Author: Gao, Yang ; Cheng, Chao ; Ai, Siming ; Lu, Rong ; Tang, Junjie ; Liu, Yaoming ; Li, Jinmiao ; Chen, Shuxia ; Wang, Yinghao ; Zhang, Ping ; Zhang, Zhihui ; Su, Shicai

The Warburg effect, a hallmark of cancer, describes the preference of cancer cells for glucose metabolism via aerobic glycolysis, leading to substantial lactate accumulation. However, the role of lactate metabolism in retinoblastoma, the primary intraocular malignancy in children, remains unclear. This study aimed to elucidate the gene expression profiles associated with lactate metabolism in retinoblastoma and their impact on tumorigenesis and ferroptosis resistance. The involvement of metabolic characteristics in retinoblastoma was analyzed by comparing single-cell RNA sequencing transcriptome profiles from normal retina tissues and retinoblastoma tissues from patient samples. The effects of lactate on retinoblastoma cell line viability and its mechanisms were examined both in vitro and in vivo. Single-cell RNA sequencing analysis revealed enhanced glycolysis in retinoblastoma cells and significant differences in lactate metabolism-related gene expression among various retinoblastoma cell types. Retinoblastoma cell lines with moderate lactate levels exhibited increased viability and resistance to ferroptosis induced by ferroptosis inducers. Additionally, lactate promoted the upregulation of monocarboxylate transporter 1 (MCT1), which facilitated lactate transport, in a dose-dependent manner in retinoblastoma cell lines. Knocking down MCT1 reduced both viability and ferroptosis resistance of retinoblastoma cell lines in a lactate-rich environment. In vivo, disrupting lactate transport through MCT1 inhibition suppressed retinoblastoma tumorigenesis and invasion in a mouse xenograft model, and this effect was reversed by the ferroptosis inhibitor liproxstatin-1. These findings highlighted the crucial role of lactate metabolism in retinoblastoma tumorigenesis and resistance to ferroptosis.

16 Apr 2025·ACS Chemical Neuroscience

Induction of Ferroptotic Cell Death by Neuromelanin Pigments in Dopaminergic Cells

Article

Author: Kaftan Öcal, Gizem ; Armagan, Güliz

Neuromelanin (NM) is an iron-rich, insoluble brown or black pigment that exhibits protective properties. However, its accumulation over time may render it a source of free radicals. In Parkinson's disease, dopaminergic neurons with the highest NM levels and increased iron content are preferentially vulnerable to degeneration. Considering NM's iron binding capacity and the critical role of iron in ferroptosis, we aimed to investigate the interplay between neuromelanin and ferroptosis in dopaminergic cells. We prepared two NM pigments: iron-free NM (ifNM) and iron-containing NM (Fe³⁺NM) and, exposed to cells. After verifying NM accumulation, cell viability was assessed in the absence or presence of antioxidants (NAC (1 mM), Trolox (100 μM)) and specific inhibitors of cell death types. Ferroptosis-related parameters, including lipid peroxidation byproducts (4-HNE), lipid ROS, glutathione, intracellular iron, GPX4, and ACSL4, and cellular iron metabolism-related proteins (TfR1, ferroportin, ferritin, IREB2) were evaluated following ifNM and Fe³⁺NM treatments, with or without Ferrostatin-1, Liproxstatin-1 and deferoxamine. Both NMs induced cell death via distinct mechanisms. Ferroptotic cell death by ifNM and Fe³⁺NM was reversed by ferrostatin-1 and NAC (p < 0.05). Significant alterations in lipid peroxidation, GPX4 levels, and iron metabolism were observed independent of NM's iron composition (p < 0.05). Ferritin levels increased following ifNM treatment, reflecting an adaptive response to iron overload, while Fe³⁺NM treatment led to ferritin depletion, possibly via ferritinophagy. Our findings reveal a distinct role of iron-rich and iron-free neuromelanin in modulating ferroptotic pathways, highlighting the potential of targeting neuromelanin-iron interactions as a therapeutic strategy to mitigate neuronal ferroptosis in Parkinson's disease.

01 Apr 2025·International Immunopharmacology

Oxidized low-density lipoprotein induced ferroptosis in nucleus pulposus cell contributes to intervertebral disc degeneration via LOX-1/NF-κB/NOX signal

Article

Author: Li, Xinhua ; Liu, Zhonghan ; Qi, Dongduo ; Huang, Yufeng ; Pan, Jie ; Wang, Diankai ; Wu, Desheng ; Li, Lijun

Oxidized low-density lipoprotein (oxLDL) activates the NF-κB signaling pathway through LOX-1, contributing to intervertebral disc degeneration (IVDD). Ferroptosis, a lipid peroxidation-driven cell death, is implicated in IVDD. This study investigates the role of ferroptosis in oxLDL-induced IVDD. Nucleus pulposus cells (NPCs) were treated with oxLDL, and ferroptosis and NF-κB p65 nuclear translocation were assessed. Bioinformatics analysis, silencing experiments, and inhibitors were used to validate the findings. In oxLDL-treated NPCs, LOX-1 and ferroptosis markers (MDA, Fe2+, lipid ROS) increased, while GSH decreased. These effects were mitigated by Liproxstatin-1 or shLOX-1. NF-κB p65 bound to LOX-1 and NOX1 promoters, forming a positive feedback loop. VAS2870 and Schisantherin A improved NPC viability and reduced ferroptosis. A mouse model showed worsening IVDD and ferroptosis over time. Clinical tissues revealed a strong correlation between LOX-1 and ferroptosis markers. oxLDL induces ferroptosis in NPCs via the LOX-1/NF-κB/NOX loop, advancing IVDD. Disrupting this loop in mice mitigated IVDD, highlighting the therapeutic potential of targeting this pathway.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Kidney Injury	Preclinical	China	Xiamen University	31 Jan 2024
Gram-Negative Bacterial Infections	Preclinical	Canada	McMaster University	11 May 2021

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