Lipid–Retinoid Metabolic Network Links Genetic Variation to Molecular Heterogeneity in Inherited Retinal Degeneration

Inherited retinal degeneration (IRD) comprises a genetically heterogeneous group of disorders in which the mechanisms linking genetic variation to molecular heterogeneity remain poorly understood. Here, we investigated the contribution of lipid and retinoid metabolism to the molecular etiology of IRD through an integrative analysis of proteomic and biochemical data. A cohort of 203 patients with inherited retinal degeneration was genetically characterized by whole-exome sequencing (WES), followed by targeted profiling of lipid-related proteins, including apolipoprotein A1 (ApoA1), apolipoprotein E (ApoE) and lipoprotein lipase (LPL), together with the quantitative assessment of systemic lipid parameters. Integrative analyses identified a coordinated lipid–retinoid–photoreceptor metabolic network linking systemic lipid metabolism with photoreceptor-associated processes. Although conventional lipid measures largely remained within clinical reference ranges, their distributions revealed substantial biological variability. Lipid-associated network architecture defined distinct patterns of molecular organization and exhibited pronounced sex-dependent differences, with female patients displaying denser and more interconnected networks than male patients. Furthermore, the integration of genetic and protein expression demonstrated that variant pathogenicity is associated with the coordinated remodeling of lipid-related molecular states. Our findings identify lipid and retinoid metabolism as integral components of the molecular architecture underlying disease heterogeneity in IRD and reveal a lipid–retinoid metabolic network linking genetic variation to coordinated molecular remodeling. These results provide new insight into the molecular mechanisms contributing to photoreceptor-associated degeneration.