bims-mideyd 2025-03-16 papers

Nat Commun. 2025 Mar 13. 16(1): 2221

PNPLA6 regulates retinal homeostasis by choline through phospholipid turnover.

Takashi Ono, Yoshitaka Taketomi, Takayoshi Higashi, Hiroyasu Sato, Chika Mochizuki-Ono, Yuki Nagasaki, Takashi Ueta, Takashi Miyai, Suzumi M Tokuoka, Yoshiya Oda, Yasumasa Nishito, Tomio Ono, Choji Taya, Satoru Arata, Sumiko Watanabe, Tomoyoshi Soga, Tetsuya Hirabayashi, Makoto Aihara, Makoto Murakami.

Although mutations in human patatin-like phospholipase PNPLA6 are associated with hereditary retinal degenerative diseases, its mechanistic action in the retina is poorly understood. Here, we uncover the molecular mechanism by which PNPLA6 dysfunction disturbs retinal homeostasis and visual function. PNPLA6, by acting as a phospholipase B, regulates choline mobilization from phosphatidylcholine and subsequent choline turnover for phosphatidylcholine regeneration in retinal pigment epithelial cells. PNPLA6-driven choline is supplied from retinal pigment epithelial cells to adjacent photoreceptor cells to support their survival. Inhibition of this pathway results in abnormal morphology, proliferation, metabolism, and functions of retinal pigment epithelial and photoreceptor cells, and mice with retina-specific PNPLA6 deletion exhibit retinitis pigmentosa-like retinal degeneration. Notably, these abnormalities are entirely rescued by choline supplementation. Thus, PNPLA6 plays an essential role in retinal homeostasis by controlling choline availability for phospholipid recycling and provide a framework for the development of an ophthalmic drug target for retinal degeneration.

DOI: https://doi.org/10.1038/s41467-025-57402-8

Front Pharmacol. 2025 ;16 1543575

Melatonin protects retinal pigment epithelium cells against ferroptosis in AMD via the PI3K/AKT/MDM2/P53 pathway.

Ping Wu, Long Zhao, Yong Du, Jing Lu, Yuxia He, Qinxin Shu, Hui Peng, Xing Wang.

Introduction: Oxidative stress-prompted degeneration of the retinal pigment epithelium (RPE) notably contributes to the onset of age-related macular degeneration (AMD). However, the pathways leading to RPE deterioration and possible preventative strategies are not yet completely comprehended.
Methods: Ferroptosis was assayed through the evaluation of lipid peroxidation (C11-BODIPY and MDA), reactive oxygen species (ROS), transmission electron microscopy (TEM), iron content measurement, q-PCR, western blotting, and immunofluorescence. To assess the structure and retinal function of RPE in mice, ERG (electroretinography), OCT (optical coherence tomography), and H&E (hematoxylin and eosin) staining were employed. Network pharmacology methods were utilized to elucidate the potential mechanisms underlying melatonin's protective effects against ferroptosis in RPE cells in AMD. Genetic engineering techniques were applied to investigate the regulatory relationships among phosphatidylinositol 3-kinase (PI3K), protein kinase-B (AKT), murine double minute-2 (MDM2), protein 53 (P53), and solute carrier family 7 member 11 (SLC7A11). In vitro knockdown experiments of MDM2 were conducted to explore its regulatory role in ferroptosis within RPE cells.
Results: Aβ1-40 can trigger ferroptosis in RPE cells. Melatonin can inhibit the oxidative stress and ferroptosis induced by Aβ1-40 in RPE cells. Melatonin exhibits a protective effect on Aβ1-40-induced AMD, significantly improving the structure of the mouse retina and RPE layer, and facilitating the restoration of visual function. Network pharmacology methods revealed that the potential targets of melatonin in AMD are closely related to ferroptosis, and indicated that the predominant pathways are significantly associated with the PI3K/AKT/MDM2/P53 signaling pathway. Knocking down the specific expression of MDM2 can significantly weaken the inhibitory effect of melatonin on oxidative stress and ferroptosis.
Discussion: Melatonin can suppress cell death by ferroptosis in RPE via the PI3K/AKT/MDM2/P53 pathway, thereby preventing and decelerating the progression of AMD.

