bims-mideyd 2025-10-12 papers

Cell Death Dis. 2025 Oct 06. 16(1): 692

Transferrin is a drug candidate for the treatment of dry age-related macular degeneration (AMD).

Jenny Youale, Karine Bigot, Thara Jaworski, Cécile Lebon, Anaïs Françon, Kimberley Delaunay, Romain Bénard, Thaïs De Bastard, Alejandra Daruich, Naël Kaddour, Thierry Bordet, Francine Behar-Cohen, Emilie Picard.

Dysregulation of iron homeostasis plays a crucial role in retinal diseases, contributing to oxidative stress, inflammation, and ferroptosis, key processes that drive the degeneration of the retinal pigment epithelium (RPE) and photoreceptors in age-related macular degeneration (AMD). Previous studies, though limited in patient numbers, have reported elevated iron levels in the aqueous humor, RPE, and Bruch's membrane of AMD patients. In this study, we aimed to confirm iron imbalance in a larger cohort of AMD patients and assess its correlation with disease stage. Elevated iron levels and a reduction in transferrin (TF) iron-binding capacity were observed in patients with early geographic atrophy (GA). RPE cells derived from human stem cells exhibited AMD-like features when exposed to iron overload or oxidized lipids. Treatment with TF appeared to restore aspects of iron homeostasis and reduce oxidative stress, mitochondrial damage, inflammation, complement activation, and ferroptosis in this model. These findings suggest that TF supplementation may represent a potential therapeutic strategy to help prevent or slow AMD progression.

DOI: https://doi.org/10.1038/s41419-025-07950-0

Cell Death Dis. 2025 Oct 06. 16(1): 687

HIF1 activity in photoreceptors drives type 3 neovascularization and retinal atrophy in a new mouse model of age-related macular degeneration.

Fredy Geiger, Thomas Heigl, Luca Merolla, Marcus Yong, Gabriele M Wögenstein, Larissa P Govers, Ioanna Tsioti, Antonia Fottner, Marijana Samardzija, Christian Grimm.

Morphological changes in the ageing eye impede oxygen delivery from the choroid to the outer retina causing tissue hypoxia, which activates a molecular response that adapts the transcriptomic fingerprint of the retina and retinal pigment epithelium (RPE). This response, orchestrated by hypoxia-inducible transcription factors (HIFs), leads to the production of pro-angiogenic factors and plays a critical role in the development and pathogenesis of age-related macular degeneration (AMD). To evaluate the specific contribution of HIF1 to this response we expressed a constitutively active form of HIF1A in rod photoreceptors of the adult mouse retina. This elicited a transcriptional response characterized by the upregulation of genes involved in cell death, inflammation and angiogenesis, all of which play an important role in AMD. The HIF1-mediated response in rods caused severe retinal degeneration, disruption of the RPE and retinal neovascularization. Pathological vessels originated from the deep vascular plexus and penetrated the RPE resembling type 3 macular neovascularization observed in over 20% of patients with neovascular AMD. Our study provides further evidence for the involvement of tissue hypoxia in the pathogenesis of AMD and highlights the potential of HIF1A as a therapeutic target.

DOI: https://doi.org/10.1038/s41419-025-08028-7

Free Radic Biol Med. 2025 Oct 06. pii: S0891-5849(25)01021-4. [Epub ahead of print]241 631-641

p66Shc silencing promotes aerobic glycolysis via signalling between the transcription factors NRF2 and HIF1-α.

Asad Lone, Reza Khazaee, Alexandra M Kozlov, Marc C J Courchesne, Karen Nygard, Dean H Betts, Robert C Cumming.

Alzheimer's disease (AD) is characterized by the progressive accumulation of toxic amyloid-β (Aβ) plaques in the brain, leading to oxidative stress, synaptic loss, and neuronal death. Despite intensive efforts, therapies targeting Aβ production or clearance have shown limited efficacy, highlighting the need for alternative strategies. A notable feature of AD is reduced cerebral glucose metabolism, which contributes to neurodegeneration. Interestingly, elevated aerobic glycolysis has been shown to protect central nervous system (CNS) cells from Aβ toxicity, yet the regulatory mechanisms underlying the metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis remain unclear. We previously found that silencing p66Shc, an adaptor protein involved in apoptosis and reactive oxygen species (ROS) production, enhances glycolysis, reduces mitochondrial ROS, and protects against Aβ-induced toxicity. Here, we investigated whether p66Shc modulates glycolysis through the Kelch-like ECH associated protein 1 (KEAP1) - nuclear erythroid 2-related factor 2 (NRF2) pathway. In the B12 glial-like cell line, p66Shc knockdown reduced KEAP1 levels, leading to stabilization of NRF2. Elevated NRF2 increased hypoxia-inducible factor 1α (HIF1α) expression, driving up glycolytic enzyme levels and glycolytic activity. Importantly, p66Shc depletion conferred protection against Aβ toxicity in an NRF2-dependent manner. Consistent with these findings, Western blot analysis of AD transgenic mouse brain tissues revealed increased p66Shc and KEAP1, and decreased NRF2 levels compared to wild-type mice. These findings reveal a previously unrecognized role for p66Shc in regulating CNS metabolism through the KEAP1-NRF2-HIF1α axis and link its expression to susceptibility to Aβ toxicity. Collectively, these results uncover a novel metabolic regulatory pathway in CNS cells and position p66Shc as a key modulator of energy metabolism and Aβ vulnerability in AD. Targeting this pathway may offer a novel metabolic approach for therapeutic intervention in AD.

Keywords: Alzheimer's disease (AD); Glycolysis; HIF1-α; KEAP1; NRF2; p66Shc

DOI: https://doi.org/10.1016/j.freeradbiomed.2025.10.007