bims-mideyd 2025-06-15 papers

Redox Biol. 2025 Jun 06. pii: S2213-2317(25)00229-0. [Epub ahead of print]85 103716

Long-term senolytic therapy with Dasatinib and Quercetin alleviates lipofuscin-dependent retinal degeneration in mice.

Bo Yang, Kunhuan Yang, Ruitong Xi, Shiying Li, Jingmeng Chen, Yalin Wu.

Dry age-related macular degeneration (AMD) is one of the common blinding eye diseases, with pathological hallmarks of lipofuscin accumulation, neuroretina atrophy and retinal pigment epithelium (RPE) degeneration. Currently, there are no effective interventions for dry AMD. Although there is already evidence suggesting a link between cellular senescence and age-related diseases, it is still unclear whether long-term senolytic therapy with Dasatinib and Quercetin (D + Q) can slow the progression of dry AMD and ultimately prevent retinal structural damage and function loss. Mice lacking the Abca4 and Rdh8 genes (Abca4-/-Rdh8-/- mice) are a preclinical model of dry AMD. In this study, we performed a 4-month senolytic therapy with D + Q on 4-month-old Abca4-/-Rdh8-/- mice. Abca4-/-Rdh8-/- mice at the age of 8 months showed obvious retinal degeneration, along with RPE senescence, lysosomal alkalinization, lipofuscin accumulation and oxidative stress. Importantly, the long-term D + Q regimen significantly alleviated the degeneration of retinal structures and function in 8-month-old Abca4-/-Rdh8-/- mice, and it effectively repressed cellular senescence, lysosomal alkalinization, lipofuscin accumulation and oxidative stress in the RPE. This study is the first to demonstrate the effect of long-term intervention with senolytics D + Q on dry AMD. Overall, these findings highlight the potential of long-term senolytic treatment as an intervention for dry AMD.

DOI: https://doi.org/10.1016/j.redox.2025.103716

Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2416046122

Feedback regulation between histone lactylation and ALKBH3-mediated glycolysis regulates age-related macular degeneration pathology.

Ying Wang, Yi-Chen Zhang, Zi-Qin Ding, Shi-Yao Xu, Ye-Ran Zhang, Hong-Jing Zhu, Chang Huang, Jia-Nan Wang, Meidong Zhu, Jiang-Dong Ji, Biao Yan, Qing-Huai Liu, Xue Chen.

Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly. It is characterized by degeneration of the retinal pigment epithelium (RPE), which can develop into choroidal neovascularization (CNV) to cause severe and rapid vision loss. Preventing this progression might help save vision, but the exact mechanisms remain unclear. In this study, using clinical AMD samples and the gene knockout mice, we reported that the m1A eraser ALKBH3 reshaped retinal metabolism to promote this progression. In RPE, the dm1ACRISPR system demonstrated that ALKBH3 demethylated the rate-limiting glycolytic enzyme HK2 to activate glycolysis, resulting in excess lactate production. This lactate promoted histone lactylation at H3K18, which in turn bound to ALKBH3 to amplify its transcription, establishing a positive feedback loop. The ALKBH3 inhibitor HUHS015 disrupted this loop, effectively mitigating RPE degeneration. Furthermore, ALKBH3 directly targeted the proangiogenic factor VEGFA to modulate the metabolic cross-talk between RPE and choroidal capillaries, thus promoting CNV. HUHS015 inhibited CNV synergistically with the anti-VEGF drug Aflibercept. Overall, our study provides critical insights into the molecular mechanisms and metabolic events that facilitates the progression from RPE degeneration to CNV in AMD, laying the groundwork for new treatments of age-related retinal disorders.

Keywords: ALKBH3; N1-methyladenosine (m1A); age-related macular degeneration (AMD); glycolysis; retinal pigment epithelium (RPE)

DOI: https://doi.org/10.1073/pnas.2416046122

World J Stem Cells. 2025 May 26. 17(5): 103100

Stem cell therapy for retinal pigment epithelium disorders.

Francesco Saverio Sorrentino, Francesco Parmeggiani, Lorenzo Gardini, Luigi Fontana, Mutali Musa, Caterina Gagliano, Marco Zeppieri.

Retinal pigment epithelium (RPE) dysfunction is involved in the advancement of numerous degenerative retinal illnesses, such as age-related macular degeneration and hereditary retinal abnormalities. Transplantation of RPE produced from stem cells has emerged as a promising therapeutic strategy to restore retinal function and prevent vision loss. However, other obstacles impede its clinical application, including immunological rejection, cell viability, functional integration, and the necessity for consistent differentiation techniques. This review offers a thorough examination of the molecular processes regulating RPE integrity, investigates recent progress in stem cell-derived RPE therapeutics, and addresses significant challenges to their broad implementation. Furthermore, we emphasize prospective avenues intended to enhance the safety, efficacy, and enduring success of RPE transplantation in clinical environments.

Keywords: Cell transplantation; Molecular stem cell mechanisms; Retinal degeneration; Retinal pigment epithelium; Stem cell therapy

DOI: https://doi.org/10.4252/wjsc.v17.i5.103100