Immune Regulation and ECM-Related Pathway Enrichment Reveal ATP2A3 as a Prognostic Biomarker for Nonspecific Orbital Inflammation: An Integrated Machine Learning and Mendelian Randomization Analysis.

Background

Nonspecific orbital inflammation (NSOI) is a heterogeneous inflammatory disorder of the orbit with an unclear etiology. ATP2A3, a key regulator of calcium homeostasis in the endoplasmic reticulum (ER), may play a pivotal role in NSOI pathogenesis. Its potential as a diagnostic biomarker merits thorough investigation.

Methods

Differentially expressed genes (DEGs) common to two GEO datasets (GSE58331 and GSE105149) were intersected with immune-related genes from the ImmPort database, yielding 89 candidates. ATP2A3 was prioritized using machine learning (ML) approaches, including LASSO, support vector machine (SVM)-RFE, and weighted gene coexpression network analysis (WGCNA). Functional enrichment was assessed using GSEA and GSVA based on genes co-expressed with ATP2A3. Immune microenvironment characteristics were evaluated using CIBERSORT and ESTIMATE. Expression of ATP2A3 was validated in GSE105149.

Results

Fifteen hub genes were identified, with ATP2A3 strongly linked to immune-related pathways. Genes positively correlated with ATP2A3 were enriched in sensory perception and extracellular matrix (ECM) organization. Immune infiltration analysis revealed a positive association between ATP2A3 expression and memory B cells, M2 macrophages, resting mast cells, monocytes, and regulatory T cells (Tregs), while naive B cells and plasma cells were negatively associated. ATP2A3 exhibited significant diagnostic potential for distinguishing NSOI.

Conclusions

In the context of NSOI, we identify ATP2A3 as a novel contributor to immune-driven pathogenesis. Its significant dysregulation in NSOI tissues relative to healthy controls underscores its potential as a prognostic marker within the inflammatory microenvironment.