Interrogating mediators of single-cell transcriptional changes in the acute damaged cerebral cortex: Insights into endothelial-astrocyte interactionsde Jager, Soliman, Theus
Mol Cell Neurosci (2025) 133, 104003
Abstract: Traumatic brain injury (TBI) induces complex cellular and molecular changes, challenging recovery and therapeutic development. Although molecular pathways have been implicated in TBI pathology, the cellular specificity of these mechanisms remains underexplored. Here, we investigate the role of endothelial cell (EC) EphA4, a receptor tyrosine kinase receptor involved in axonal guidance, in modulating cell-specific transcriptomic changes within the damaged cerebral cortex. Utilizing single-cell RNA sequencing (scRNA-seq) in an experimental TBI model, we mapped transcriptional changes across various cell types, with a focus on astrocytes and ECs. Our analysis reveals that EC-specific knockout (KO) of EphA4 triggers significant alterations in astrocyte gene expression and shifts predominate subclusters. We identified six distinct astrocyte clusters (C0-C5) in the damaged cortex including as C0-Mobp/Plp1+; C1-Slc1a3/Clu+; C2-Hbb-bs/Hba-a1/Ndrg2+; C3-GFAP/Lcn2+; C4-Gli3/Mertk+, and C5-Cox8a+. We validate a new Sox9+ cluster expressing Mertk and Gas, which mediates efferocytosis to facilitate apoptotic cell clearance and anti-inflammatory responses. Transcriptomic and CellChat analyses of EC-KO cells highlights upregulation of neuroprotective pathways, including increased amyloid precursor protein (APP) and Gas6. Key pathways predicted to be modulated in astrocytes from EC-KO mice include oxidative phosphorylation and FOXO signaling, mitochondrial dysfunction and ephrin B signaling. Concurrently, metabolic and signaling pathways in endothelial cells-such as ceramide and sphingosine phosphate metabolism and NGF-stimulated transcription-indicate an adaptive response to a metabolically demanding post-injury hypoxic environment. These findings elucidate potential interplay between astrocytic and endothelial responses as well as transcriptional networks underlying cortical tissue damage.Copyright © 2025 Elsevier Inc. All rights reserved.
Regulation of inflammatory responses: Harnessing the Ruan Mai Jian targeting of EphA2/ephrinA1 pathway to enhance atherosclerosis ameliorationZhao, Zhang, Wang
et alPhytomedicine (2025) 138, 156398
Abstract: Atherosclerosis is a major contributor to global cardiovascular morbidity and mortality, driven by the chronic inflammatory proliferation of vascular smooth muscle cells (VSMCs), which destabilizes atherosclerotic plaques. The EphA2/ephrinA1 signaling pathway plays a critical role in modulating VSMC inflammatory responses, making it an attractive therapeutic target. However, the clinical application of EphA2 inhibitors remains limited due to safety concerns. Ruan Mai Jian (RMJ), a traditional Chinese herbal medicine, has demonstrated potential efficacy in treating atherosclerosis, though its precise mechanisms remain insufficiently characterized. To date, no study has investigated a Chinese medicine compound capable of regulating atherosclerotic inflammatory responses via the EphA2/ephrinA1 pathway. This study aims to determine whether RMJ treats atherosclerosis both in vivo and in vitro by modulating the EphA2/ephrinA1 pathway, while evaluating its potential hepatic and renal toxicity.A combination of in vivo (ApoE-/- murine model) and in vitro studies was employed to investigate the effects of RMJ on atherosclerotic progression, inflammatory markers, and VSMC function.ApoE-/- mice were fed a high-fat diet to induce atherosclerosis and subsequently treated with RMJ at varying doses. Serum lipid levels, inflammatory cytokines (TNF-α, IL-6, IL-1β), and plaque morphology were analyzed. Immunohistochemical and Western blot analyses were performed to assess the modulation of the EphA2/ephrinA1 pathway. VSMC proliferation and migration assays were conducted to evaluate the effects of RMJ on cellular behavior in vitro.RMJ treatment significantly attenuated serum lipid levels, reduced systemic inflammation, and stabilized atherosclerotic plaques by increasing collagen content and decreasing lipid deposition. RMJ downregulated EphA2 expression and upregulated ephrinA1, effectively inhibiting VSMC proliferation and migration through suppression of the AKT1/ERK1/2 signaling cascade. Importantly, no hepatic or renal toxicity was observed in treated mice, indicating a favorable safety profile.RMJ demonstrates significant therapeutic potential for the treatment of atherosclerosis, primarily through modulation of the EphA2/ephrinA1 signaling pathway, resulting in reduced inflammation and VSMC proliferation. Its efficacy, combined with the absence of hepatotoxicity or nephrotoxicity, highlights RMJ as a promising candidate for further investigation as a novel therapeutic agent for atherosclerotic cardiovascular disease.Copyright © 2025 Elsevier GmbH. All rights reserved.
Ephrin A1 functions as a ligand of EGFR to promote EMT and metastasis in gastric cancerLi, Sun, Cui
et alEMBO J (2025) 44 (5), 1464-1487
Abstract: Distant metastasis is the major cause of gastric cancer mortality, and epidermal growth factor receptor (EGFR) activation plays critical roles in gastric cancer dissemination. However, EGFR targeting therapies in gastric cancer show only marginal effects, and the molecular mechanisms of oncogenic EGFR signaling remain poorly defined. Here, we report Ephrin A1 as a novel ligand of EGFR in gastric cancer. Ephrin A1 facilitates colonization and metastasis of gastric cancer cells in vitro and in vivo via inducing epithelial-mesenchymal transition (EMT). Ephrin A1 directly interacts with EGFR and induces EGFR dimerization, phosphorylation and activation of downstream signaling. Ephrin A1-induced EMT can be rescued by EGFR signaling inhibitors or knockout of EGFR, but not depletion of its classical receptor EphA2. Moreover, Ephrin A1 protein level correlates with EGFR phosphorylation levels in gastric cancer patients. Collectively, our work uncovers Ephrin A1 as a functional ligand of EGFR and highlights the potential role of the Ephrin A1/EGFR/EMT regulatory axis in cancer metastasis.© 2025. The Author(s).
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