Soyoung Park

All Publications

• Targeting ATF6 reduces pathological neovascularization and improves visual outcomes in retinal disease models. Scientific reports Bradley, A., Park, S., Park, S., Kim, K., Galdamez, A., Min, H., Diaz-Aguilar, M. S., Hartnett, M. E., Lee, E. J., Lin, J. H. 2025; 15 (1): 33070

  Abstract

  Pathological retinal neovascularization is a cause of vision loss in diseases including retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and diabetic retinopathy. The Unfolded Protein Response (UPR) is an intracellular signal transduction mechanism that is activated by ER stress and upregulates many proteins, including angiogenesis factors like VEGF and HIF-1α. This suggests that UPR genes and pathways may drive retinal angiogenesis. Here, we tested the role of the UPR regulator Activating Transcription Factor 6 (ATF6) in pathological and developmental retinal angiogenesis. We induced pathological retinal neovascularization in Atf6-/- mice using the oxygen-induced retinopathy (OIR) model and found significantly preserved visual function, accompanied by decreased retinal neovascularization, endothelial cell proliferation, and UPR transcriptional program induction. When we chemically blocked ATF6 signaling by intraocular injection of the small molecule Ceapin-A7, we also saw suppressed retinal expression of UPR genes. Additionally, in postnatal day 7 Atf6-/- mice when the retinal vasculature is developing in response to physiologic intraocular hypoxia, there was a transient but significant defect in pruning and retinal blood vessel extension. Together, our results demonstrate ATF6's causal role in developmental and pathological retinal angiogenesis and highlight its potential as a therapeutic target to preserve vision in retinal neovascularization diseases.

  View details for DOI 10.1038/s41598-025-15393-y

  View details for PubMedID 41006433

  View details for PubMedCentralID PMC12475287

• Transcriptomic Profiling of Small Molecule Atf6 Modulators in the Retina. FASEB journal : official publication of the Federation of American Societies for Experimental Biology Diaz-Aguilar, M. S., Galdamez, A., Chea, L., Le, M., Park, S., Min, H., Lee, E. J., Lin, J. H. 2025; 39 (16): e70940

  Abstract

  The Unfolded Protein Response (UPR) maintains endoplasmic reticulum (ER) homeostasis and is essential for retinal health. Activating Transcription Factor 6 (ATF6) controls a key UPR branch and upregulates genes that mitigate ER stress. Small molecule modulators of ATF6 have been characterized in cell culture models that increase or decrease the amount of the cleaved, transcriptional activator domain of ATF6 generated from the full-length precursor. However, the effects of these small molecule ATF6 modulators remain unclear in vivo, in part because of the lack of antibodies that robustly detect the cleaved, activated form of ATF6 in model organisms like mice. Here, we used targeted RNA sequencing (RNA-seq) to assess the transcriptional response to intraocular delivery of Ceapin-A7 (an ATF6 inhibitor) and AA147 (an ATF6 activator) in the mouse retina. Using this strategy, we demonstrate that Ceapin-A7 significantly suppressed ATF6 transcriptional targets, whereas AA147 induced ATF6-regulated genes in retinal tissue of the eye. We also show that neither small molecule ATF6 modulator caused retinal cell death, compromised vision, or triggered ER stress by histology, functional testing, and transcriptional analysis. These results identify a transcriptional strategy to sensitively detect and quantify Ceapin-A7 and AA147 modulation of ATF6 in vivo. These findings also identify nontoxic conditions for further in vivo evaluation of small molecule ATF6 modulators in mouse vision loss disease models linked to ER stress.

  View details for DOI 10.1096/fj.202501459R

  View details for PubMedID 40827849

• Single-Cell RNA-Seq Dissects ATF6 Function in Rods and Cones in Mature Retinal Organoids Bradley, A., Min, H., Park, S., Temme, W., Park, S., Lee, E., Lin, J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2025

  View details for Web of Science ID 001558878100005

• Targeting unfolded protein response mitigates retinal neovascularization in Vldlr-/- model Park, S., Galdamez, A., Bradley, A., Le-Maciukiewicz, M., Stevenson, E., Chea, L., Temme, W., Lee, E., Lin, J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2025

  View details for Web of Science ID 001560010500025

• Single-Cell RNA Sequencing Highlights ER Stress and Inflammation in Endothelial and Glial Cells in Vldlr-/- Mouse Retina Galdamez, A., Park, S., Bradley, A., Le, M., Stevenson, E., Chea, L., Temme, W., Lee, E., Lin, J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2025

  View details for Web of Science ID 001561711600014

• The PERK-eIF2α-ATF4 Axis Is Involved in Mediating ER-Stress-Induced Ferroptosis via DDIT4-mTORC1 Inhibition and Acetaminophen-Induced Hepatotoxicity. Antioxidants (Basel, Switzerland) Nghiem, T. T., Nguyen, K. A., Kusuma, F., Park, S., Park, J., Joe, Y., Han, J., Chung, H. T. 2025; 14 (3)

