bims-mideyd 2026-10-11 papers

Toxicol Appl Pharmacol. 2026 Oct 09. pii: S0041-008X(26)00373-X. [Epub ahead of print] 118077

ATF3 inhibits retinal pigment epithelial cell injury by activating HSPA5:A mechanistic insight for diabetic retinopathy.

Xiang Li, Hongpei Cui, Xiaoyang Shi, Manli Li, Chao Niu, Yongfeng Gao.

Diabetic retinopathy (DR) is the leading cause of vision loss in working-age adults. Heat shock protein family A (Hsp70) member 5 (HSPA5) has been reported to be a core ferroptosis-related gene in DR, while its regulatory mechanism remains unclear. DEGs were screened from the GSE233164 dataset with strict thresholds (P < 0.01, |log2FC| > 3). Bioinformatics enrichment and PPI network analyses were performed to screen genes. Clinical samples from 49 DR patients and 49 healthy controls were used for external validation. HG-induced ARPE-19 cell models were established to evaluate cell viability, proliferation, apoptosis, oxidative stress, ferroptosis, and inflammation. The ATF3-HSPA5 transcriptional regulatory relationship was predicted by JASPAR and verified via ChIP and dual-luciferase assays. 171 DEGs were screened, and 39 core genes were retained for network analysis. HSPA5 was consistently downregulated in HG-stimulated ARPE-19 cells and DR clinical samples, with a high diagnostic AUC of 0.93. HG exposure triggered RPE cell dysfunction, oxidative damage, ferroptosis, and inflammation, all of which were significantly rescued by HSPA5 overexpression. ATF3 was also downregulated in DR models and clinical samples and positively correlated with HSPA5. Mechanistically, ATF3 directly bound and transcriptionally activated the HSPA5 promoter. Rescue experiments confirmed that HSPA5 knockdown completely abolished the protective effects of ATF3 against HG-induced cell injury and ferroptosis. ATF3 alleviates HG-induced retinal pigment epithelial cell injury and ferroptosis by transcriptionally activating HSPA5. The ATF3-HSPA axis represents a potential therapeutic target for DR.

Keywords: Activating transcription factor 3; Diabetic retinopathy; Ferroptosis; Heat shock protein family A (Hsp70) member 5; Retinal pigment epithelial cell

DOI: https://doi.org/10.1016/j.taap.2026.118077

J Cell Physiol. 2026 Oct;241(10): e70241

Sestrin1 Ameliorates Senescence and Mediates the Protective Effects of Exercise Against Hepatic Abnormality in C57BL/6J Mice.

Xuege Yang, Yuchen Zou, Xiuru Li, Zhili Rong, Yanmei Niu, Li Fu.

Liver aging is characterized by structural remodeling and functional decline, frequently driven by mitochondrial dysfunction and senescence-associated secretory phenotype (SASP). Sestrins (SESNs) are a family of stress-inducible proteins, among which Sestrin1 and Sestrin2 are crucial for maintaining metabolic and redox homeostasis, yet their specific involvement in hepatic senescence remains unclear. In the present study, in vivo experiments were performed using WT mice at young, middle, and old ages, together with aged Sestrin1-/- and Sestrin2-/- mice. The aged mice displayed multifaceted hepatic dysfunction, accompanied by a progressive, age-dependent decline of hepatic Sestrin1 and Sestrin2 expression. Intriguingly, hepatic cellular senescence, lipid deposition, oxidative stress and inflammation were significantly exacerbated in Sestrin1-/- mice compared to Sestrin2-/- and WT mice. To further explore the underlying mechanism, senescent AML12 cells overexpressing Sestrin1 were treated with or without mitochondrial division inhibitor-1 (Mdivi-1). Mechanistically, Sestrin1 preserved mitochondrial homeostasis by promoting mitochondrial fission via dynamin-related protein 1 (Drp1), a master regulator of mitochondrial fission, and curtailing the leakage of mitochondrial DNA (mtDNA) into the cytoplasm, profoundly suppressing the cGAS-STING pathway. However, these effects were abolished upon mitochondrial fission inhibition. Given that exercise training is a potent anti-aging strategy known to upregulate SESNs protein levels, we further demonstrated that Sestrin1 is indispensable for its hepatoprotective benefits. Collectively, our results identified that the Sestrin1/Drp1/cGAS-STING axis plays a pivotal role in liver aging and positioned Sestrin1 as a vital therapeutic target, serving as a key mediator of the anti-aging benefits of exercise training.

Keywords: Drp1; Sestrin1; cGAS/STING; exercise training; hepatic senescence; mitochondrial dysfunction; mtDNA

DOI: https://doi.org/10.1002/jcp.70241

Front Physiol. 2026 ;17 1953962

Applications of single-cell transcriptomics in glaucoma research: from the aqueous humor outflow pathway to retinal ganglion cell neurodegeneration.

