2. Academic Validation
  3. Lactylation-induced ALKBH5 targets RNF123 to worsen retinal Müller cell activation through PKM2-regulated Glycolysis in diabetic retinopathy

Lactylation-induced ALKBH5 targets RNF123 to worsen retinal Müller cell activation through PKM2-regulated Glycolysis in diabetic retinopathy

  • J Transl Med. 2025 Oct 15;23(1):1105. doi: 10.1186/s12967-025-07129-3.
Shasha Luo 1 2,  Ye Sun 3,  Yifan Hu 3,  Yujia Xu 3
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Wuxi No. 2 People's Hospital (Jiangnan University Medical Center), Wuxi, 214000, China. luoshasha403@163.com.
  • 2 Department of Ophthalmology, Wuxi No. 2 People's Hospital, Affiliated Wuxi Clinical College of Nantong University, Wuxi, 214000, China. luoshasha403@163.com.
  • 3 Department of Ophthalmology, Jiangnan University Wuxi School of Medicine, Wuxi, 214000, China.
PMID: 41094513 DOI: 10.1186/s12967-025-07129-3
Abstract

Background: Ubiquitin Ligase RNF123 affects a variety of pathological processes, but little is known about its regulatory mechanism. This study defined the regulatory mechanisms of RNF123 in Müller cell activation in diabetic retinopathy (DR).

Methods: RNF123 expression was analyzed in the retina of DR patients and diabetic mice. Müller cell line MIO-M1 treated with high glucose (HG) was used to explore the upstream and downstream signal regulation mechanism of RNF123 in vitro. Müller cell activation and glycolysis were indicated using cell viability, cell migration, levels of inflammatory factors, GFAP and GS expression levels, extracellular acidification rate and lactate production. Diabetic rat models induced by streptozotocin were used to investigate the critical role of the RNF123-glycolytic axis in DR in vivo.

Results: RNF123 expression was decreased in the retina of DR patients, diabetic mice and HG-stimulated Müller cells. HG-induced pathological activation of MIO-M1 cells, manifested as increased viability, migration, inflammatory factors production and GFAP expression and decreased GS expression, and also increased glycolysis. These pathological changes were reversed by RNF123 overexpression. Glycolysis inhibition by 2-DG reversed RNF123 knockdown-induced Müller cell activation. RNF123 targeting ubiquitination of PKM2 in HG-induced MIO-M1 cell activation. HG-induced downregulation of RNF123 was regulated by ALKBH5 and IGF2BP1-mediated m6A modification. HG-induced upregulation of ALKBH5 was mediated by histone lactylation. The lactate-ALKBH5-RNF123-PKM2 regulatory axis was involved in HG-induced Müller cell activation and retinal damage of the diabetic rats.

Conclusions: Lactate increases glycolysis through the ALKBH5-RNF123-PKM2 signaling axis to form a feedback regulation mechanism to activate Müller cells, which is an important pathological mechanism of DR.

Keywords

Diabetic retinopathy; Glycolysis; Histone lactylation; Müller cells; N6-Methyladenosine; RNF123; Ubiquitination.

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