bims-unfpre 2025-10-26 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–10–26
fourteen papers selected by
Susan Logue, University of Manitoba

On-genetic inactivation of caspase-3 and P53 increases cancer cell fitness by PDIA4 redistribution.
Endoplasmic reticulum stress and oxidative imbalance is the missing link in fibromyalgia pathophysiology.
ER stress induced mitochondrial dysfunction drives Treg instability in coronary artery disease.
IL-1β priming triggers an adaptive stress response that enhances pancreatic β-cell resilience to subsequent cytotoxic inflammatory insult.
Concentrated Growth Factor Induces ER Stress and Apoptosis by Increasing Ceramide Generation in Selected Tumour Cell Lines.
Endoplasmic reticulum stress, calcium homeostasis and the aging heart.
LncRNA ENST00000532153.1 alleviates podocyte injury by inhibiting PARP1-mediated PARylation of ATF3 in diabetic kidney disease.
Chronic ER Stress Triggers Cell-Surface Chaperones as the Therapeutic Targets of CAR Cells in Acute Myeloid Leukemia.
A structural basis for chaperone repression of stress signaling from the endoplasmic reticulum.
Ailanthone induces apoptosis in U-2OS cells through the endoplasmic reticulum stress.
Heme and hemozoin induce platelet cell death through UPR-induced apoptosis and ferroptosis in vivax malaria.
LRRC59 inhibits perk pathway‑induced apoptosis and promotes cell proliferation, migration and invasion in colorectal cancer cells.
Endoplasmic reticulum in the axon: Insights into structural dynamics and implications in neurodegeneration.
The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.

Oncogene. 2025 Oct 21.

On-genetic inactivation of caspase-3 and P53 increases cancer cell fitness by PDIA4 redistribution.

Gal Twito, Faiza Amterat Abu Abayed, Ayelet Gilad, Suma Biadsy, Noa Gavriel, Suad Sheikh Suliman, Yarden Mizrahi, Hila Megged, Mor Tenenboim, Naim Abu-Freha, Aeid Igbaria.

Numerous cellular pathways are known to cause resistance in cancer cells. The unfolded protein response (UPR), a signaling pathway activated during proteostasis stress in the endoplasmic reticulum (ER), is an adaptive process to increase cancer cell fitness. However, the molecular mechanism between ER stress, UPR activation, and chemoresistance is insufficiently understood. Here, we report that ER stress induction and UPR activation are necessary for chemoresistance to cisplatin and doxorubicin. Mild ER stress is a sufficient precondition for cancer cells to evade cisplatin- and doxorubicin-associated cell death. Mechanistically, ER stress induction results in the redistribution of PDIA4 from the ER to the cytosol, facilitated by the c-tail-anchored proteins DNAJB12 and DNAJB14 and the cytosolic HSC70-cochaperone SGTA. In the cytosol, PDIA4 forms an inhibitory interaction with caspase-3 and wt-p53, leading to their attenuation and increased cancer cell proliferation. Furthermore, we show that PDIA4 must originate from the ER to inhibit caspase-3 and wt-p53 in the cytosol. Silencing PDIA4, DNAJB12/14, or SGTA rescues wt-p53 and caspase-3 activity. Finally, we found that in tumors isolated from colorectal cancer patients, PDIA4 and DNAJB12 are highly expressed compared to their healthy tissues; this expression is associated with the induction of the UPR. Our data show a novel non-genetic mechanism to inhibit apoptosis and suggest PDIA4, DNAJB12/14, and SGTA as novel therapeutic targets to rescue apoptosis and inhibit proliferation in cancer cells.

DOI: https://doi.org/10.1038/s41388-025-03606-7
Sci Rep. 2025 Oct 21. 15(1): 36729

Endoplasmic reticulum stress and oxidative imbalance is the missing link in fibromyalgia pathophysiology.

Önder Otlu, Tuğba Raika Kıran, Rabia Aydoğan Baykara, Mehmet Erdem, Feyza İnceoğlu.

