Established a dual-stressor mouse model mimicking sleep loss and screen-induced light exposure.

Proved that short-term sleep deprivation exacerbates light-induced retinal damage.

Identified ferroptosis as the central convergent mechanism via transcriptomic profiling.

Validated Liproxstatin-1 as a potential intervention against stress-amplified retinal degeneration.

Sleep deprivation (SD) and excessive light exposure (LD) are increasingly prevalent stressors in modern life, yet their combined impact on retinal integrity remains unclear. This study investigates how SD amplifies LD-induced retinal injury and explores the mechanistic role of ferroptosis-a regulated, iron-dependent form of lipid peroxidation–driven cell death.

We established a dual-stressor mouse model with four groups: control, SD, LD, and SD + LD. Retinal structure and function were evaluated via OCT, ERG, histology, and behavioral tests. Mechanistic insights were obtained from transcriptomic profiling, immunostaining, electron microscopy, and pharmacological inhibition using Liproxstatin-1 (Lip-1).

While SD alone caused no overt damage, SD + LD synergistically exacerbated retinal degeneration. Transcriptomic and molecular analyses revealed pronounced ferroptosis activation in the SD + LD group-marked by reduced antioxidant defenses (↓GPX4, xCT, GCH1, FSP1), elevated lipid peroxidation (↑4-HNE, MDA, ALOX15, ACSL4), disrupted iron homeostasis (↑HO-1, ↓FPN, ↓FTH1), and mitochondrial shrinkage. Lip-1 treatment reversed these changes and preserved retinal function.

Short-term sleep deprivation exacerbated light-induced retinal injury by promoting ferroptosis, as indicated by disrupted antioxidant capacity, enhanced lipid peroxidation, and disturbed iron homeostasis. Treatment with Lip-1 substantially attenuated these changes.

Retinal degeneration

Sleep deprivation

Light damage

Ferroptosis

Oxidative stress

Dual-stressor model

© 2026 The Authors. Published by Elsevier Inc.