  Abstract

  Ferroptosis, a regulated form of cell death characterized by lipid peroxidation and iron accumulation, is increasingly recognized for its role in disease pathogenesis. The unfolded protein response (UPR) has been implicated in both endoplasmic reticulum (ER) stress and ferroptosis-mediated cell fate decisions; yet, the specific mechanism remains poorly understood. In this study, we demonstrated that ER stress induced by tunicamycin and ferroptosis triggered by erastin both activate the UPR, leading to the induction of ferroptotic cell death. This cell death was mitigated by the application of chemical chaperones and a ferroptosis inhibitor. Among the three arms of the UPR, the PERK-eIF2α-ATF4 signaling axis was identified as a crucial mediator in this process. Mechanistically, the ATF4-driven induction of DDIT4 plays a pivotal role, facilitating ferroptosis via the inhibition of the mTORC1 pathway. Furthermore, acetaminophen (APAP)-induced hepatotoxicity was investigated as a model of eIF2α-ATF4-mediated ferroptosis. Our findings reveal that the inhibition of eIF2α-ATF4 or ferroptosis protects against APAP-induced liver damage, underscoring the therapeutic potential of targeting these pathways. Overall, this study not only clarifies the intricate role of the PERK-eIF2α-ATF4 axis in ER-stress-and erastin-induced ferroptosis but also extends these findings to a clinically relevant model, providing a foundation for potential therapeutic interventions in conditions characterized by dysregulated ferroptosis and ER stress.

  View details for DOI 10.3390/antiox14030307

  View details for PubMedID 40227255

  View details for PubMedCentralID PMC11939615

• PKR Mediates the Mitochondrial Unfolded Protein Response through Double-Stranded RNA Accumulation under Mitochondrial Stress INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Kusuma, F., Park, S., Nguyen, K., Elvira, R., Lee, D., Han, J. 2024; 25 (14)

  Abstract

  Mitochondrial stress, resulting from dysfunction and proteostasis disturbances, triggers the mitochondrial unfolded protein response (UPRMT), which activates gene encoding chaperones and proteases to restore mitochondrial function. Although ATFS-1 mediates mitochondrial stress UPRMT induction in C. elegans, the mechanisms relaying mitochondrial stress signals to the nucleus in mammals remain poorly defined. Here, we explored the role of protein kinase R (PKR), an eIF2α kinase activated by double-stranded RNAs (dsRNAs), in mitochondrial stress signaling. We found that UPRMT does not occur in cells lacking PKR, indicating its crucial role in this process. Mechanistically, we observed that dsRNAs accumulate within mitochondria under stress conditions, along with unprocessed mitochondrial transcripts. Furthermore, we demonstrated that accumulated mitochondrial dsRNAs in mouse embryonic fibroblasts (MEFs) deficient in the Bax/Bak channels are not released into the cytosol and do not induce the UPRMT upon mitochondrial stress, suggesting a potential role of the Bax/Bak channels in mediating the mitochondrial stress response. These discoveries enhance our understanding of how cells maintain mitochondrial integrity, respond to mitochondrial dysfunction, and communicate stress signals to the nucleus through retrograde signaling. This knowledge provides valuable insights into prospective therapeutic targets for diseases associated with mitochondrial stress.

  View details for DOI 10.3390/ijms25147738

  View details for Web of Science ID 001278590800001

  View details for PubMedID 39062980

  View details for PubMedCentralID PMC11276775

• Neurodegeneration Risk Factor, EIF2AK3 (PERK), Influences Tau Protein Aggregation. The Journal of biological chemistry Park, G., Xu, K., Chea, L., Kim, K., Safarta, L., Song, K., Wu, J., Park, S., Min, H., Hiramatsu, N., Han, J., Lin, J. H. 2022: 102821

  Abstract

  Tauopathies are neurodegenerative diseases caused by pathologic misfolded tau protein aggregation in the nervous system. Population studies implicate EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), better known as PERK (protein kinase R-like endoplasmic reticulum kinase), as a genetic risk factor in several tauopathies. PERK is a key regulator of intracellular proteostatic mechanisms - Unfolded Protein Response (UPR) and Integrated Stress Response (ISR). Previous studies found that tauopathy-associated PERK variants encoded functional hypomorphs with reduced signaling in vitro. But, it remained unclear how altered PERK activity led to tauopathy. Here, we chemically or genetically modulated PERK signaling in cell culture models of tau aggregation and found that PERK pathway activation prevented tau aggregation while inhibition exacerbated tau aggregation. In primary tauopathy patient brain tissues, we found that reduced PERK signaling correlated with increased tau neuropathology. We found that tauopathy-associated PERK variants targeted the ER luminal domain; and two of these variants damaged hydrogen bond formation. Our studies support that PERK activity protects against tau aggregation and pathology. This may explain why people carrying hypomorphic PERK variants have increased risk for developing tauopathies. Finally, our studies identify small molecule augmentation of PERK signaling as an attractive therapeutic strategy to treat tauopathies by preventing tau pathology.

