Evidence map›Paper›PMID 40640087›Full record

ArticleChinese medical journal2026

MLL1 downregulation drives hair cell ferroptosis via mitochondrial and endoplasmic reticulum stress mechanisms through PERK-eIF2α-ATF4-Chop and PI3K/Akt-Lrp1 signaling pathway.

Chang Liu, Siyu Qiu, Wen Li, Liping Zhao, Yingzi He, Xiangli Zeng

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PubMed Full text at PMC Publisher
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Article in Chinese medical journal, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
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2citing papers in PubMed
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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

6 authors.

Chang LiuDepartment of Otolaryngology-Head and Neck Surgery , The Third Affiliated Hospital of Sun Yat-Sen University , Guangzhou , Guangdong510630 , China.
Siyu QiuENT institute and Department of Otorhinolaryngology , Eye & ENT Hospital , Fudan University , Shanghai200031 , China.
Wen LiENT institute and Department of Otorhinolaryngology , Eye & ENT Hospital , Fudan University , Shanghai200031 , China.
Liping ZhaoENT institute and Department of Otorhinolaryngology , Eye & ENT Hospital , Fudan University , Shanghai200031 , China.
Yingzi HeENT institute and Department of Otorhinolaryngology , Eye & ENT Hospital , Fudan University , Shanghai200031 , China.
Xiangli ZengDepartment of Otolaryngology-Head and Neck Surgery , The Third Affiliated Hospital of Sun Yat-Sen University , Guangzhou , Guangdong510630 , China.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundSensorineural hearing loss is characterized by irreversible hair cell (HC) degeneration. Ferroptosis, which is marked by the accumulation of reactive oxygen species and elevated levels of lipid peroxidation products, has been shown to contribute to drug-mediated auditory impairment. This study aimed to elucidate the role of mixed-lineage leukemia 1 (MLL1) in HC survival in the auditory system.

methodsThe HEI-OC1 auditory cell line and postnatal cochlear explants were evaluated using MM-102, a specific MLL1 histone methyltransferase inhibitor. Western blotting, quantitative polymerase chain reaction, electron microscopy, and immunofluorescence were used to elucidate the role of MLL1 in regulating ferroptosis in HC injury. RNA sequencing (RNA-seq) was used to analyze the molecular mechanisms of MLL1 intervention in HC injury from an epigenetic perspective.

resultsOur findings demonstrated that immunofluorescence staining revealed a crucial role of MM-102 in promoting intracellular accumulation of lipid peroxides and ferrous ions. Subsequent analysis showed MLL1 downregulation-induced mitochondrial dysfunction and endoplasmic reticulum (ER) stress, with transmission electron microscopy imaging confirming ultrastructural alterations in mitochondria and ER. Mechanistic investigations identified the PERK-eIF2α-ATF4-Chop signaling axis as the regulatory pathway, evidenced by Western blotting quantification of phosphorylated PERK (p-PERK), ATF4, and Chop levels. RNA-seq analysis revealed 741 differentially expressed genes (335 upregulated and 406 downregulated). Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis specifically highlighted significant enrichment of the PI3K/Akt-Lrp1 pathway, with corresponding activation patterns of phospho (p)-Akt and Lrp1 confirmed through Western blotting analysis.

conclusionsMLL1 downregulation initiates ferroptosis in cochlear HCs. This process is intrinsically associated with the activation of mitochondrial dysfunction and ER stress. The study highlights the importance of MLL1 in HC survival, suggesting its potential as a therapeutic target for treating hearing loss.

Indexed as

FerroptosisHair Cells, AuditoryHistone-Lysine N-MethyltransferaseMyeloid-Lymphoid Leukemia ProteinActivating Transcription Factor 4AnimalsCell LineDown-RegulationeIF-2 KinaseEndoplasmic Reticulum StressEukaryotic Initiation Factor-2HumansMitochondriaPhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktSignal TransductionActivating Transcription Factor 4eIF-2 KinaseEukaryotic Initiation Factor-2Histone-Lysine N-MethyltransferaseKMT2A protein, humanMyeloid-Lymphoid Leukemia ProteinPhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktTranscription Factor CHOPEndoplasmic reticulum stressEpigenetic modificationFerroptosisHair cellKMT2A protein, human

Identifiers

PMID40640087
PMCPMC13544771

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.