine · 2024Article
- Acetaminophen impairs ferroptosis in the hippocampus of septic mice by regulating glutathione peroxidase 4 and ferroptosis suppressor protein 1 pathways.Brain and behavior · 2023Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundNeuronal ferroptosis is a major cause of cognitive impairment and mortality in patients with sepsis-associated encephalopathy (SAE). A low dose of acetaminophen (APAP) in septic mice can prevent ferroptosis in the hippocampal tissue; however, the underlying mechanism is unknown. This study aimed to investigate the mechanism by which APAP reduces ferroptosis in the hippocampal tissues of septic mice.
methodsA mouse model of SAE was established, and the ferroptosis pathway inhibitors RSL3 and iFSP1+RSL3 were used in addition to APAP for the interventions, respectively. The 7-day survival rate of the mice was recorded, and cognitive function was examined using the Morris water maze test. Hematoxylin and eosin staining was performed to observe hippocampal tissue damage. Hippocampal iron and malondialdehyde (MDA) were measured using chemical colorimetric methods. Immunofluorescence was used to detect the reactive oxygen species (ROS) content in hippocampal tissues.
resultsRSL3 reversed the efficacy of APAP on improving cognitive dysfunction in septic mice but did not obviously reverse the survival rate of mice enhanced by APAP. RSL3 aggravated APAP-induced hippocampal tissue damage in mice attenuated by APAP. RSL3 inhibited glutathione peroxidase 4 (GPX4) expression and increased ferroptosis suppressor protein 1 (FSP1) and 4-hydroxy-2-nonenal (4-HNE) expression. RSL3 also reversed the effects of APAP in reducing iron, MDA, and ROS levels in the hippocampal tissues of septic mice. iFSP1+RSL3 further reversed the effect of APAP on ameliorating cognitive dysfunction in septic mice and successfully reversed the survival rate of mice enhanced by APAP. iFSP1+RSL3 aggravated APAP-induced cerebral hippocampal damage. iFSP1+RSL3 inhibited both GPX4 and FSP1, further reversing the effect of APAP on the reduction in iron, 4-HNE, ROS, and MDA levels in the cerebral hippocampus of mice with sepsis.
conclusionThese data suggest that APAP inhibits ferroptosis in the cerebral hippocampus of septic mice through the GPX4 and FSP1 pathways.
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