  Fibromyalgia syndrome (FMS) is a chronic pain disorder characterized by widespread musculoskeletal pain, fatigue, and cognitive dysfunction. Although its exact pathophysiology remains unclear, emerging evidence suggests that endoplasmic reticulum (ER) stress and oxidative stress play significant roles in its development. This study aimed to investigate the involvement of ER stress in FMS by evaluating key ER stress markers and oxidative stress parameters in patients with FMS. A total of forty-four FMS patients and matched healthy controls were included in the study. Serum levels of ER stress markers were measured using enzyme-linked immunosorbent assay (ELISA). Additionally, oxidative stress markers were assessed to examine their relationship with ER stress in FMS. The ER stress parameters were significantly higher in the FMS group compared to controls. Furthermore, oxidative stress markers were elevated, reinforcing the interconnection between ER stress and oxidative stress in FMS pathogenesis. These findings suggest that ER stress plays a crucial role in the pathophysiology of FMS, likely contributing to disease progression through oxidative stress-related mechanisms. Targeting ER stress and oxidative stress pathways may represent a promising therapeutic strategy for FMS management. Future studies should focus on large-scale clinical investigations to further elucidate these pathways and develop effective treatment approaches.

Keywords:  ATF6; CHOP; Chronic pain; ER stress; Fibromyalgia; GRP78; Oxidative stress; PERK

DOI:  https://doi.org/10.1038/s41598-025-20737-9
EMBO Mol Med. 2025 Oct 21.

ER stress induced mitochondrial dysfunction drives Treg instability in coronary artery disease.

Smriti Parashar, Mohammad Oliaeimotlagh, Payel Roy, Qingkang Lyu, Anusha Bellapu, Mikhail Fomin, Sunil Kumar, Yan Wang, Chantel C McSkimming, Coleen A McNamara, Klaus Ley.

  Under conditions of chronic unresolved inflammation characteristic of atherosclerosis, regulatory CD4+ T cells (Tregs) become unstable and convert to cytotoxic exTregs. The mechanism driving this conversion in humans is unclear. Here, we show unresolved endoplasmic reticulum (ER) stress as a key factor driving Treg instability. Human exTregs undergo ER stress and consequent mitochondrial dysfunction that remains unchecked due to defective mitophagy. Integrated stress response (ISR), a pathway that can trigger inflammatory signaling, is also upregulated in exTregs. exTregs are highly apoptotic and are more susceptible to stress-mediated cellular dysfunction due to their senescent state. In a phenotype reminiscent of exTregs, Tregs from coronary artery disease (CAD) patients show high ER stress and mitochondrial depolarization. This is further exacerbated in CD4+ T cells residing in atherosclerotic plaques. Pro-atherosclerotic stressors such as oxLDL and interferon-γ induce ER stress and mitochondrial dysfunction in Tregs in vitro. We conclude that the maladaptive inflammatory environment in atherosclerosis triggers ER stress and mitochondrial dysfunction, contributing to Treg instability in CAD.

Keywords:  Atherosclerosis; ER Stress; Mitochondrial Dysfunction; Tregs; exTregs

DOI:  https://doi.org/10.1038/s44321-025-00322-3
Cell Death Dis. 2025 Oct 21. 16(1): 744

IL-1β priming triggers an adaptive stress response that enhances pancreatic β-cell resilience to subsequent cytotoxic inflammatory insult.

Carolina Sétula, Ingrid Pensado-Evans, Andrea Scelza-Figueredo, Miranda Sol Orellano, Ignacio Rodríguez-Valero, Eduardo Spinedi, Raghavendra G Mirmira, Luz Andreone, Marcelo Javier Perone.

