Oxidative stress promotes the progression of age-related macular degeneration by up-regulating Spp1 to activate the JAK/STAT signaling pathway

  • Sci Rep. 2026 Apr 20;16(1):18273. doi: 10.1038/s41598-026-48556-6.
Qi Zeng  1 ,  Xingyu Hua  1 ,  Yutong Liu  1 ,  Sha Wang  2  3  4  5
Affiliations
  • 1. Department of Ophthalmology, Hunan Provincial People's Hospital(The First-Affiliated Hospital of Hunan Normal University), Changsha City, Hunan Province, China.
  • 2. Eye Center of Xiangya Hospital, Central South University, 86 Xiangya Road, Kaifu District, Changsha City, Hunan Province, China. [email protected].
  • 3. Hunan Key Laboratory of Ophthalmology, Changsha City, Hunan Province, China. [email protected].
  • 4. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha City, Hunan Province, China. [email protected].
  • 5. National key clinical specialty of ophthalmology, Changsha, China. [email protected].
PMID: 42009803 DOI: 10.1038/s41598-026-48556-6
Abstract

Age-related macular degeneration (AMD) is the leading cause of visual impairment in elderly people, and due to the unclear specific pathogenesis, eradication treatment cannot be carried out. This study aims to explore the molecular regulatory network and signal transduction mechanism related to the pathogenesis of AMD, with the expectation of providing a theoretical basis for the analysis of the pathological mechanism of AMD and the discovery of potential therapeutic targets. Sodium iodate (NaIO3) was used to induce AMD in mice, and optical coherence tomography (OCT) was used to detect macular degeneration and retinal thickness in their eyes. Differentially expressed mRNAs or proteins were then obtained using differential analysis. Gene set enrichment analysis (GSEA) was used to identify underlying signaling pathways associated with AMD. ARPE-19 cells were induced with H2O2, and cellular oxidative stress was evaluated. Secreted phosphoprotein 1 (SPP1) expression was verified using quantitative Real-Time PCR (qRT-PCR) and western blot (WB). The relationship between SPP1 expression and signaling pathways was verified using the WB assay. Cell counting kit 8 (CCK-8) was performed to verify the effect of secreted SPP1 expression on the survival of retinal pigment epithelium (RPE) cells. Transcriptomic and proteomic analyses revealed that SPP1 was significantly upregulated in AMD, and a key pathway was obtained: the JAK-STAT signaling pathway. In vitro experiments showed that SPP1 was significantly over-expressed in the AMD group, accompanied by elevated oxidative stress levels. Furthermore, SPP1 knockdown indirectly suppressed JAK-STAT pathway activation by downregulating CD44 expression, thereby contributing to the survival of RPE cells. Overall, this study demonstrates that oxidative stress may promote AMD progression by impairing RPE cell survival through inducing SPP1-mediated CD44 upregulation and JAK-STAT pathway activation.

Keywords
Age-related macular degeneration; JAK-STAT signaling pathway; Oxidative stress; Retinal pigment epithelium cells; Secreted phosphoprotein 1.
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