bims-unfpre 2025-12-21 papers

Issue of 2025–12–21
five papers selected by
Susan Logue, University of Manitoba

Commun Biol. 2025 Dec 16.

Imaginal discs produce neuropeptide-like precursor 1 to alleviate ER stress in response to warm temperatures.

Il-Ju Kim, Do-Hyoung Kim, Young-Joon Kim.

In mammals, prolonged heat stress induces an endoplasmic reticulum (ER) stress response that can damage internal organs. In Drosophila, larvae grow and develop into adults faster at warmer temperatures (e.g., 30°C) than at lower temperatures, but with reduced body size and fertility. In this study, we show that the neuropeptide gene neuropeptide-like precursor 1 (Nplp1) alleviates temperature-induced ER stress in imaginal discs. Warm temperatures increase production of a specific Nplp1 splice variant that inhibits PKR-like endoplasmic reticulum kinase (PERK) activation and cell death. Nplp1 inhibits Dilp8 expression through the PERK/ATF4/Yki pathway, thereby enabling imaginal disc growth and ecdysone homeostasis under warm temperature conditions. These findings provide valuable insights into how animals cope with elevated temperatures.

DOI: https://doi.org/10.1038/s42003-025-09323-x

Nat Commun. 2025 Dec 19.

SPLiCR-seq: A CRISPR-Based Screening Platform for RNA splicing Identifies Novel Regulators of IRE1α-XBP1 Signaling Under ER Stress.

Qianqian Ying, Yongchen Chen, Luochen Shen, Yang Xu, Ruilin Tian.

RNA splicing is fundamental to cellular function, yet systematic investigation of its complex regulation has been limited by existing methods. Here, we present SPLiCR-seq (SPLicing regulator identification through CRISPR screening), a high-throughput CRISPR screening platform that enables direct measurement of RNA splicing outcomes for pooled genetic perturbations, overcoming limitations of traditional fluorescence-based approaches. Applying SPLiCR-seq to investigate XBP1 splicing during the unfolded protein response (UPR), we conduct targeted and genome-wide screens across diverse cellular contexts, revealing both common and cell-type specific regulators. Notably, we identify GADD34 (PPP1R15A) as a novel modulator of IRE1α-XBP1 signaling, demonstrating that it directly interacts with IRE1α and functions independently of its canonical role in eIF2α dephosphorylation. Pharmacological inhibition of GADD34 using Sephin1 effectively suppressed XBP1 splicing and alleviated CAR-T cell exhaustion in an ex vivo model, leading to enhanced tumor-killing capacity across multiple cancer models. This work not only establishes a powerful new tool for systematically studying RNA splicing regulation but also uncovers a promising therapeutic strategy for improving CAR-T cell immunotherapy through modulation of the IRE1α-XBP1 pathway.

DOI: https://doi.org/10.1038/s41467-025-67633-4

Discov Oncol. 2025 Dec 13.

Endoplasmic reticulum stress-related genes play a role in the prognosis of lung adenocarcinoma.

Mingming Tang, Shi Zhang, Xingni Zhou, Zhigang Cai.

BACKGROUND: Lung adenocarcinoma (LUAD) has a high mortality rate. The signaling of endoplasmic reticulum (ER) stress sensor can regulate cancer progression. We aimed to investigate the relationship between ER stress-related genes and LUAD prognosis.
METHODS: Gene expression and clinical data of LUAD patients were downloaded from The Cancer Genome Atlas (TCGA) database. GSE68465 from Gene Expression Omnibus (GEO) was used for validation analysis. Two ER stress-related datasets were downloaded from MSigDB. ER stress-related genes which significantly correlated with the prognosis of LUAD were selected to construct ER score model. Patients were divided into two groups based on the median value of ER sore. The prognosis of patients in different groups was compared. Unsupervised hierarchical clustering analysis was used to identify different LUAD subtypes. Features with significantly correlation of prognosis were used to construct a nomogram. The expression of key ER stress-related genes in LUAD cells was experimentally validated.
RESULTS: Seven genes (EIF2AK3, IGFBP1, SHC1, GSK3A, EIF4G1, MBTPS2, and PSMC6) significantly associated with prognosis were used to construct the ER score model. The patients in the high ER score group had worse prognosis in both TCGA and GEO datasets. Patients with higher ER scores tended to have higher pathologic_T, pathologic_N, pathologic_M, and stage. There was a significant difference in prognosis between the two subtypes identified according to the model gene (p < 0.05). The nomogram constructed with stage, ER score and cluster showed a great performance for predicting prognosis. Experimental validation confirmed the downregulation of EIF2AK3 and the upregulation of IGFBP1, SHC1, GSK3A, EIF4G1, MBTPS2, and PSMC6 in LUAD cells.
CONCLUSION: The nomogram constructed by ER score and clinical features showed good predictive performance on LUAD. This study provided new insights into understanding the role of ER stress in LUAD.

