Single-cell RNA sequencing reveals the role of heat shock protein 90AA1 in Müller cell proliferation via the Necroptosis/MAPK pathway in diabetic retinopathy

Abstract

This study investigates the role of heat shock protein 90AA1 (HSP90AA1) in the proliferation of Müller cells (MCs) within the context of diabetic retinopathy (DR). Using single-cell RNA sequencing (scRNA-seq) on retinal samples from four diabetic and two nondiabetic patients, we integrated bioinformatics analyses with experimental exploration using in vivo and in vitro DR models to investigate MC pathogenesis in DR. Our findings identified nine major retinal cell types and elucidated how diabetes disrupts retinal cell type composition, gene expression profiles, and intercellular communication. HSP90AA1, significantly downregulated in the MCs of the diabetic patients, emerged as a potential hub gene, with its associated pathways involving necroptosis (RIP1/RIP3/MLKL) and mitogen-activated protein kinase (MAPK) signaling. Furthermore, our results from DR models suggeste that the downregulation of HSP90AA1 may induce DR-related MC proliferation. This study provides novel insights into the cellular and molecular mechanisms underlying DR, highlighting the suppressive role of HSP90AA1 in MC proliferation as a promising therapeutic target for DR.