bims-unfpre 2025-07-06 papers

Issue of 2025–07–06
four papers selected by
Susan Logue, University of Manitoba

BMC Cancer. 2025 Jul 01. 25(1): 1050

Sulforaphane induces cell morphology change and cell apoptosis by activating endoplasmic reticulum stress in glioblastoma.

Nan Li, Yan Jiang, Ajun Wang, Tongchao Jiang, Huimin Dai, Chengyu Xia, Tongcui Jiang.

BACKGROUND: Sulforaphane (SFN), a naturally occurring isothiocyanate derived from cruciferous vegetables, has shown promise as a multitargeted therapeutic agent in glioblastoma (GBM). This study aimed to elucidate the role and underlying molecular mechanisms of SFN in regulating GBM progression, particularly through the endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) pathways.
METHODS: Primary human glioma cells and established GBM cell lines were treated with various concentrations of SFN. RNA sequencing and qPCR analyses were conducted to identify transcriptional changes associated with the UPR pathway. Western blot and immunofluorescence were used to assess the expression and subcellular localization of key ER stress-related proteins. A CHOP knockdown model was employed to examine the functional role of CHOP in SFN-induced apoptosis. Additionally, normal human astrocytes (HA) were used to evaluate the selectivity of SFN's cytotoxicity. In vivo validation was performed using an intracranial glioma xenograft mouse model.
RESULTS: SFN significantly induced apoptotic cell death in GBM cells. Mechanistically, SFN activated multiple branches of the UPR, notably increasing the expression and nuclear translocation of ATF4 and CHOP. CHOP knockdown markedly attenuated SFN-induced apoptosis. RNA-seq and KEGG enrichment analyses confirmed the involvement of the ER stress pathway. Treatment with 4-phenylbutyrate (4-PBA) suppressed SFN-induced cytotoxicity, further supporting ER stress-mediated apoptosis. In vivo, SFN reduced tumor burden and upregulated ER stress markers in intracranial tumor tissues. Importantly, SFN had minimal cytotoxic effects on normal astrocytes, suggesting a favorable therapeutic window.
CONCLUSIONS: This study demonstrates that SFN induces GBM cell apoptosis via activation of the UPR pathway, particularly through the ATF4-CHOP axis. These findings support the potential of SFN as a promising therapeutic agent for glioblastoma.

Keywords: Cleaved Caspase-3; Endoplasmic reticulum stress; Glioblastoma; In vivo model; Sulforaphane; Unfolded protein response

DOI: https://doi.org/10.1186/s12885-025-14378-4

Cell Death Dis. 2025 Jul 03. 16(1): 486

N6-methyladenosine-mediated upregulation of MANF promotes ER stress resistance in renal cell carcinoma.

Junjie Cen, Dongliang Zhao, Xin Shi, Jinlong Chen, Hang Zhou, Yanping Liang, Chengpeng Gui, Wei Chen, Junhang Luo, Xu Chen.

Renal cell carcinoma (RCC) remains a significant clinical challenge due to its increasing incidence and resistance to conventional therapy. This study identifies an unprecedented mechanism by which mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to RCC progression. From single-cell transcriptome, we observed a significant upregulation of MANF in RCC compared to its progenitor cells, the proximal tubular cells. Mechanistically, decreased N6-methyladenosine (m6A) modification on MANF mRNA, mediated by the upregulation of the m6A demethylase ALKBH5, led to reduced RNA degradation and increased MANF protein expression. Furthermore, while the common von Hippel-Lindau (VHL) deletion in RCC results in the accumulation of misfolded proteins and endoplasmic reticulum (ER) stress, increased MANF efficiently mitigated ER stress by binding to phosphorylated inositol-requiring enzyme-1 alpha (IRE1α) and inhibited its phosphorylation, indicating that MANF-mediated ER stress resistance compensates for the negative effects of VHL depletion and contributes to the survival of RCC. Our findings highlight a potential therapeutic strategy for RCC by targeting the m6A-mediated regulation, directly degrading MANF protein or inhibiting its function.

DOI: https://doi.org/10.1038/s41419-025-07798-4

Sci Rep. 2025 Jul 02. 15(1): 22916

The interplay between endoplasmic reticulum stress and inflammation in multiple sclerosis.

Zhila Maghbooli, Forough Azam Sayahpour, Tarlan Varzandi, Mahya Rouhollahi Masoumi, Mohammad Ali Sahraian.

Endoplasmic reticulum (ER) stress is one of the hallmarks of neurodegenerative diseases. This study aimed to investigate the role of ER stress in interaction with inflammatory markers in patients with multiple sclerosis (MS). The participants in the current study were recruited in two age and sex-matched groups: 44 recently diagnosed MS patients and 53 control subjects. Differential gene expression of C/EBP homologous protein (CHOP), 78-kDa glucose-regulated protein (GRP78), and circulating levels of interleukin (IL)-1β and tumor necrosis factor (TNF-α) were assessed in MS patients and controls. The results showed that serum levels of TNF-α were significantly higher in MS patients than in the control group (p = 0.01), but not IL-1β serum levels. As for ER stress markers, there were no changes in CHOP expression levels in MS patients compared to the control group (p = 0.2). In contrast, GRP78 showed significant upregulation in MS patients compared to the control group (p = 0.0001). This study showed that the interaction between GRP78 and TNF-α influences the risk of MS (beta = 1.43, 95%CI:1.09-1.87, p = 0.01). Our data suggest that the interaction between TNF-α and GRP78 may modulate ER stress in MS patients.

Keywords: Endoplasmic reticulum; GRP78; Multiple sclerosis; TNF-α

DOI: https://doi.org/10.1038/s41598-025-06996-6

iScience. 2025 Jul 18. 28(7): 112714

The TWEAK/Fn14 signaling mediates skeletal muscle wasting during cancer cachexia.

Meiricris Tomaz da Silva, Anirban Roy, Anh Tuan Vuong, Aniket S Joshi, Cristeena Josphien, Meghana V Trivedi, Sajedah M Hindi, Vihang A Narkar, Ashok Kumar.

Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting. The TWEAK-Fn14 system regulates muscle mass in diverse conditions. However, its role in the regulation of muscle mass during cancer cachexia remains less understood. Here, we demonstrate that the levels of Fn14 are induced in skeletal muscle of multiple mouse models of cancer cachexia. Muscle-specific deletion of Fn14 reduces myofiber atrophy in mouse models of pancreatic and lung cancer cachexia. Silencing of Fn14 in KPC pancreatic cancer cells prior to their implantation in mice attenuates tumor growth without affecting myofiber size. Muscle-specific deletion of Fn14 reduces the gene expression of various components of the PERK and IRE1α arms of the unfolded protein response during KPC tumor growth. The inhibition of PERK improves protein synthesis and average myotube diameter in TWEAK-treated cultures. Altogether, our study suggests that the inhibition of TWEAK/Fn14 signaling can attenuate tumor growth and muscle wasting during cancer cachexia.

Keywords: Cancer; Cell biology; Molecular biology

DOI: https://doi.org/10.1016/j.isci.2025.112714