Keywords: Endoplasmic reticulum stress; Immune; Lung adenocarcinoma; Nomogram; Prognosis

DOI: https://doi.org/10.1007/s12672-025-04240-1

Cell Death Discov. 2025 Dec 17. 11(1): 559

Endoplasmic reticulum stress-mediated programmed cell death in the tumor microenvironment.

Hongyu Chai, Qian Hu, Shun Yao, Shuoguo Ma, Wei Su.

Endoplasmic reticulum stress (ERS) dynamically regulates cell fate decisions within the tumor microenvironment (TME) through the PERK, IRE1α, and ATF6 pathways of the unfolded protein response (UPR), forming an "ERS-Death Axis" interconnected with apoptosis, autophagy, pyroptosis, and ferroptosis. Its molecular network involves CHOP-mediated apoptotic imbalance, NLRP3 inflammasome-activated pyroptosis, the ATF4-CHAC1 axis-driven ferroptosis, and the dual roles of autophagy (protective or pro-death). Oxidative stress further amplifies the biological functions of this network. The ERS-Death Axis exhibits significant heterogeneity across different tumors. Therapeutic strategies targeting this axis have demonstrated clear potential, including specific modulation of core UPR molecules, pathway activation by natural compounds, synergistic combinations with immune checkpoint inhibitors and metabolic interventions, and enhanced targeting and efficacy through nanodelivery systems. However, clinical translation faces key challenges such as tumor heterogeneity, drug delivery efficiency, and complex resistance mechanisms. In-depth elucidation of the tumor-specific mechanisms underlying the ERS-Death Axis will provide crucial theoretical support for overcoming bottlenecks in cancer therapy and optimizing combination treatment regimens, propelling this axis to become a core target for precision oncology.

DOI: https://doi.org/10.1038/s41420-025-02862-6

Biochem Biophys Rep. 2026 Mar;45 102359

Unraveling the role of mitochondrial unfolded protein response in colorectal cancer.

Jihao Shi, Lexi Wu, Chuwen Tian, Haotian Chen.

Colorectal cancer (CRC) ranks among the most prevalent malignancies globally and is the third leading cause of cancer - related deaths. Despite advancements in diagnosis and treatment, prognosis for CRC patients, especially those with advanced or metastatic disease, remains difficult due to its heterogeneity. Mitochondria, central to cellular activity, and the mitochondrial unfolded protein response (UPRmt), a stress - responsive pathway, are involved in various physiological and pathological processes. Recent studies have emphasized the importance of UPRmt in cancer biology. In this research, we explored the role of UPR - related genes (MRGs) in CRC. Through analyzing transcriptional profiles and clinical data of CRC patients, we identified different molecular subtypes according to MRG expression, which were related to patient prognosis, immune cell infiltration, and drug sensitivity. We also developed a prognostic signature based on key MRGs with strong predictive power for patient survival and treatment response. Additionally, the study of the spatial distribution of MRGs in tumor tissues revealed their heterogeneous expression and potential influence on tumor biology. Overall, our findings clarify the role of UPR in CRC and highlight its potential as a target for personalized cancer therapy.

Keywords: Colorectal cancer; Database; Single-cell RNA sequencing; Unfolded protein response

DOI: https://doi.org/10.1016/j.bbrep.2025.102359