Pancreatic β-cells fine-tune glucose homeostasis through insulin secretion. The endoplasmic reticulum (ER) is critical for insulin production, relying on the unfolded protein response (UPR) to adapt to the body's fluctuating demands. Islets from both type 1 (T1D) and type 2 diabetes (T2D) exhibit inflammation, β-cell dysfunction, and loss. ER stress is present in the inflamed islets of autoimmune diabetes-prone mice and individuals with T1D and T2D. Inflammatory cytokines induce ER stress and disrupt UPR regulation, driving β-cell apoptosis and contributing to diabetes development. Inflammatory cytokines, e.g., IL-1β, impair β-cell function and survival, contributing to diabetes pathogenesis by inducing stress, altering gene expression, driving dedifferentiation, and reducing insulin production. Paradoxically, β-cells exhibit a high density of IL-1R1, and IL-1R1/KO mice display impaired glucose tolerance and reduced insulin secretion. Postprandial IL-1β secreted by macrophages helps maintain blood glucose homeostasis. These observations suggest that circulating low IL-1β concentrations may have physiologically relevant roles; however, their effects on β-cell function and survival remain unclear due to conflicting reports. Preconditioning β-cells with physiological circulating levels of IL-1β (IL-1βlow) induced a resilient state, protecting them from pro-inflammatory cytokine (CYT)-induced cell death while preserving glucose-stimulated insulin secretion through hormesis. IL-1βlow-treated INS-1E cells reduced CYT-induced NO secretion by suppressing NF-κB signaling and decreasing iNOS expression, correlating with reduced β-cell death. IL-1βlow conditioning reduced ER stress and upregulated p-eIF2α in response to CYT, thereby enhancing the expression of ER chaperones and biomarkers linked to improved β-cell identity/functionality. Transcriptomic analysis revealed that IL-1βlow preconditioning mitigated the CYT-induced loss of genes involved in β-cell function/identity, and suppressed the expression of genes linked to NF-κB signaling, cytokine-induced inflammation, and apoptosis. IL-1βlow treatment counteracted the upregulation of stress-related genes triggered by pro-inflammatory stimuli. Enhancing IL-1βlow-induced stress-response hormesis may provide a novel strategy to sustain β-cell function and survival during harmful diabetic inflammation.

DOI: https://doi.org/10.1038/s41419-025-08059-0
J Cell Mol Med. 2025 Oct;29(20): e70916

Concentrated Growth Factor Induces ER Stress and Apoptosis by Increasing Ceramide Generation in Selected Tumour Cell Lines.

Andrea Palermo, Francesco Spedicato, Anna Giudetti, Daniele Vergara, Franco Ferrante, Alessandro D'amuri, Laura Giannotti, Benedetta Di Chiara Stanca, Christian Demitri, Fabrizio Damiano, Eleonora Stanca, Luisa Siculella.

  Concentrated growth factor (CGF), a blood-derived autologous biomaterial, is increasingly utilised in regenerative medicine and, recently, in cancer-related surgeries. Rich in cytokines, platelets, nucleated cells and fibrin scaffolds, CGF offers therapeutic promise but requires rigorous safety evaluation in oncology. This study explores the effects of CGF-conditioned medium (CGF-CM) on breast cancer (MCF7, MDA-231) and osteosarcoma (SaOS-2, MG-63) cell lines. Our findings reveal that CGF-CM selectively induces cytotoxic effects in MCF7 and SaOS-2 cells, while no cytotoxicity was observed in MDA-231 and MG-63 cells. Early apoptosis in MCF7 and SaOS-2 cells was accompanied by mitochondrial dysfunction, evidenced by an increased BAX/BCL-2 ratio and cytochrome c release. CGF-CM treatment also elevated ceramide and triglyceride levels, linking lipid metabolic changes to cancer cell death. Endoplasmic reticulum (ER) stress markers, ATF6 and XBP1, were significantly upregulated in MCF7 and SaOS-2 cells, highlighting the role of ER stress in CGF-CM-induced cytotoxicity. Furthermore, CGF-CM inhibited autophagic flux, as demonstrated by altered LC3 and p62 protein levels, disrupting cellular homeostasis and contributing to apoptosis. These findings highlight the selective cytotoxic effects of CGF-CM on specific cancer cell lines. The intricate interplay between mitochondrial dysfunction, ER stress, autophagy inhibition and lipid metabolism highlights its complex mechanisms of action.

Keywords:  CGF; ER‐stress; apoptosis; autophagy; breast cancer; ceramide; osteosarcoma

DOI:  https://doi.org/10.1111/jcmm.70916
Can J Physiol Pharmacol. 2025 Oct 24.

Endoplasmic reticulum stress, calcium homeostasis and the aging heart.

Izabela Quest, Marek Michalak.

