Biochimica et biophysica acta. Molecular cell researchJul 21, 2026

Lack of RSL1D1 weakens iron storage and triggers cell death and aging in eye support cells in diabetic retinopathy

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 23, 2026

Abstract

RSL1D1 and FTH1 expression were significantly reduced in the retinal pigment epithelium of diabetic mice.

RSL1D1 is an RNA-binding protein that may modulate senescence and ferroptosis in diabetic retinopathy.
Downregulation of RSL1D1 is associated with increased cellular senescence and disrupted iron balance, leading to ferroptosis in retinal pigment epithelium cells.
High glucose treatment reduces the interaction between RSL1D1 protein and FTH1 mRNA, potentially affecting FTH1 stability.
Overexpression of RSL1D1 enhances the interaction with FTH1 mRNA, which may help stabilize its expression.
FTH1 knockdown can compromise the protective effects of RSL1D1 overexpression on senescence and ferroptosis in retinal pigment epithelium cells.

Simplified

Ribosomal L1 domain-containing protein 1 (RSL1D1) is an RNA-binding protein that relates to senescence. Nevertheless, the mechanism of RSL1D1 in modulating senescence and ferroptosis in diabetic retinopathy (DR) remains undefined. The DR mice were developed by intraperitoneal injection of STZ, and AAV targeting RPE was used for gene intervention. ARPE-19 cells were infected using oe-RSL1D1 and sh-FTH1 lentivirus before 30 mM high glucose (HG) exposure. Cell damage was assessed by measuring the expression of senescence and ferroptosis markers in ARPE-19 cells, along with oxidative stress indicators and Fe²⁺ levels. RSL1D1 and FTH1 expression were significantly reduced in the retinal pigment epithelium (RPE) layer of diabetic mice and HG-induced ARPE-19 cells. Downregulation of RSL1D1 led to RPE cell senescence and dysregulated iron homeostasis-induced ferroptosis. HG treatment reduced the interaction between RSL1D1 protein and FTH1 mRNA in ARPE-19 cells, while RSL1D1 overexpression enhanced this interaction, thereby stabilizing FTH1 mRNA expression. The alleviating effects of RSL1D1 overexpression on retinal pigment epithelium cell senescence and ferroptosis in vitro and in vivo were compromised by FTH1 knockdown. Overall, this study unveils a posttranscriptional regulation of FTH1 by RSL1D1 and uncovers the implication of RSL1D1/FTH1 in cellular senescence and ferroptosis in DR.

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Lack of RSL1D1 weakens iron storage and triggers cell death and aging in eye support cells in diabetic retinopathy

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