bims-mideyd 2026-06-14 papers

Front Pharmacol. 2026 ;17 1803187

Salvianolic acid a attenuates sodium iodate-induced ferroptosis in age-related macular degeneration models via the SLC7A11/GPX4 axis.

Jing Wu, Li Luo, Yulu Huang, Jun Li, Xia Li.

Introduction: Oxidative stress-mediated retinal pigment epithelial (RPE) cell injury is a key pathological feature of age-related macular degeneration (AMD). Ferroptosis-an iron-dependent form of regulated cell death driven by lipid peroxidation-has been increasingly identified as a critical executor of RPE degeneration and a key pathogenic mechanism in AMD. This study aimed to investigate the mechanism by which Salvianolic acid A (SalA) alleviates ferroptosis in RPE cells under sodium iodate (NaIO3)-induced damage.
Methods: Using in vitro (ARPE-19 cells) and in vivo (mice) NaIO3-induced injury models. We assessed cell viability, ferroptosis markers (iron, lipid peroxidation, glutathione), mitochondrial ultrastructure, and key protein expression via biochemical assays, flow cytometry, transmission electron microscopy, and Western blotting.
Results: SalA pretreatment effectively mitigated NaIO3-induced ferroptosis, reducing lipid peroxidation, iron overload, and mitochondrial damage. Mechanistically, SalA upregulated the key ferroptosis regulators SLC7A11 and GPX4. Critically, this protection was significantly attenuated by the SLC7A11 inhibitor erastin, confirming the essential role of this axis. In mice, SalA attenuated NaIO3-induced retinal structural damage and enhanced SLC7A11/GPX4 expression in retina tissues.
Conclusion: This study identifies SalA as a potent inhibitor of ferroptosis in RPE cells, primarily through activation of the SLC7A11/GPX4 axis. These findings suggest that SalA may hold therapeutic potential for AMD and provide a preliminary pharmacological basis for further exploration in retinal degenerative diseases.

Keywords: SLC7A11/GPX4 pathway; age-related macular degeneration; ferroptosis; retinal pigment epithelium; salvianolic acid A

DOI: https://doi.org/10.3389/fphar.2026.1803187

Am J Pathol. 2026 Jun 11. pii: S0002-9440(26)00167-7. [Epub ahead of print]

Metformin activates AMPK-TFEB signaling to restore lysosomal and mitochondrial homeostasis and suppress EMT in oxidative stress-injured retinal pigment epithelium.

Sumin Son, Yoonha Kim, Kyoung-Jin Jang, Dong-Eun Kim.

Disruption of lysosomal homeostasis and accumulation of dysfunctional mitochondria contribute to degenerative pathologies including age-related macular degeneration (AMD). Here, we investigated how inhibition of autophagic lysosome reformation (ALR) alters lysosomal dynamics, mitophagy, and downstream stress signaling in retinal pigment epithelial (RPE) cells, and whether these changes are pharmacologically reversible. In ARPE-19 cells, ALR inhibition by nocodazole or siRNA-mediated depletion of kinesin-1 (UKHC) and dynamin-2 (DNM2) induced enlarged lysosomes with reduced degradative capacity, impaired mitophagic turnover, and accumulation of dysfunctional mitochondria. ALR blockade increased reactive oxygen species (ROS) and cytosolic Ca2+, promoted activation and mitochondrial translocation of protein kinase C (PKC), and triggered phosphorylation of glycogen synthase kinase-3β with subsequent stabilization of SNAIL, consistent with epithelial-to-mesenchymal transition (EMT). Metformin restored lysosomal homeostasis by activating AMPK and enhancing transcription factor EB (TFEB)-dependent lysosome biogenesis, thereby improving autophagic flux, limiting ROS/Ca2+ accumulation, suppressing PKC activation, and attenuating EMT-associated marker changes. In a sodium iodate-induced oxidative injury model, metformin preserved RPE microtubule architecture and reduced lysosomal and mitochondrial abnormalities. Although these findings rely on a prolonged monolayer culture system and an acute injury model, they support a protective role for AMPK-TFEB-driven lysosome restoration in RPE stress resilience and suggest lysosome-directed repurposing potential for metformin in degenerative retinal disease.

Keywords: Autophagic lysosome reformation (ALR); Epithelial–mesenchymal transition (EMT); Lysosomal homeostasis; Mitochondrial dysfunction; Retinal pigment epithelium (RPE)

DOI: https://doi.org/10.1016/j.ajpath.2026.05.009

Sci Rep. 2026 Jun 08.

Arsenic exposure promotes retinal pigment epithelium dysfunction and oxidative stress via NF-κB pathway.

Lan Zhong, Yumei Tao, Liming Tao.