Aging is a process characterized by the progressive decline in physiological function and increased susceptibility to disease. Many cellular functions, including unfolded protein responses (UPR, an endoplasmic reticulum (ER) stress coping mechanism), Ca2+ signaling, cellular signaling and inflammatory responses are affected by aging. These significantly impact Ca2+ handling by cardiac cells and the architecture of cardiomyocytes, leading to impaired contractility, and increased risk of arrhythmias. Cellular Ca2+ homeostasis and the UPR are interdependent, therefore, understanding and influencing these key cellular pathways should provide new therapeutic strategies for managing age-related cardiac diseases. Modulating Ca2+ handling and cellular stress pathways presents distinctive approaches to preventing molecular alterations linked to aging, while providing opportunities to reduce molecular damage and promote the effectiveness of cellular repair processes.

DOI: https://doi.org/10.1139/cjpp-2025-0190
Cell Mol Life Sci. 2025 Oct 25. 82(1): 363

LncRNA ENST00000532153.1 alleviates podocyte injury by inhibiting PARP1-mediated PARylation of ATF3 in diabetic kidney disease.

Qun Yu, Meilin Yang, Shangwei Lu, Hong Su, Yue Liu, Xia Zhang, Xiaoting Fan, Zhimei Lv, Rong Wang.

  Podocyte injury is a key event in the progression of diabetic kidney disease (DKD), and the role of long noncoding RNAs (lncRNAs) in DKD and podocyte injury is emerging. RNA sequencing, fluorescence in situ hybridization and real-time PCR results revealed that the expression of the lncRNA ENST00000532153.1 (lncRNA 153) was downregulated in patients with DKD and correlated with clinical parameters. Moreover, the overexpression of lncRNA 153 mitigated podocyte injury caused by high glucose (HG) stimulation. Following RNA-pulldown and mass spectrometry analysis, KEGG enrichment analysis revealed that the lncRNA 153 binding protein is primarily involved in protein processing in the endoplasmic reticulum (ER). Poly (ADP-ribose) polymerase 1 (PARP1) was subsequently identified as the binding protein of lncRNA 153. PARP1, a marker protein for apoptosis, was found to be upregulated in the kidneys of patients with DKD. Knockdown of PARP1 in podocytes under HG conditions resulted in the inhibition of ER stress and apoptosis, leading to the alleviation of podocyte injury both in vitro and in vivo. Furthermore, this study revealed that activating transcription factor 3 (ATF3) is a novel protein that interacts with PARP1, and that the interaction between them is involved in the regulation of gene transcription. Mechanistic studies demonstrated that lncRNA 153 binds to PARP1, inhibiting its interaction with ATF3 and subsequently reducing the transcriptional activity of ATF3, ultimately alleviating podocyte injury in DKD by suppressing ER stress and apoptosis. Therefore, our study suggests that lncRNA 153 and PARP1 may be attractive therapeutic targets for DKD.

Keywords:  ATF3; Apoptosis; Diabetic kidney disease; Endoplasmic reticulum stress; LncRNA ENST00000532153.1; PARP1

DOI:  https://doi.org/10.1007/s00018-025-05866-8
Adv Sci (Weinh). 2025 Oct 23. e11573

Chronic ER Stress Triggers Cell-Surface Chaperones as the Therapeutic Targets of CAR Cells in Acute Myeloid Leukemia.

Yimin Zhou, Zhenfei Zhong, Peng Hu, Weigang Wang, Ying Song, Na Yang, Fangyan He, Yajie Li, Qi Sa, Yanmei Yang, Qinmiao Sun, Tonghua Yang, Beibei Zhang, Dahua Chen.

  Acute myeloid leukemia (AML) is a heterogeneous malignancy with low survival rates, primarily due to its inherent complexity. This underscores the urgent need to identify specific targets for precision medicine. Here, multi-omics approaches are utilized and discover that AML cells undergo chaperone-mediated chronic endoplasmic reticulum (ER) stress. Through integrative analyses of single-cell RNA-seq, cell-surface proteomes, and cellular biology, ER chaperone proteins (e.g., HSP90B1 and P4HB) are identified as potential neoantigens that translocate to the cell surface upon chronic ER stress. These results suggest that these proteins, especially in FLT3-ITD+ AML cells, show great promise as diagnostic markers and therapeutic targets. To explore the therapeutic potential, chimeric antigen receptor-natural killer (CAR-NK) cells targeting surface-localized HSP90B1 are engineered. These engineered cells show selective cytotoxicity both in vitro and in animal models. This study not only identifies neoantigens as specific biomarkers refining AML classification, but also emphasizes the potential of immunotherapy-based precision treatments for AML.