Keywords: Aβ1-40; age-related macular degeneration; ferroptosis; melatonin; retinal pigment epithelium

DOI: https://doi.org/10.3389/fphar.2025.1543575

Diabet Med. 2025 Mar 11. e70014

LncRNA CASC2 mediates SOCS6 mRNA stabilization via U2AF2 recruitment to modulate macrophage polarisation in diabetic retinopathy.

Fan Xiao, Feipeng Wu, Peipei Zhong, Tian Hu, Rong Luo.

BACKGROUND: Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes and a leading cause of vision loss among diabetic individuals. Retinal pigment epithelium (RPE) cells play a crucial role in the pathophysiology of DR by releasing cytokines and exosomal cargo, such as long non-coding RNAs (lncRNAs), that modulate local immune responses, maintain retinal immune homeostasis and influence macrophage polarisation. Recent studies suggest that lncRNA cancer susceptibility candidate 2 (CASC2) may be involved in the regulation of DR progression. However, the regulatory mechanisms linking CASC2 with RPE cells and its role in macrophage polarisation remain insufficiently understood.
METHODS: Various types of cells, including human retinal pigment epithelial cells (ARPE-19), THP-1 monocytes and additional retinal cell lines, were cultured under normal glucose and high glucose conditions. ARPE-19 cells were exposed to oxidative stress, inflammatory stimulation, or hypoxic conditions. Plasma and aqueous humour samples were collected from DR patients and diabetic controls. Exosomes were extracted from AREP-19 cells and characterised. Various gene and protein expression analyses were performed using techniques including quantitative reverse transcription polymerase chain reaction, Western blot, immunofluorescence, flow cytometry, enzyme-linked immunosorbent assay, and histological staining. Cell proliferation and migration were assessed using Cell Counting Kit-8 assays and Transwell migration assays, respectively. The interactions among CASC2, suppressor of cytokine signalling 6 (SOCS6), and U2 small nuclear RNA auxiliary factor 2 (U2AF2) were explored using RNA immunoprecipitation and dual-luciferase reporter assays. An in vivo diabetic rat model was established.
RESULTS: lncRNA CASC2 expression levels were significantly lower in plasma and aqueous humour from DR patients compared to those from diabetic patients without retinopathy. Overexpression of CASC2 significantly attenuated DR and inflammatory damage both in vitro and in vivo. We demonstrated that exosomal CASC2 from ARPE-19 cells mediated macrophage polarisation by inhibiting M1 polarisation and promoting M2 polarisation. Our findings suggest that CASC2 regulates this polarisation through the stabilisation of SOCS6 mRNA via U2AF2.
CONCLUSION: CASC2 derived from RPE cells was transported to macrophages, inducing M2 polarisation by stabilising SOCS6 mRNA through the recruitment of U2AF2. This research may provide a foundation for developing novel therapeutic strategies for DR.

Keywords: SOCS6; U2AF2; diabetic retinopathy; lncRNA CASC2; macrophage polarisation

DOI: https://doi.org/10.1111/dme.70014

Int J Mol Sci. 2025 Mar 05. pii: 2334. [Epub ahead of print]26(5):

Sodium Iodate-Induced Ferroptosis in Photoreceptor-Derived 661W Cells Through the Depletion of GSH.

Chao Chen, Han Wang, Jiuyu Yang, Bi Zhao, Yutian Lei, Hanqiao Li, Kunhuan Yang, Benying Liu, Yong Diao.

Oxidative stress-induced photoreceptor cell death is closely associated with the etiology of age-related macular degeneration (AMD), and sodium iodate (SI) has been widely used as an oxidant stimulus in AMD models to induce retinal pigment epithelium (RPE) and photoreceptor cell death. However, the mechanism underlying SI-induced photoreceptor cell death remains controversial and unclear. In this study, we elucidate that ferroptosis is a critical form of cell death induced by SI in photoreceptor-derived 661W cells. SI disrupts system Xc-, leading to glutathione (GSH) depletion and triggering lipid peroxidation, thereby promoting ferroptosis in photoreceptor-derived 661W cells. Additionally, SI enhances intracellular Fe2+ levels, which further facilitates reactive oxygen species (ROS) accumulation, making the 661W cells more susceptible to ferroptosis. Exogenous GSH, as well as specific inhibitors of ferroptosis such as Fer-1 and antioxidants like NAC, significantly attenuate SI-induced ferroptosis in photoreceptor-derived 661W cells. These findings provide new insights into the mechanisms of ferroptosis as a key pathway in SI-induced photoreceptor-derived 661W cell death.

