KDM6A promotes diabetic retinopathy via H3K27me3-dependent ferroptosis in Müller cells

  • Cell Death Dis. 2026 Apr 29;17(1):571. doi: 10.1038/s41419-026-08816-9.
Yanjun Wen  #  1  2 ,  Siyue Luo  #  1  3 ,  Cheng Hu  4  5  6 ,  Yikang Ji  4  5  6 ,  Yulin Zhang  1  3 ,  Xu Wang  4  5  6 ,  Xin Huang  7  8 ,  Yan Wei  9  10
Affiliations
  • 1. Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
  • 2. Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai, China.
  • 3. NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Chinese Academy of Medical Sciences, Shanghai, China.
  • 4. Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5. College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Disease, Shanghai, China.
  • 6. Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
  • 7. Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • 8. Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai, China. [email protected].
  • 9. Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • 10. NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Chinese Academy of Medical Sciences, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 42049713 DOI: 10.1038/s41419-026-08816-9
Abstract

Diabetic retinopathy (DR), a leading cause of blindness, is driven by pathological angiogenesis and vascular leakage, but the underlying epigenetic mechanisms remain poorly defined. Here, we identify the Histone Demethylase KDM6A as a critical epigenetic regulator promoting DR pathogenesis via Müller cells. KDM6A expression is significantly elevated in human DR retinas and diabetic mouse models. Intravitreal silencing of Kdm6a ameliorates retinal vascular dysfunction, reducing neovascularization, leakage, and acellular capillaries while restoring endothelial tight junctions. Single-cell RNA Sequencing revealed that Kdm6a knockdown specifically suppresses VEGF signaling and attenuates Ferroptosis. Müller cell-specific Kdm6a overexpression exacerbated DR vascular pathology, while in vitro co-cultures confirmed that KDM6A in Müller cells induces endothelial dysfunction. Mechanistically, KDM6A demethylates H3K27me3 at the promoters of pro-ferroptotic genes (e.g., Tfr1, Cybb, Atg7), thereby promoting Ferroptosis in Müller cells under high glucose conditions. Crucially, pharmacological or genetic inhibition of KDM6A mitigated high glucose-induced Ferroptosis. Our findings establish KDM6A-mediated epigenetic control of Müller cell Ferroptosis as a fundamental regulator of diabetic retinal vasculopathy and nominate KDM6A as a promising therapeutic target for DR.

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