Effect of Endogenous FGF21 Deficiency on the Inflammatory Microenvironment of the Retina

  • Front Biosci (Landmark Ed). 2026 Apr 27;31(4):47702. doi: 10.31083/FBL47702.
Ting-Ting Zhao  1  2 ,  Ming-Kai Chang  3 ,  Bai-Yun Shen  2 ,  Hao-Ran Guo  3 ,  Yu-Tong Han  3 ,  Wen-Fei Wang  2  3
Affiliations
  • 1. Department of Ophthalmology, Aier Eye Hospital, Jinan University, 510071 Guangzhou, Guangdong, China.
  • 2. Department of Fundus Diseases, Nanning Aier Eye Hospital, 530000 Nanning, Guangxi, China.
  • 3. School of Life Science, Northeast Agricultural University, 150030 Harbin, Heilongjiang, China.
PMID: 42052818 DOI: 10.31083/FBL47702
Abstract

Background: While the systemic metabolic role of Fibroblast Growth Factor 21 (FGF21) is well-established, its function in retinal homeostasis and its link to retinal diseases like age-related macular degeneration (AMD) and diabetic retinopathy (DR) remains poorly understood. This study investigated the impact of endogenous FGF21 deficiency on the retinal immune microenvironment.

Methods: Retinal structure was assessed in FGF21 KO and wild-type mice using spectral-domain optical coherence tomography. Transcriptomic profiles of the retina/choroid were analyzed by RNA-seq. Differentially expressed genes (DEGs) were identified (DESeq2, FDR <0.05), clustered, and interrogated by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Immune-cell composition was inferred with ImmuCellAI.

Results: FGF21 KO mice showed no overt retinal structural defects under baseline conditions. Nevertheless, 449 DEGs were identified (293 up, 156 down in knockout). Pathway analysis revealed significant enrichment of cytokine-cytokine receptor interaction, chemokine signaling, and Jak-STAT cascades. Immune deconvolution indicated a significant increase in M2-polarised macrophages (p < 0.01) without change in total macrophage number. Expression of key inflammatory mediators including Il1b was concordantly altered.

Conclusions: This work establishes endogenous FGF21 as a crucial local immunomodulator and defines a novel mechanistic link to retinal disease susceptibility, supporting its further exploration as a therapeutic target.

Keywords
FGF21; RNA-Seq; immunomodulation; macrophages; retina.
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