Oxidative Phosphorylation Pathway in Ankylosing Spondylitis: Multi-Omics Analysis and Machine Learning

Abstract

Introduction

Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the axial skeleton, characterized by immune microenvironment dysregulation and elevated cytokines like TNF-α and IL-17. Mitochondrial oxidative phosphorylation (OXPHOS), crucial for immune cell function and survival, is implicated in AS pathogenesis. This study explores OXPHOS-related mechanisms in AS, identifies key genes using machine learning, and highlights potential therapeutic targets for precision medicine.

Materials and Methods

Peripheral blood mononuclear cells (PBMCs) bulk transcriptomic and single-cell RNA sequencing (scRNA-seq) data from AS patients were analyzed to investigate the role of the OXPHOS pathway in AS. Weighted gene co-expression network analysis (WGCNA) was performed to identify key gene modules associated with OXPHOS. Machine learning techniques, including support vector machine with recursive feature elimination (SVM-RFE), random forest, and least absolute shrinkage and selection operator (LASSO), were applied to identify significant AS-related genes. Real-time PCR (RT-PCR) was used to quantify gene expression, examine their patterns in specific cell subtypes, and explore their functional implications.

Results

Pathway enrichment analysis identified OXPHOS as a significantly enriched pathway distinguishing AS patients from healthy controls, with high normalized enrichment scores and significant group separation in principal component analysis. ScRNA-seq revealed significantly higher OXPHOS scores in AS patients, especially in dendritic cells (DCs) and monocytes, highlighting cell type-specific dysregulation. WGCNA identified two key gene modules (MEyellow and MEtan) that are closely associated with OXPHOS. Three hub genes—LAMTOR2, APBB1IP, and DGKQ—were screened using machine learning methods and validated by RT-PCR and scRNA-seq. Among them, LAMTOR2 was significantly more highly expressed in patients with AS, and functional analyses showed that it plays a role in promoting TH17 cell differentiation, which highlights its potential as a therapeutic target for ankylosing spondylitis.

Conclusion

This multi-omics study provides valuable insights into the complex interplay between OXPHOS and AS. The identified genes, particularly LAMTOR2, serve as potential therapeutic targets, contributing to our understanding of AS mechanisms and paving the way for precision medicine in AS treatment.