Keywords: GSH; ferroptosis; photoreceptor; sodium iodate

DOI: https://doi.org/10.3390/ijms26052334

Int J Mol Sci. 2025 Feb 21. pii: 1858. [Epub ahead of print]26(5):

C/EBP Homologous Protein Expression in Retinal Ganglion Cells Induces Neurodegeneration in Mice.

William C Mayhew, Balasankara Reddy Kaipa, Linya Li, Prabhavathi Maddineni, Yogapriya Sundaresan, Abbot F Clark, Gulab S Zode.

The progressive loss of retinal ganglion cell (RGC) axons leading to irreversible loss of vision is the pathological hallmark of glaucoma. However, the pathological mechanisms of RGC degeneration are not completely understood. Here, we investigated the role of chronic endoplasmic reticulum (ER) stress in glaucomatous neurodegeneration. To evaluate whether chronic ER stress-induced transcriptional factors, activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) are induced in RGCs; we utilized human donor tissue and the microbead occlusion model of glaucoma. Additionally, we performed the intravitreal injection of adeno-associated virus (AAV) 2 to express CHOP selectively in RGCs in C57BL/6 mice and evaluated its effect on RGC function and structure by pattern electroretinogram (PERG) and whole-mount retina staining with the RBPMS antibody. Here, we report that the ATF4-CHOP pathway is activated in the retinas of human glaucoma donor eyes and a mouse model of ocular hypertension. Further, the expression of CHOP in RGCs led to a significant loss of function, as evidenced by reduced PERG. Notably, the expression of CHOP in the retina induced a significant structural loss of RGCs within 15 weeks of injection. Altogether, our studies indicate that the expression of CHOP in RGCs leads to neurodegeneration in mice.

Keywords: ATF4; CHOP; ER stress; glaucoma; neurodegeneration; retinal ganglion cells

DOI: https://doi.org/10.3390/ijms26051858

Cell Death Dis. 2025 Mar 08. 16(1): 163

Menin maintains lysosomal and mitochondrial homeostasis through epigenetic mechanisms in lung cancer.

Jun-Bo Yuan, Gui-Xin Gu, Bang-Ming Jin, Qing Han, Bing-Hui Li, Li Zhang, Bin Xu, Xuan Zhu, Guang-Hui Jin.

Lysosome-mediated autophagy (including mitophagy) is crucial for cell survival and homeostasis. Although the mechanisms of lysosome activation during stress are well recognized, the epigenetic regulation of lysosomal gene expression remains largely unexplored. Menin, encoded by the MEN1 gene, is a chromatin-related protein that is widely involved in gene transcription via histone modifications. Here, we report that menin regulates the transcription of specific lysosomal genes, such as CTSB, CTSE, and TFE3, through MLL-mediated H3K4me3 reprogramming, which is necessary for maintaining lysosomal homeostasis. Menin also directly controls the expression of SQSTM1 and MAP1LC3B to maintain autophagic flux in a manner independent of AMPK/mTORC1 pathways. Furthermore, loss of menin led to mitochondrial dysfunction, elevated levels of reactive oxygen species (ROS), and genome instability. In genetically engineered mouse models, Men1 deficiency resulted in severe lysosomal and mitochondrial dysfunction and an impaired self-clearance ability, which further led to metabolite accumulation. SP2509, a histone demethylase inhibitor, effectively reversed the downregulation of lysosomal and mitochondrial genes caused by loss of Men1. Our study confirms the previously unrecognized biological and mechanistic importance of menin-mediated H3K4me3 in maintaining organelle homeostasis.

DOI: https://doi.org/10.1038/s41419-025-07489-0