Mitophagy-related molecular signatures in ulcerative colitis revealed by machine learning and molecular dynamics

TL;DR

This study identifies key genes and a potential drug for ulcerative colitis by analyzing mitophagy-related molecular patterns and immune-metabolic interactions.

Contribution

Novel mitophagy-related biomarkers and a potential therapeutic agent for UC are identified using machine learning and molecular dynamics.

Findings

35 UC-associated mitophagy-related genes were identified, linked to immune activation and fatty acid metabolism.

Two UC subtypes were defined: a metabolism-dominant subtype and an inflammation-activated subtype.

Galunisertib showed strong binding to CD55 and reduced inflammation in UC cell models.

Abstract

Ulcerative colitis (UC) is a lifelong, chronic inflammatory disorder, characterized by recurrent and diffuse inflammation of the rectal and colonic mucosa. Increasing evidence suggests that impaired mitophagy contributes to immune dysregulation and epithelial injury in UC. However, the mitophagy-related molecular landscape and its therapeutic potential remain largely unexplored.

Mitophagy-related genes (MRGs) were intersected with differentially expressed genes to identify UC-associated MRGs. Functional enrichment, immune infiltration, and consensus clustering analyses were performed to characterize molecular subtypes. Three machine learning methods were employed to identify diagnostic models. Candidate therapeutic agents were identified by the CMap database.

A total of 35 UC-associated MRGs were identified, enriched in cell activation, fatty acid metabolism, and the PPAR signaling pathway, revealing strong immunometabolic coupling in UC. Consensus clustering stratified UC patients into two subtypes: a metabolism-dominant subtype (C1) and an inflammation-activated subtype (C2). Three hub genes—CD55, CPT1A, and SLC16A1—were screened and validated as robust diagnostic markers. Drug prediction and molecular docking revealed strong binding between galunisertib and CD55, which was further validated by molecular dynamics simulations. In vitro, galunisertib significantly suppressed inflammatory cytokine release in LPS-induced UC cell models.

This study delineated the mitophagy-related molecular signatures of UC and identified CD55, CPT1A, and SLC16A1 as key biomarkers linking mitochondrial dysfunction, metabolic reprogramming, and immune activation. Furthermore, galunisertib was proposed as a potential therapeutic agent, providing a theoretical basis for UC therapy.

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