Transcriptomic Profiling of the Human Retina Reveals Inflammatory and Metabolic Signatures Associated With Clinical Severity After Retinal Detachment

Purpose: Retinal detachment (RD) remains an ophthalmologic emergency with high anatomical success rates after surgery but often suboptimal visual outcomes. This study aimed to identify transcriptomic signatures linked with clinical severity in human RD to uncover the molecular basis of variability in functional recovery. Methods: Full-length RNA sequencing (RNA-seq) was performed on freshly collected human retinas from patients with rhegmatogenous RD. Principal component analysis was used to derive a composite severity framework, which guided subsequent analysis (differential gene expression, protein-protein interaction, multivariable modeling, and functional enrichment) to identify potential biomarkers and pathways associated with disease severity. Results: Transcriptomic changes were primarily driven by a core severity axis, highlighting baseline best-corrected visual acuity and macular/foveal involvement as clinically interpretable proxies of severity. Severe RD was characterized by strong upregulation of immune and inflammatory genes and pathways, along with activation of Rho-GTPase pathways and G protein-coupled receptors-signaling, suggesting an active immune microenvironment. Consistent downregulation of metabolic and photoreceptor associated pathways, reflecting mitochondrial dysfunction and bioenergetic failure, was also observed. Transcriptomic shifts seemed to occur beyond clinically relevant severity thresholds rather than along linear gradients. PTPRC, FCGR3A, and SCARB1 emerged as central hub proteins with potential biomarker value. Unexpected enrichment of sensory and olfactory receptor pathways suggested a potential contribution to post-detachment neurodegeneration. Individual variables largely recapitulated these transcriptional signatures, reinforcing their applicability in stratification. Conclusions: Inflammation, immune dysregulation, and metabolic impairment emerged as key molecular indicators of severe RD, supporting the development of molecular-based stratification and potential adjuvant therapies.