Keywords:  acute myeloid leukemia; cell surface chaperone; chimeric antigen receptor; chronic ER stress; immunotherapy; natural killer cell

DOI:  https://doi.org/10.1002/advs.202511573
Mol Cell. 2025 Oct 23. pii: S1097-2765(25)00817-2. [Epub ahead of print]

A structural basis for chaperone repression of stress signaling from the endoplasmic reticulum.

Lisa Neidhardt, Joanne Tung, Miriam Kuchersky, Jakub Milczarek, Vasileios Kargas, Katherine Stott, Rina Rosenzweig, David Ron, Yahui Yan.

  The endoplasmic reticulum (ER) unfolded protein response (UPR) is tuned by the balance between unfolded proteins and chaperones. Reserve chaperones suppress UPR transducers via their stress-sensing luminal domains, but the underlying mechanisms remain unclear. The ER chaperone AGR2 is known to repress the UPR transducer IRE1β. Here, structural prediction, X-ray crystallography, and NMR spectroscopy identify critical interactions between an AGR2 monomer and a regulatory loop in IRE1β's luminal domain. However, in the repressive complex, it is an AGR2 dimer that binds IRE1β. Cryoelectron microscopy (cryo-EM) reconstruction explains this feature: one AGR2 protomer engages the regulatory loop, while the second asymmetrically binds IRE1β's luminal domain's C terminus, blocking IRE1β-activating dimerization. Molecular dynamic simulations indicate that the second, disruptive AGR2 protomer exploits rare fluctuations in the IRE1β dimer that expose its binding site. Thus, AGR2 disrupts IRE1β dimers to suppress the UPR, priming the system for activation by chaperone clients that compete for AGR2.

Keywords:  endoplasmic reticulum; intestinal mucin; molecular chaperones; protein multimerization; signal transduction; transmembrane protein; unconventional splicing; unfolded protein response

DOI:  https://doi.org/10.1016/j.molcel.2025.09.032
Front Immunol. 2025 ;16 1633643

Ailanthone induces apoptosis in U-2OS cells through the endoplasmic reticulum stress.

Yue Zhang, Taiding Wu, Chang Li, Nianfang Luo, Jun Wang, Jingxian Li, Min Tian, Lei Liu, Ruiting Li, Jingyi Zhang.

   Background: Osteosarcoma (OS) is a malignant bone tumor that commonly occurs in children and adolescents, characterized by poor treatment outcomes and prognosis, highlighting the urgent need for alternative therapies. Endoplasmic reticulum stress (ERS) induces a series of cascade reactions known as the unfolded protein response (UPR), which is a crucial stress mechanism that cells utilize to cope with disrupted endoplasmic reticulum function and is widely involved in the apoptosis of tumor cells. Excessive UPR can lead to an overload of protein levels within cells, disrupting homeostasis and exhausting energy, ultimately inducing apoptosis in OS cells. Ailanthone (AIL), a natural compound derived from the root bark or stem bark of Ailanthus altissima (Mill.) Swingle, exhibits broad-spectrum anticancer activity across multiple tumor types. Its antitumor mechanism involves the modulation of endoplasmic reticulum stress (ERS)-associated proteins, including the upregulation of apoptotic markers (PERK, eIF2α, ATF4, CHOP) and pro-apoptotic factors (BAX, caspase-3, Bim), alongside the downregulation of the anti-apoptotic protein BCL-2. This study aims to investigate whether AIL induces apoptosis in OS cells via ERS.
Materials and methods: The effects of AIL (0-1.0 µmol/L) on the proliferation and migration of U-2OS cultured for 24 h were evaluated using the cell counting kit-8 assay and scratch wound healing assays. The optimal concentration of 0.6 µmol/L was selected for subsequent experiments. Western blot analysis was performed to measure the protein levels of ERS-related factors at different time points (0-24 h) following AIL treatment. Finally, the apoptosis rate of U-2OS cells after 24 h of culture at the optimal concentration was assessed by flow cytometry.
Results: AIL exhibited a dose-and time-dependent inhibitory effect on U-2OS cell growth, significantly reducing cell proliferation and migration rates while promoting apoptosis. After AIL treatment, the levels of ERS-related proteins and pro-apoptotic proteins increased, while anti-apoptotic protein level decreased.
Conclusion: AIL inhibited the proliferation of human OS cells and induced apoptosis through the ERS pathway. It represented a potential therapeutic agent for OS treatment.

