bims-scepro 2026-01-04 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2026–01–04
eighteen papers selected by
William Grey, University of York

ER-diffusion barriers exist in hematopoietic stem cell mitoses, but are not required for lysosomal asymmetric cell division.
Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.
Molecular and phenotypic blueprint of human hematopoiesis links proliferation stress to stem cell aging.
Mutant p53 promotes clonal hematopoiesis through generating a chronic inflammatory microenvironment.
Laminin Receptor Characterization in Acute Myeloid Leukemia: Integrin α7β1 Defines leukemic cells with Migratory Potential.
Deep learning predicts haematopoietic stem cell ageing from 3D chromatin images.
Shear stress governs hematopoietic stem cell fate to promote inflammation-induced aging.
Biomacromolecule driven ex vivo expansion of hematopoietic stem cells: Molecular mechanisms and engineering strategies.
Hsp70-Bim interaction mediated mitophagy as a potential therapeutic target for CML stem cells.
Overcoming the sorafenib resistance mechanism in FLT3-mutated acute myeloid leukemia: molecular basis and new targets.
CDK4/6 inhibition overcomes venetoclax resistance mechanisms with enhanced combination activity in acute myeloid leukemia.
Methods for Measuring TNFα-Induced Autophagy in Cancer Cells.
PRKN-Mediated Ubiquitin-Proteasome Degradation of METTL3 Promotes Cellular Senescence.
PEX14 powers OPTN (optineurin) to drive peroxisome turnover.
Simultaneous single-cell proteomics and epigenetic analysis of histone deacetylase inhibition in human cells.
Highlights from the Susan Lindquist School on Proteostasis-EMBO|FEBS Lecture Course, 16-19 September, 2025, Espoo, Finland.
A multi-scale feature fusion of deep learning network for classifying acute leukemia genetic subtypes from blood smear images.
Genomic mechanisms of resistance to venetoclax in multiple myeloma with t(11;14)(CCND1;IGH).

Exp Hematol. 2025 Dec 31. pii: S0301-472X(25)00643-5. [Epub ahead of print] 105364

ER-diffusion barriers exist in hematopoietic stem cell mitoses, but are not required for lysosomal asymmetric cell division.

Florin Schneiter, Dirk Loeffler, Timm Schroeder.

  Hematopoietic stem cells (HSCs) maintain the blood system by balancing self-renewal versus mature blood cell generation. One mechanism contributing to this balance is asymmetric cell division (ACD), which relies on tightly regulated intracellular compartmentalization. In other cell types, endoplasmic reticulum diffusion barriers (ER-DBs) contribute to the targeted distribution of cellular components and cell fate regulators during ACDs. Here, we identify ER-DBs as a feature of a subset of HSC divisions. Using fluorescence recovery after photobleaching (FRAP) and time-lapse confocal microscopy, we observe ER-DBs in around 30% of mitotic HSCs. These ER-DBs are significantly weakened by Fingolimod, a potent inhibitor of sphingosine-1-phosphate receptor and ceramide synthesis, implicating sphingolipid metabolism in their regulation. We find that strong ER-DBs are not required for the asymmetric inheritance of lysosomes during HSC ACD. This demonstrates that ER diffusion barriers are present and regulated during HSC division and are an additional mechanism orchestrating molecular polarization and asymmetric inheritance in HSC divisions, independently of the mechanism regulating lysosomal asymmetry. TEASER ABSTRACT: Endoplasmic diffusion barriers (ER-DBs) control the distribution of cell fate regulators during divisions, also contributing to asymmetric cell division (ACD). Here, we demonstrate that ER-DBs are also present in a subset of HSC divisions and that their strength depends on sphingolipid metabolism. While they are not required for HSC lysosomal asymmetric cell division, these barriers are an additional mechanism orchestrating polarization and asymmetric inheritance in HSC divisions.