Xiaolu Hao, Dajiang Wang, Zhaohui Li, Shaojun Wang.

Glaucoma is the leading cause of irreversible blindness worldwide, driven by progressive retinal ganglion cell (RGC) degeneration. While genetic and environmental risk factors have been identified, the cell-type-specific mechanisms underlying pathogenesis remain incompletely understood. Single-cell RNA sequencing (scRNA-seq) enables high-resolution analysis of cellular heterogeneity, developmental trajectories and intercellular communication networks. This review synthesizes recent scRNA-seq advances across two critical domains in glaucoma research: (1) aqueous humor outflow pathway (AHOP) physiology and pathology; (2) primary open-angle glaucoma (POAG) pathogenesis. We identify convergent themes, including mitochondrial dysfunction as a shared mechanism across subtypes, the central role of neuroinflammation in RGC degeneration, and the therapeutic potential of metabolic interventions. We further discuss challenges in translating animal models to human disease, integrating multi-species datasets, and resolving cell-type-specific susceptibility. Finally, we highlight emerging directions in spatial transcriptomics, multi-omics integration, and precision medicine.

Keywords: aqueous humor outflow pathway; glaucoma; mitochondrial dysfunction; neurodegeneration; neuroinflammation; retinal ganglion cells; single-cell RNA sequencing

DOI: https://doi.org/10.3389/fphys.2026.1953962

Redox Rep. 2026 Dec 31. 31(1): 2698189

Coordinated mitochondrial quality control underlies oxidative stress resilience in MUSE stem cells.

Domenico Aprile, Sura Hilal Ahmed Al-Sammarraie, Alessia Ambrosino, Mohd Shahzaib, Yesuf Siraj, Afshin Samiminemati, Nicola Alessio, Gianfranco Peluso, Giovanni Di Bernardo, Umberto Galderisi.

BACKGROUND: Reactive oxygen species (ROS) regulate stem-cell function, but sustained exposure causes oxidative damage, mitochondrial dysfunction and exhaustion. Multilineage-differentiating Stress-Enduring (MUSE) cells, a rare SSEA-3⁺ MSC subset, tolerate ROS-rich environments, although the mechanisms remain unclear.
METHODS: We compared MUSE, Non-MUSE (SSEA-3⁻) and MSCs after H₂O₂ exposure, assessing ROS clearance, mtDNA integrity, 8-oxo-dG, antioxidant and BER responses, mitochondrial morphology/function, mitophagy and biogenesis, with focus on the PGC-1α/NRF2 axis. Three independent biological replicates were analyzed by imaging, qPCR, flow cytometry and biochemical assays.
RESULTS: MUSE cells showed greater resistance to oxidative stress than MSCs and Non-MUSE cells. After H₂O₂, they displayed lower ROS accumulation (~15-25%), preserved mtDNA integrity, reduced 8-oxo-dG, rapid induction of antioxidant and BER-related genes, and maintenance of mitochondrial morphology, membrane potential and respiratory activity. MUSE cells also showed enhanced mitophagy, with >2-fold increased LAMP1-MitoTracker colocalization and induction of PINK1/phospho-Ub-S65, together with increased biogenesis, including ~45% higher COX-I/SDHA ratio, TFAM induction and PGC-1α activation at 48 h.
CONCLUSION: MUSE cells coordinate antioxidant defense, DNA repair, mitophagy and biogenesis through a remove-and-replace program that preserves mitochondrial function during oxidative stress.

Keywords: MUSE stem cells; NRF2; PGC-1α; mitochondrial DNA damage; mitochondrial biogenesis; mitochondrial quality control; mitophagy; oxidative stress; reactive oxygen species

DOI: https://doi.org/10.1080/13510002.2026.2698189

iScience. 2026 Oct 16. 29(10): 117640

B cells in the retinal pigment epithelium change with aging and IgM availability.

Sarah E Webster, Nicholas Deleon, Naomi L Tsuji, Daken Heck, Michael J Clemente, Nichol E Holodick.

Maintenance of the retina, the CNS tissue responsible for vision, is critical during aging. Historically considered immune privileged, the retina was thought to lack traditional immune components with resident glial cells maintaining tissue integrity. Emerging evidence suggests that immune suppression, rather than immune absence, governs retinal tolerance. Here, we identify B lymphocytes isolated from the retinal pigment epithelium (RPE), a CNS barrier niche, and show that their activation state and antibody repertoire are associated with secreted immunoglobulin M (IgM) availability and aging. In the absence of secreted IgM, B cells isolated from the RPE display a more activated phenotype and an altered B cell receptor repertoire, with age further modifying VH usage and CDR-H3 properties and expansion. Functionally, RPE B cells secrete antibodies following stimulation. These findings provide a foundation for understanding humoral regulation in CNS barrier tissues and mechanisms linking immune function to retinal aging and health.

Keywords: B cells; aging; retina

DOI: https://doi.org/10.1016/j.isci.2026.117640