METTL3-mediated m⁶A modification targets the regulation of PCBP1 expression, thereby modulating GPX4 levels and intracellular Fe²⁺ homeostasis to influence ferroptosis and contribute to juvenile sepsis-associated brain injury.
5 affiliations
- 1Department of Emergency, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
- 2Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China.
- 3Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
- 4Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China. [email protected].
- 5Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. [email protected].
Abstract
Juvenile sepsis-associated brain injury (SABI) lacks effective targeted therapies, and ferroptosis has emerged as a critical pathogenic mechanism. N⁶-methyladenosine (m⁶A) modification is increasingly recognized as a key epitranscriptomic regulator in inflammatory and neurological disorders, yet its role in ferroptosis regulation during SABI remains unexplored. Here, we identify a novel METTL3-PCBP1-ferroptosis axis that drives hippocampal neuronal injury in SABI. Using a cecal ligation and puncture (CLP)-induced rat SABI model and an in vitro co-culture system of lipopolysaccharide (LPS)-stimulated microglia with primary hippocampal neurons, we demonstrate that SABI significantly upregulates methyltransferase-like 3 (METTL3) expression and global m⁶A modification levels in the hippocampus. MeRIP-seq reveals that poly(rC)-binding protein 1 (Pcbp1) mRNA-encoding an iron chaperone that maintains cellular iron homeostasis-exhibits the most pronounced increase in m⁶A modification among cell death-related genes, with site-specific methylation at position 1151 (GGACA motif). This modification recruits the m⁶A reader YTH domain-containing family protein 2 (YTHDF2), promoting Pcbp1 mRNA decay and subsequent PCBP1 protein downregulation. Loss of PCBP1 reduces glutathione peroxidase 4 (GPX4) expression-likely through impaired mRNA binding-and disrupts intracellular Fe²⁺ homeostasis, ultimately triggering ferroptosis characterized by lipid peroxidation and mitochondrial damage. Notably, METTL3 knockdown restores PCBP1 expression, normalizes Fe²⁺ levels, upregulates GPX4, and attenuates ferroptosis and hippocampal injury; however, concurrent PCBP1 knockdown reverses these protective effects. Furthermore, PCBP1 overexpression in SABI rats rescues ferroptosis and neurological deficits. Collectively, our findings establish that METTL3-mediated m⁶A modification of Pcbp1 mRNA exacerbates ferroptosis and SABI pathogenesis, identifying the METTL3/PCBP1 axis as a promising therapeutic target for juvenile SABI.
Related
- Programmable DNA-peptide nanostructures for multivalent regulation of intracellular signalling
- METTL7B-Mediated m6A Modification of PLEKHA4 Suppresses Ferroptosis via Reducing AURKA Ubiquitination to Promote Papillary Thyroid Cancer Progression.
- ERK5 Signaling and Ferroptosis in Bone Homeostasis: Emerging Connections and Therapeutic Perspectives
- Stress-induced vtRNA1-1 modulates redox homeostasis and ferroptosis susceptibility in hepatocellular carcinoma cells.
- Cooperative inhibition of mTORC1 disrupts iron–redox homeostasis and triggers ferritinophagy-dependent ferroptosis in hepatocellular carcinoma
BibTeX
@article{tang2026mettl3mediated,
title = {{METTL3-mediated m⁶A modification targets the regulation of PCBP1 expression, thereby modulating GPX4 levels and intracellular Fe²⁺ homeostasis to influence ferroptosis and contribute to juvenile sepsis-associated brain injury.}},
author = {Fajuan Tang and Hu Gao and Bin Chen and Junjie Ning and Min Yang and Xihong Li and Lina Qiao},
journal = {Cell biology and toxicology},
year = {2026},
month = aug,
doi = {10.1007/s10565-026-10239-3},
url = {https://europepmc.org/article/MED/42957911},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - METTL3-mediated m⁶A modification targets the regulation of PCBP1 expression, thereby modulating GPX4 levels and intracellular Fe²⁺ homeostasis to influence ferroptosis and contribute to juvenile sepsis-associated brain injury.
AU - Fajuan Tang
AU - Hu Gao
AU - Bin Chen
AU - Junjie Ning
AU - Min Yang
AU - Xihong Li
AU - Lina Qiao
PY - 2026
DA - 2026/08/03
JO - Cell biology and toxicology
DO - 10.1007/s10565-026-10239-3
UR - https://europepmc.org/article/MED/42957911
AB - Juvenile sepsis-associated brain injury (SABI) lacks effective targeted therapies, and ferroptosis has emerged as a critical pathogenic mechanism. N⁶-methyladenosine (m⁶A) modification is increasingly recognized as a key epitranscriptomic regulator in inflammatory and neurological disorders, yet its role in ferroptosis regulation during SABI remains unexplored. Here, we identify a novel METTL3-PCBP1-ferroptosis axis that drives hippocampal neuronal injury in SABI. Using a cecal ligation and puncture (CLP)-induced rat SABI model and an in vitro co-culture system of lipopolysaccharide (LPS)-stimulated microglia with primary hippocampal neurons, we demonstrate that SABI significantly upregulates methyltransferase-like 3 (METTL3) expression and global m⁶A modification levels in the hippocampus. MeRIP-seq reveals that poly(rC)-binding protein 1 (Pcbp1) mRNA-encoding an iron chaperone that maintains cellular iron homeostasis-exhibits the most pronounced increase in m⁶A modification among cell death-related genes, with site-specific methylation at position 1151 (GGACA motif). This modification recruits the m⁶A reader YTH domain-containing family protein 2 (YTHDF2), promoting Pcbp1 mRNA decay and subsequent PCBP1 protein downregulation. Loss of PCBP1 reduces glutathione peroxidase 4 (GPX4) expression-likely through impaired mRNA binding-and disrupts intracellular Fe²⁺ homeostasis, ultimately triggering ferroptosis characterized by lipid peroxidation and mitochondrial damage. Notably, METTL3 knockdown restores PCBP1 expression, normalizes Fe²⁺ levels, upregulates GPX4, and attenuates ferroptosis and hippocampal injury; however, concurrent PCBP1 knockdown reverses these protective effects. Furthermore, PCBP1 overexpression in SABI rats rescues ferroptosis and neurological deficits. Collectively, our findings establish that METTL3-mediated m⁶A modification of Pcbp1 mRNA exacerbates ferroptosis and SABI pathogenesis, identifying the METTL3/PCBP1 axis as a promising therapeutic target for juvenile SABI.
SN - 0742-2091
SN - 1573-6822
ER -