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults and is closely linked to dysfunction of the retinal pigment epithelium (RPE). Arsenic (As), a ubiquitous environmental toxicant present in drinking water and food, has been implicated in multiple chronic diseases. However, its role in AMD remains unclear. This study aimed to investigate the effects of As exposure on AMD-related retinal injury and to elucidate the underlying molecular mechanisms using in vitro and in vivo experimental models. ARPE-19 cells were treated with sodium iodate (NaIO3) to establish an AMD-like injury model and then exposed to 1 µM As to assess cell viability, apoptosis, oxidative stress, mitochondrial dysfunction, autophagy-related changes and epithelial barrier integrity. Evaluation of NF-κB signaling pathway activation using molecular biology techniques. In vivo, a NaIO3-induced mouse model of AMD was established and combined with As exposure at 25 ppm to to validate retinal damage, oxidative stress, mitochondrial impairment, and barrier dysfunction. ShRNA-mediated silencing of NF-κB was further used to confirm pathway involvement. As exposure significantly aggravated NaIO3-induced injury in ARPE-19 cells and mouse retinas. In vitro, As reduced cell viability and enhanced apoptosis, inflammatory responses, reactive oxygen species accumulation, mitochondrial dysfunction, autophagy dysregulation, and epithelial barrier disruption. In vivo, As exacerbated retinal structural damage, increased oxidative stress, impaired mitochondrial function, and further reduced the expression of tight junction proteins in NaIO3-treated mice. Mechanistically, these effects were accompanied by sustained activation of the NF-κB signaling pathway. ShRNA-mediated silencing of NF-κB partially reversed As-induced retinal damage in vivo. Our study found that As exposure exacerbated AMD-like retinal degeneration via NF-κB pathway. These findings identified As as a potentially modifiable environmental risk factor for AMD and suggested that individuals in As-endemic regions may benefit from targeted retinal screening. Moreover, NF-κB pathway targets inhibition emerged as a candidate strategy for mitigating As-exacerbated retinal injury.

Keywords: Age-related macular degeneration; As; NF-κB pathway; RPE

DOI: https://doi.org/10.1038/s41598-026-55608-4

Cell Signal. 2026 Jun 12. pii: S0898-6568(26)00325-6. [Epub ahead of print] 112670

The role of TRAF6 in regulating MAP3K7/P38/MAPK pathway in the epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy.

Zhen Chen, Zhengrong Yang, Zhongyin Hu, Mingshu Lei, Qian Li, Weina Zhang, Lin Chen, Yuhan Su, Ninghua Ni.

Proliferative vitreoretinopathy (PVR) is a major cause of blindness. Surgery remains the primary clinical intervention, but its outcomes are frequently unsatisfactory. A deeper understanding of PVR pathophysiology is therefore essential for developing new treatments. TRAF6 is a multifunctional intracellular adaptor protein that regulates diverse biological processes, yet its role in PVR is unknown. Here, we investigated the function of TRAF6 in PVR and its downstream mechanisms using a mouse model and ARPE-19 cells. The results demonstrated that TRAF6 expression was upregulated in the retinas of PVR model mice and in ARPE-19 cells. Knockdown of TRAF6 alleviated PVR progression in mice by suppressing inflammation and the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells. Conversely, TRAF6 overexpression in ARPE-19 cells exacerbated TGF-β1-induced EMT. Mechanistically, TRAF6 positively regulated MAP3K7 expression via a protein-protein interaction. Knockdown of TRAF6 inhibited P38/MAPK signaling pathway activation by reducing MAP3K7 expression. Furthermore, knockdown of TRAF6 attenuated the promoting effect of MAP3K7 overexpression on TGF-β1-induced EMT in RPE cells. In conclusion, TRAF6 knockdown protects against PVR in mice by inhibiting the MAP3K7 and p38 MAPK pathways.

Keywords: Epithelial-mesenchymal transition; MAP3K7; Proliferative vitreoretinopathy; Retinal pigment epithelial cells; TRAF6

DOI: https://doi.org/10.1016/j.cellsig.2026.112670

Clin Exp Ophthalmol. 2026 Jun 07.

Interpreting Hyperreflective Foci in Age-Related Macular Degeneration: A Critical Review of Cell Origins, Evolving Terminology and Clinical Utility.

Thomas Desmond, Hemal Mehta, Weng Sehu, Svetlana Cherepanoff.

BACKGROUND: Hyperreflective foci identified on optical coherence tomography are promising biomarkers in age-related macular degeneration. However, their clinical application is limited by inconsistent definitions and ongoing uncertainty regarding their cellular origin. This review critically evaluates the evidence underlying hyperreflective foci definitions, examines competing hypotheses of cellular origin, and assesses their clinical utility.
METHODS: A structured critical review was conducted using a systematic search of MEDLINE and Scopus in July 2025, identifying 164 publications reporting hyperreflective foci in age-related macular degeneration. Eligible studies included clinical imaging, clinicopathological, and histological investigations. Given substantial heterogeneity in study design and outcome measures, findings were synthesised interpretively across three domains: imaging definitions, cellular origin, and clinical associations.
RESULTS: Clinical OCT definitions for hyperreflective foci were heterogeneous across studies. Histologically, hyperreflective foci correspond to pigment-laden epithelioid cells that consistently express monocyte/macrophage markers (CD68, CD163, IBA1) and lack retinal pigment epithelium markers (RPE65, peropsin). These cells are interpreted as pigment-containing macrophages that have ingested RPE-derived material, or as transdifferentiated RPE cells. Clinically, increasing hyperreflective foci burden is associated with disease severity, progression to geographic atrophy, and localised functional deficits, although associations with neovascular conversion and treatment response are inconsistent.
CONCLUSIONS: The available evidence suggests hyperreflective foci are pigment-containing immune cells, although altered or displaced retinal pigment epithelium cells may also be involved, and independent replication is required. Interpreting hyperreflective foci within this biological context may refine their role in disease monitoring and risk stratification. Establishing consensus imaging criteria, grounded in cellular identity, will be important for clinical translation.

Keywords: CD47; age‐related macular degeneration (AMD); biomarker; epithelial‐mesenchymal transition; histology; hyperreflective foci (HRF); immunohistochemistry; melanophage; optical coherence tomography

DOI: https://doi.org/10.1111/ceo.70128