AUTHOR=de Castro Júlia Nicoliello Pereira , Monte Ana Rafaela Carvalho , de Oliveira Ana Carolina Rodrigues  , Acacio Julia Dezordi , Rodrigues Thiago Adalton Rosa , Barboni Mirella Telles Salgueiro , Liber André Maurício Passos , Bonci Daniela Maria Oliveira , Ventura Dora Fix , Costa Fernando Ferreira , Camargo Ana Carolina Lima , de Melo Mônica Barbosa 
  
TITLE=Sickle cell retinopathy molecular investigation through proteomic analysis of Townes HbSS mice retinas
  
JOURNAL=Experimental Biology and Medicine
  
VOLUME=Volume 251 - 2026
  
YEAR=2026
  
URL=https://www.ebm-journal.org/journals/experimental-biology-and-medicine/articles/10.3389/ebm.2026.11228
  
DOI=10.3389/ebm.2026.11228
  
ISSN=1535-3699
  
ABSTRACT=Sickle cell retinopathy (SCR) is the most important ocular manifestation in sickle cell disease (SCD). Retinal tissue is highly sensible to vaso-occlusion and hypoxia observed in SCR pathophysiology, with consequent vessel remodeling and ultimately neovascularization in its proliferative form. Severe cases are followed by vitreous hemorrhage and retinal detachment, with 10–20% of vision loss in affected eyes. Current treatment options such as anti-VEGF (Vascular Endothelial Growth Factor) injections and laser photocoagulation are based on other proliferative retinopathies, without pre-clinical and clinical studies specific for SCR. To gain insights into disease-associated molecular pathways and to support the identification of candidate biomarkers and therapeutic targets, we performed comparative proteomic analysis in retinas of Townes HbSS mice, a humanized mouse model of sickle cell anemia (SCA), and C57BL/6J as controls. Blood hematological and metabolic features, retinal activity, and morphology were characterized. Comparative label-free proteomic analysis of retinas from Townes HbSS (N = 5) and control (N = 7) groups was performed in a LTQ Orbitrap Velos equipment, followed by functional enrichment and interaction analysis. The Townes HbSS group presented blood parameters consistent with the SCA phenotype, and retinal degeneration was indicated by functional and morphological alterations in external layers. Pathways of energetic metabolism and phototransduction were enriched among the downregulated proteins, and the molecular downregulation profile of Cnga1 and Slc24a1, related to photoreceptor activation, was validated by RT-qPCR. These findings highlight hypoxia-associated molecular adaptations in metabolic respiration and phototransduction linked to retinal degeneration. Taken together, our results contribute to a more comprehensive characterization of the molecular landscape underlying sickle cell retinopathy.