bims-unfpre 2025-12-07 papers

Issue of 2025–12–07
six papers selected by
Susan Logue, University of Manitoba

Cell Death Discov. 2025 Dec 05.

Bidirectional crosstalk between ER stress and lipid metabolism: From proteostasis to tumor adaptation.

Yueling Wu, Huijuan Luo, Zhiwei Pan, Weiping Chen, Lei Bi.

Endoplasmic reticulum (ER) stress is a central adaptive response that maintains proteostasis under diverse metabolic and environmental challenges. In cancer, ER stress and lipid metabolism form a tightly coupled, bidirectional regulatory network that integrates protein quality control with lipid remodeling. Through the unfolded protein response (UPR), ER stress reprograms lipid synthesis, oxidation, and storage to sustain energy balance and membrane integrity. Conversely, dysregulated lipid accumulation disrupts ER homeostasis and amplifies stress signaling, creating a feedback loop between metabolic and proteostatic imbalance. Proteostasis systems, including the ubiquitin-proteasome system (UPS) and autophagy, cooperate with UPR signaling to fine-tune this adaptive balance and enhance tumor survival under stress. This review highlights the bidirectional crosstalk between ER stress and lipid metabolism from the perspective of proteostasis-driven tumor adaptation and summarizes emerging therapeutic strategies such as small-molecule modulators, natural products, and combination therapies that target this adaptive network to overcome drug resistance and improve cancer treatment.

DOI: https://doi.org/10.1038/s41420-025-02878-y

Life Sci Alliance. 2026 Feb;pii: e202503485. [Epub ahead of print]9(2):

The unfolded protein response in progeria arteries originates from non-endothelial cell types.

Raquel A Silva, Fatih Sarigol, G Elif Karagöz, Selma Osmanagic-Myers, Roland Foisner.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease caused by a mutation in LMNA, leading to the expression of a prelamin A variant called progerin. HGPS hallmarks include accelerated cardiovascular disease and atherosclerosis, caused in part by ER stress-induced apoptosis of vascular smooth muscle cells. As a dysregulated unfolded protein response (UPR) can induce endothelial cell (EC) pathology during aging, we investigated whether loss of proteostasis contributes to EC dysfunction in HGPS, using an endothelium-specific HGPS mouse model. Contrary to previous reports in vascular smooth muscle cells and fibroblasts, we found no robust activation of UPR in ECs constitutively expressing progerin, and cells retained the ability to elicit potent UPR when exposed to external ER stress. Unlike aortic tissue derived from mice with endothelium-specific progerin expression, aorta from Lmna G609G/+ mice with ubiquitous progerin expression showed up-regulation of the UPR, suggesting that the UPR in HGPS aorta is primarily rooted in non-ECs. Analysis of scRNA-Seq datasets from aorta in Lmna G609G/G609G mice confirmed this hypothesis. Our data indicate that UPR activation is a cell-type-specific phenomenon in progerin-expressing arteries.

DOI: https://doi.org/10.26508/lsa.202503485

Nat Commun. 2025 Dec 02. 16(1): 10842

Dynamic Organellar Mapping in yeast reveals extensive protein localization changes during ER stress.

Anna Platzek, Klára Odehnalová, Julia P Schessner, Georg H H Borner, Sebastian Schuck.

Sophisticated techniques are available for systematic studies of yeast cell biology. However, it remains challenging to investigate protein subcellular localization changes on a proteome-wide scale. Here, we apply Dynamic Organellar Mapping by label-free mass spectrometry to detect localization changes of native, untagged proteins during endoplasmic reticulum (ER) stress. We find that hundreds of proteins shift between cellular compartments. For example, we show that numerous secretory pathway proteins accumulate in the ER, thus defining the extent and selectivity of ER retention of misfolded proteins. Furthermore, we identify candidate cargo proteins of the ER reflux pathway, determine constituents of reticulon clusters that segregate from the remainder of the ER and provide evidence for altered nuclear pore complex composition and nuclear import. These findings uncover protein relocalization as a major aspect of cellular reorganization during ER stress and establish Dynamic Organellar Maps as a powerful discovery tool in yeast.

DOI: https://doi.org/10.1038/s41467-025-66946-8

iScience. 2025 Dec 19. 28(12): 113891

Cochlear endoplasmic reticulum stress causes connexin 26 degradation is involved in age-related hearing loss.

Xue Bai, Bing Liao, Wen-Hui Hu, Mei-Qun Wang, Yu Sun, Xu-Bo Chen, Kai Xu.

Age-related hearing loss (ARHL) represents a progressive auditory disorder. Growing evidence indicates that degradation of connexin 26 (Cx26) in cochlear may constitute one of the pathogenic mechanisms in ARHL. However, the molecular mechanisms underlying age-related Cx26 degradation remain unclear. We systematically analyzed Cx26 expression patterns in C57BL/6J mice across different age groups and confirmed an age-dependent downregulation of Cx26 in the mouse cochlea. Notably, we observed concurrent upregulation of endoplasmic reticulum (ER) stress markers Glucose-regulated protein 78 (GRP78) and protein disulfide isomerase (PDI) in aged cochlear tissues. Furthermore, in vitro experiments demonstrated that ER stress significantly reduced Cx26 protein levels in cochlear explants. Mechanistically, we observed enhanced expression of ubiquitination-related proteins Nedd4 and Eps15 with evident colocalization with Cx26 in an ER stress mouse model. In summary, our findings demonstrate that Cx26 ubiquitination mediated by cochlear ER stress is the main cause of Cx26 degradation in the cochlea of aged mice.