Keywords:  Ailanthone; apoptosis; endoplasmic reticulum stress; osteosarcoma; unfolded protein response

DOI:  https://doi.org/10.3389/fimmu.2025.1633643
Blood Adv. 2025 Oct 20. pii: bloodadvances.2024015623. [Epub ahead of print]

Heme and hemozoin induce platelet cell death through UPR-induced apoptosis and ferroptosis in vivax malaria.

Milena Tavares Gomes, Isabel Matos Medeiros-de-Moraes, Adriana Vieira-de-Abreu, Isaclaudia G Azevedo-Quintanilha, Thayane Modesto Fontes, Alan De Brito Carneiro, Pedro Azambuja, Neal D Tolley, Jesse W Rowley, Barbara Albuquerque Carpinter, Marcelo U Ferreira, Raquel Muller Gonçalves-Lopes, Vinicius Novaes Rocha, Ana Lucia Rosa Nascimento, Wanessa Araújo Carvalho, Kézia K G Scopel, Robert A Campbell, Patricia Torres Bozza, Andrew S Weyrich, Guy A Zimmerman, Marcus V G Lacerda, Hugo C Castro Faria Neto, Eugenio Damaceno Hottz.

Malaria is a highly prevalent infectious disease caused by Plasmodium parasites. Plasmodium intraerythrocytic replication leads to hemolysis-driven intermittent febrile crisis in patients. Additionally, the lysis of unparasitized red blood cells (RBC) contributes to anemia and endotoxemia. Because thrombocytopenia is an important feature of vivax and severe falciparum malaria, we hypothesized that increased hemolysis in malaria contributes to severe thrombocytopenia by releasing endogenous and parasite toxins (i.e., heme and hemozoin) capable of inducing programmed cell death in platelets. Using complementary biochemical, ultrastructural, pharmacological and molecular approaches, we examined response to stress and cell death pathways that were elevated in the transcriptome of platelets during vivax malaria and evaluated markers of hemolysis that correlated with thrombocytopenia. We found that heme in plasma from thrombocytopenic vivax malaria, but not nonthrombocytopenic vivax or falciparum malaria, induced platelet cell death ex vivo. Platelet stimulation with heme and hemozoin induced apoptotic and necrotic cell death features, with stronger necrosis triggered by hemozoin. Heme and hemozoin activated apoptotic caspases, but only heme induced calpain-dependent Bcl-xL degradation, which was not required for platelet apoptosis. We unmasked a caspase-independent intrinsic apoptosis program mechanism depending on the endoplasmic reticulum (ER)-stress sensor and unfolded protein response (UPR) trigger IRE-Iα. We observed inflammasome activation, but not pyroptosis. Instead, we distinguished a necrotic cell death feature consistent with ferroptosis dependent on lipid peroxidation and regulated by DGAT1/2 enzymes, which was the main pathway for hemozoin-induced thrombocytopenia in vitro. Taken together, our results identify novel pathways of regulated cell death in platelets that were associated with thrombocytopenia in malaria and may have potential implications for other hemolytic disorders.

DOI: https://doi.org/10.1182/bloodadvances.2024015623
Oncol Rep. 2026 Jan;pii: 5. [Epub ahead of print]55(1):

LRRC59 inhibits perk pathway‑induced apoptosis and promotes cell proliferation, migration and invasion in colorectal cancer cells.

Xingdong Hou, Yuting Wang, Yuzhuo Chen, Peiyan Zhong, Guangzhi Wang, Baicheng Li, Bowei Lu, Hanyu Jiang, Shili Ning.

