Single-cell RNA Sequencing Reveals the Role of Heat Shock Protein 90AA1 in Müller Cell Proliferation via the Necroptosis/MAPK Pathway in Diabetic Retinopathy

Ying Yan; Hongjian Yang; Qiaonuo Wei; Doudou Yu; Chengyuan Gao; Bo Diao; Yanping Song; Xiao Chen

doi:10.1016/j.exer.2025.110508

Single-cell RNA Sequencing Reveals the Role of Heat Shock Protein 90AA1 in Müller Cell Proliferation via the Necroptosis/MAPK Pathway in Diabetic Retinopathy

Exp Eye Res. 2025 Jul 3:110508. doi: 10.1016/j.exer.2025.110508. Online ahead of print.

Authors

Ying Yan¹, Hongjian Yang², Qiaonuo Wei², Doudou Yu², Chengyuan Gao¹, Bo Diao³, Yanping Song¹, Xiao Chen⁴

Affiliations

¹ Department of Ophthalmology in Central Theater General Hospital, Wuhan, Hubei, China.
² The First School of Clinical Medicine,Southern Medical University, Guangzhou, Guangdong, China.
³ Department of Ophthalmology in Central Theater General Hospital, Wuhan, Hubei, China; Labortary of basic medical in Central Theater General Hospital, Wuhan, Hubei, China.
⁴ Department of Ophthalmology in Central Theater General Hospital, Wuhan, Hubei, China; The First School of Clinical Medicine,Southern Medical University, Guangzhou, Guangdong, China. Electronic address: cxcx@sum.edu.cn.

PMID: 40617280
DOI: 10.1016/j.exer.2025.110508

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.

Keywords: MAPK; Müller cells; diabetic retinopathy; heat shock protein 90AA1; necroptosis; single-cell RNA sequencing.