  View details for DOI 10.1016/j.jbc.2022.102821

  View details for PubMedID 36563857

• Reduction in endoplasmic reticulum stress activates beige adipocytes differentiation and alleviates high fat diet-induced metabolic phenotypes. Biochimica et biophysica acta. Molecular basis of disease Lee, J. M., Park, S., Lee, D., Ginting, R. P., Lee, M. R., Lee, M. W., Han, J. 2021; 1867 (5): 166099

  Abstract

  Endoplasmic reticulum (ER) stress is closely associated with various metabolic diseases, such as obesity and diabetes. Development of beige/brite adipocytes increases thermogenesis and helps to reduce obesity. Although the relationship between ER stress and white adipocytes has been studied considerably, the possible role of ER stress and the unfolded protein response (UPR) induction in beige adipocytes differentiation remain to be investigated. In this study we investigated how ER stress affected beige adipocytes differentiation both in vitro and in vivo. Phosphorylation of eIF2α was transiently decreased in the early phase (day 2), whereas it was induced at the late phase with concomitant induction of C/EBP homologous protein (CHOP) during beige adipocytes differentiation. Forced expression of CHOP inhibited the expression of beige adipocytes markers, including Ucp1, Cox8b, Cidea, Prdm16, and Pgc-1α, following the induction of beige adipocytes differentiation. When ER stress was reduced by the chemical chaperone tauroursodeoxycholic acid (TUDCA), the expression of the beige adipocytes marker uncoupling protein 1 (UCP1) was significantly enhanced in inguinal white adipose tissue (iWAT) and high fat diet (HFD)-induced abnormal metabolic phenotype was improved. In summary, we found that ER stress and the UPR induction were closely involved in beige adipogenesis. These results suggest that modulating ER stress could be a potential therapeutic intervention against metabolic dysfunctions via activation of iWAT browning.

  View details for DOI 10.1016/j.bbadis.2021.166099

  View details for PubMedID 33556486

• ER Stress Induces Cell Cycle Arrest at the G2/M Phase Through eIF2α Phosphorylation and GADD45α. International journal of molecular sciences Lee, D., Hokinson, D., Park, S., Elvira, R., Kusuma, F., Lee, J. M., Yun, M., Lee, S. G., Han, J. 2019; 20 (24)

  Abstract

  Endoplasmic reticulum (ER) stress is known to influence various cellular functions, including cell cycle progression. Although it is well known how ER stress inhibits cell cycle progression at the G1 phase, the molecular mechanism underlying how ER stress induces G2/M cell cycle arrest remains largely unknown. In this study, we found that ER stress and subsequent induction of the UPR led to cell cycle arrest at the G2/M phase by reducing the amount of cyclin B1. Pharmacological inhibition of the IRE1α or ATF6α signaling did not affect ER stress-induced cell cycle arrest at the G2/M phase. However, when the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) phosphorylation was genetically abrogated, the cell cycle progressed without arresting at the G2/M phase after ER stress. GEO database analysis showed that growth arrest and DNA-damage-inducible protein α (Gadd45α) were induced in an eIF2a phosphorylation-dependent manner, which was confirmed in this study. Knockdown of GADD45α abrogated cell cycle arrest at the G2/M phase upon ER stress. Finally, the cell death caused by ER stress significantly reduced when GADD45α expression was knocked down. In conclusion, GADD45α is a key mediator of ER stress-induced growth arrest via regulation of the G2/M transition and cell death through the eIF2α signaling pathway.

  View details for DOI 10.3390/ijms20246309

  View details for PubMedID 31847234

  View details for PubMedCentralID PMC6940793

• Modulation of Protein Synthesis by eIF2α Phosphorylation Protects Cell from Heat Stress-Mediated Apoptosis. Cells Park, S., Lim, Y., Lee, D., Elvira, R., Lee, J. M., Lee, M. R., Han, J. 2018; 7 (12)

  Abstract

  Global warming poses a considerable threat to human health, necessitating a proper understanding of mechanisms underlying cell death in the pathogenesis of heat-related diseases. Although mechanisms governing cytoplasmic response to heat are well understood, processes regulating cellular response to disruption of proteostasis in the endoplasmic reticulum (ER) due to heat stress remain unclear. The current study reveals that hyperthermic conditions may lead to a disturbance of ER homeostasis, also known as ER stress. Subsequent activation of the unfolded protein response (UPR) resulted in concomitant induction of cell death. Among the three UPR signaling pathways, the eIF2α phosphorylation pathway, and not the IRE1α/ATF6α pathways, is likely the main contributor to cell death under heat stress. Considering the role of eIF2α in translational control, we investigated the protective effect of translation rate on heat stress-mediated cell death. When protein synthesis was attenuated using cycloheximide or homoharringtonine, cell death due to heat stress was significantly reduced. In summation, we propose that transient modulation of protein synthesis by eIF2α phosphorylation has a pivotal role in protecting cells from heat stress-induced apoptosis. Therefore, pharmacological agents that promote eIF2α phosphorylation or reduce ER stress may contribute to the development of promising therapeutic approaches against heat-related diseases.

  View details for DOI 10.3390/cells7120254

  View details for PubMedID 30544621

  View details for PubMedCentralID PMC6316477