  Leucine‑rich repeat‑containing protein 59 (LRRC59), a 244‑amino‑acid endoplasmic reticulum membrane protein, is implicated in the tumorigenesis of multiple malignancies. However, its functional significance in colorectal cancer (CRC) remains poorly understood. In the present study, LRRC59 expression in CRC tissues was evaluated using immunohistochemistry and western blotting. Colony formation, Cell Counting Kit‑8, wound healing and Transwell assays, in in vivo xenograft models, were used to evaluate the effect of LRRC59 on CRC progression. Apoptosis was analyzed using flow cytometry and western blotting. The interaction between LRRC59 and the protein kinase RNA‑like endoplasmic reticulum kinase (PERK) pathway was verified using the starBase database and western blotting. It was found that LRRC59 expression was significantly higher in CRC tissues than in normal tissues. LRRC59 knockdown in HCT116 and LoVo cells inhibited proliferation, migration and invasion and promoted apoptosis, and the PERK pathway was significantly activated. In vivo subcutaneous tumorigenesis assays corroborated these in vitro findings. Treatment with a PERK pathway‑specific inhibitor reduced the apoptosis of HCT116 and LoVo cells with LRRC59 knockdown. These findings suggest that LRRC59 is not only significantly upregulated in CRC but also mechanistically drives tumor progression by coordinating pro‑oncogenic processes, including enhanced proliferation, migration and invasion. Importantly, mechanistic evidence was provided that LRRC59 inhibits apoptosis by suppressing the PERK signaling axis, identifying this molecule a target in the development of CRC therapeutic strategies.

Keywords:  PERK pathway; apoptosis; colorectal cancer; endoplasmic reticulum stress; leucine‑rich repeat‑containing protein 59

DOI:  https://doi.org/10.3892/or.2025.9010
Neurobiol Dis. 2025 Oct 22. pii: S0969-9961(25)00369-9. [Epub ahead of print] 107152

Endoplasmic reticulum in the axon: Insights into structural dynamics and implications in neurodegeneration.

Trang Dai Vu, Hyun Sung.

  The endoplasmic reticulum (ER) is an interconnected and highly dynamic organelle essential for multiple cellular functions. In neurons, the ER extends into axons, where it plays a pivotal role in maintaining neuronal polarity. The unique structural and dynamic adaptations of the axonal ER enable it to meet the specialized demands of neurons, ranging from compartmentalized physiological regulation to long-distance intracellular communication. Recent studies have shown that axonal ER supports the regulation of organelle remodeling and trafficking in a spatiotemporal manner, processes that become compromised in aged neurons. Moreover, disruptions in the structure and dynamics of the axonal ER have increasingly become associated with neurodegenerative diseases, including hereditary spastic paraplegia, amyotrophic lateral sclerosis, and peripheral neuropathies. This review synthesizes current knowledge of axonal ER biology, highlighting its structural and dynamic characteristics, its impact on organelle arrangement and distribution, and its pathological implications in neurodegeneration. By consolidating recent advances, this review outlines emerging questions and future directions in axonal ER research, a field gaining recognition for its contribution to neuronal dysfunction and neurodegenerative pathomechanisms.

Keywords:  Axon; Axonal transport; ER-shaping proteins; Endoplasmic reticulum; Membrane contact sites; Neurodegenerative diseases; Organelle dynamics

DOI:  https://doi.org/10.1016/j.nbd.2025.107152
Blood. 2025 Oct 20. pii: blood.2024026749. [Epub ahead of print]

The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.

Kentson Lam, Yoon Joon Kim, Evelyn Li-Ting Tan, Carlo Miguel Ong, Andrea Zoey Liu, Fanny Jiahua Zhou, Mary Jean Sunshine, Bernadette Chua, Silvia Vicenzi, Katelyn Zhining Chen, Helena Yu, Pierce Ford, Jie-Hua Zhou, Yuning Hong, Eric J Bennett, Leslie A Crews, Edward D Ball, Robert Signer.

Oncogenic growth places great strain and dependence on protein homeostasis (proteostasis). This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers at tolerable doses, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and increased autophagic flux to preserve proteostasis. Genetic inactivation of HSF1 sensitized AML cells to proteasome inhibition, marked by accumulation of unfolded protein, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival and significant slowing of disease progression and extension of survival in vivo. Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed human AML cells, and significantly reduced AML burden and extended survival in vivo. Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and colony formation, and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, compared to normal hematopoietic stem/progenitor cells. Combined autophagy/proteasome inhibition activated a terminal integrated stress response, which was surprisingly driven by Protein kinase R (PKR). These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.

DOI: https://doi.org/10.1182/blood.2024026749