Keywords: cell biology; molecular biology; neuroscience

DOI: https://doi.org/10.1016/j.isci.2025.113891

Cell Death Dis. 2025 Dec 01. 16(1): 876

Comparative transcriptomic analysis of retinal response to diverse cellular stresses reveals relative contributions of different cell death processes and signalling networks.

Subhradeep Sarkar, Ramaraj Kannan, Trailokyanath Panigrahi, Karthickraja Veeramani, Thirumalesh Mb, Shom Shanker Bhattacharya, Arkasubhra Ghosh.

Retinal degeneration comprises a diverse group of progressive disorders leading to visual impairment and ultimately blindness. These include inherited retinal dystrophies (IRDs), diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma, affecting millions worldwide. The underlying pathology involves dysfunction and death of photoreceptor cells and the retinal pigment epithelium (RPE), driven by various stress-induced cell death mechanisms. Although multiple pathways have been reported, the relative contribution of each remains incompletely understood, highlighting the need for further investigation. Therefore, we studied how different stress types that induce retinal degeneration alter the global gene expression profile in vivo (C57BL/6 mice), aiming to identify predominant cell death mechanisms as well as key genes and networks. Retinal toxicity was induced using established models of oxidative stress, hypoxia, endoplasmic reticulum (ER) stress, and chronic inflammation. Transcriptomic profiling revealed both unique and convergent gene expression changes associated with each stressor. In total, 170, 328, 146, and 151 genes were significantly altered under oxidative stress, inflammation, ER stress, and hypoxia, respectively (Log2 fold change >2 or <-2; p < 0.05). Genes such as Arhgap26, Ccdc9, Ube2e2, and Fndc3b were commonly dysregulated across ER stress, inflammation, and oxidative stress, whereas Nfix, Elp6, Naca, and Plcd3 were selectively altered in oxidative stress, inflammation, ER stress, and hypoxia, respectively. Analysis of cell death-related gene subsets revealed that pyroptosis was commonly activated across different stress types. Additionally, autophagy-mediated cell death, ferroptosis, and extrinsic apoptosis were preferentially associated with oxidative stress, chronic inflammation, and hypoxia, respectively. Both ER and oxidative stress models showed strong activation of autophagy-associated cell death. Together, these findings delineate distinct molecular signatures and predominant cell death mechanisms triggered by specific stressors, providing important insights that could aid in developing targeted therapies to prevent or slow retinal degeneration.

DOI: https://doi.org/10.1038/s41419-025-08257-w

bioRxiv. 2025 Nov 21. pii: 2025.11.20.689560. [Epub ahead of print]

Progesterone receptors drive advanced breast cancer phenotypes including circulating tumor-and stem-like cell expansion in the context of ESR1 mutation.

Thu H Truong, Noelle E Gillis, Amy R Dwyer, Rosemary J Huggins, Kyla M Hagen, Sai Harshita Posani, Nuri A Temiz, Carlos Perez Kerkvliet, Ellie M Piepgras, Julie H Ostrander, Geoffrey L Greene, Carol A Lange.

Endocrine therapy resistance remains a major challenge in the treatment of advanced estrogen receptor positive (ER+) breast cancer. This can be driven by acquired mutations in the estrogen receptor gene ( ESR1 ), such as Y537S or D538G, that primarily emerge in patients with prior aromatase inhibitor therapy and results in constitutive estrogen-independent ER activity. Progesterone receptors (PR) are important modifiers of ER activity, in part via direct binding. We previously showed that PR mediates expansion of cancer stem-like cell (CSC) populations and promotes tamoxifen resistance in nuclear ER/PR transcriptional complexes. In this study, we sought to define whether PR function changes in the context of ESR1 mutations. PR readily interacted with wild type (WT), but not Y537S or D538G ERs. RNA-seq and ChIP-seq studies demonstrated that ER+ breast cancer models expressing Y537S ER exhibited a distinct response to progesterone. CSC populations were enhanced in Y537S ER+ cells compared to WT ER+ cells. PR knockdown demonstrated that this property required PR expression but was unresponsive to antiprogestins. Moreover, we identified PR-dependent transcriptional programs such as the unfolded protein response (UPR) that can be leveraged to target CSC populations in Y537S ESR1 -mutant breast cancer. The UPR activator ErSO, but not UPR inhibitors, blocked expansion of CSCs in WT as well as Y537S ER + models. Together, our findings demonstrate a critical interplay between PR and mutant ER function and provide insight into PR-driven pathways including hyperactivation of the stress-sensing UPR that can be exploited as potential therapeutic avenues in advanced ER+ breast cancer.

DOI: https://doi.org/10.1101/2025.11.20.689560