2. Academic Validation
  3. Endothelial JMJD1C drives pathological ocular neovascularization by activating SREBF2-dependent cholesterol biosynthesis

Endothelial JMJD1C drives pathological ocular neovascularization by activating SREBF2-dependent cholesterol biosynthesis

  • Free Radic Biol Med. 2026 Mar 16:246:181-195. doi: 10.1016/j.freeradbiomed.2026.01.024.
Yang Yu 1,  Zhangyu Liu 2,  Jiayu Huang 2,  Xun Qin 2,  Xi Chen 2,  Huiling Nie 2,  Jin Yao 3,  Juxue Li 4,  Qin Jiang 5
Affiliations

Affiliations

  • 1 The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China; Department of Ophthalmology, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
  • 2 The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
  • 3 The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
  • 4 State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: [email protected].
  • 5 The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
PMID: 41548765 DOI: 10.1016/j.freeradbiomed.2026.01.024
Abstract

Background: Pathological ocular neovascularization is closely linked to aberrant histone modifications, yet the underlying molecular mechanisms remain incompletely defined. This study investigates the role of the Histone Demethylase JMJD1C and its encoding gene Jmjd1c in driving pathological angiogenesis and evaluates its therapeutic potential in ocular proliferative vascular diseases.

Methods: Jmjd1c expression was examined in mouse models of ocular neovascularization and in endothelial cells (ECs) using immunostaining, qRT-PCR, and Western blotting. The pro-angiogenic functions of JMJD1C were assessed through EdU incorporation, Transwell migration, tube-formation, and spheroid-sprouting assays in vitro, as well as retinal flat-mount isolectin-B4 staining and H&E staining in vivo. RNA Sequencing, immunostaining, qPCR, Western blotting, and ChIP-qPCR were employed to dissect the molecular mechanisms by which JMJD1C regulates pathological angiogenesis.

Results: Endothelial-specific deletion of Jmjd1c markedly reduced pathological neovascularization in both oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models. Loss of JMJD1C impaired endothelial cell proliferation, migration, tube formation, and sprouting angiogenesis. Mechanistically, Jmjd1c deletion suppressed Srebf2 transcription and Cholesterol biosynthesis by increasing repressive H3K9me2 histone marks in endothelial cells. Pharmacological inhibition of JMJD1C similarly attenuated neovascularization in wild-type mice.

Conclusions: JMJD1C acts as a key regulator of pathological ocular angiogenesis through histone demethylation-mediated control of endothelial Cholesterol biosynthesis. These findings establish JMJD1C and the Jmjd1c-Srebf2 regulatory axis as promising therapeutic targets for ocular vascular diseases.

Keywords

Cholesterol biosynthesis; Histone methylation; JMJD1C; Pathological angiogenesis; SREBF2.

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