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Deciphering mitochondrial dysfunction in keratoconus: Insights into ACSL4 from machine learning-based bulk and

Yuchen Cai1,2, Tianyi Zhou1,2, Xueyao Cai3

  • 1Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Computational and Structural Biotechnology Journal
|June 11, 2025
PubMed
Summary

Mitochondrial dysfunction plays a key role in keratoconus (KC), a leading cause of corneal transplants. The study identifies ACSL4 as a crucial biomarker linked to KC development and potential therapeutic strategies.

Keywords:
ACSL4Corneal stromal cellsKeratoconusMitochondrial dysfunctionSingle cell transcriptome

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Area of Science:

  • Ophthalmology
  • Molecular Biology
  • Genetics

Background:

  • Keratoconus (KC) is a major cause of corneal transplantation worldwide.
  • Mitochondrial abnormalities are observed in KC, but mechanisms are poorly understood.

Purpose of the Study:

  • To investigate the role of mitochondrial dysfunction in keratoconus pathogenesis.
  • To identify key molecular players and potential biomarkers for KC.

Main Methods:

  • Transcriptomics analysis of KC datasets to identify mitochondria-related differentially expressed genes (mDEGs).
  • Functional pathway analysis, protein-protein interaction (PPI) network construction, and machine learning (ML) for hub gene screening.
  • Validation using quantitative PCR, Western blot, and an in vitro KC model.

Main Results:

  • 104 mDEGs were identified, enriched in pathways of oxidative stress, apoptosis, ferroptosis, and inflammation.
  • Nine characteristic genes were validated, with ACSL4 identified as a promising biomarker, particularly in corneal stromal cells (CSCs).
  • ACSL4 expression increased with decreased substrate stiffness in vitro and correlated with immune cell infiltration in KC.

Conclusions:

  • Mitochondrial dysfunction, particularly involving ACSL4, is implicated in keratoconus pathogenesis.
  • ACSL4 serves as a potential novel biomarker for understanding KC mechanisms and developing future therapies.