Keywords:  Endoplasmic reticulum; asymmetric cell division; diffusion barrier; expansion culture; hematopoietic stem cell; organelle inheritance; sphingolipids

DOI:  https://doi.org/10.1016/j.exphem.2025.105364
Science. 2026 Jan;391(6780): 52-58

Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.

Gaurav Agarwal, Mateusz Antoszewski, Xueqin Xie, Yash Pershad, Uma P Arora, Chi-Lam Poon, Peng Lyu, Andrew J Lee, Chun-Jie Guo, Tianyi Ye, Laila Barakat Norford, Anna-Lena Neehus, Lucrezia Della Volpe, Lara Wahlster, Diyanath Ranasinghe, Tzu-Chieh Ho, Trevor S Barlowe, Arthur Chow, Alexandra Schurer, James Taggart, Benjamin H Durham, Omar Abdel-Wahab, Kathy L McGraw, James M Allan, Ruslan Soldatov, Alexander G Bick, Michael G Kharas, Vijay G Sankaran.

Somatic mutations that increase the fitness of hematopoietic stem cells (HSCs) drive their expansion in clonal hematopoiesis (CH) and predispose individuals to blood cancers. Population variation in the growth rate and potential of mutant clones suggests that genetic factors may confer resilience against CH. Here, we identified a noncoding regulatory variant, rs17834140-T, that protects against CH and myeloid malignancies by selectively down-regulating the RNA-binding protein MSI2 in HSCs. By modeling variant effects and mapping MSI2 binding targets, we uncovered an RNA network that maintains human HSCs and influences CH risk. Variant rs17834140-T was associated with slower CH expansion, and stem cell MSI2 levels modified ASXL1-mutant HSC clonal dominance. These findings leverage natural resilience to illuminate posttranscriptional regulation in human HSCs, suggesting that inhibition of MSI2 or its targets could be rational strategies for blood cancer prevention.

DOI: https://doi.org/10.1126/science.adx4174
J Exp Med. 2026 Feb 02. pii: e20251805. [Epub ahead of print]223(2):

Molecular and phenotypic blueprint of human hematopoiesis links proliferation stress to stem cell aging.

Emanuele Lettera, Luca Basso-Ricci, Edoardo Carsana, Kety Giannetti, Teresa Tavella, Luca Seffin, Giacomo Farina, Nicolò Gualandi, Pamela Quaranta, Elena Lo Furno, Guido Pacini, Lucrezia Della Volpe, Kerstin B Kaufmann, Laura Garcia-Prat, Raisa Jofra Hernandez, Alex Murison, Alicia G Aguilar-Navarro, Stefano Beretta, Anastasia Conti, Eugenia Flores-Figueroa, Marco Ometti, Ivan Merelli, Alessandro Aiuti, Stephanie Z Xie, Serena Scala, Raffaella Di Micco.

Hematopoietic stem/progenitor cells (HSPC) aging has long been associated with myeloid skewing, reduced clonal output, and impaired regenerative capacity, but quantitative immunophenotypic and functional analysis across the human lifespan has been lacking. Here, we provide a comprehensive phenotypic, transcriptional, and functional dissection of human hematopoiesis from youth to advanced age. Although primitive hematopoietic stem cell (HSC) numbers were stable during aging, overall cellularity declined, especially for erythroid and lymphoid lineages. HSPCs from older individuals exhibited repopulating frequencies comparable with those from younger donors in both primary and secondary xenografts; however, aged HSCs displayed impaired differentiation, chromatin and cell cycle dysregulation, and poor tolerance to activation-induced proliferative stress, resulting in DNA damage and senescence-like features after xenotransplantation. Importantly, imposing proliferative stress on young human HSPCs in vivo recapitulated key aging-associated phenotypic and functional declines. Together, our findings identify dysregulated activation responses as a defining feature of HSPC aging and establish proliferative stress-based xenotransplantation models as powerful platforms for investigating age-related hematopoietic dysfunctions.

DOI: https://doi.org/10.1084/jem.20251805
J Clin Invest. 2025 Dec 30. pii: e184285. [Epub ahead of print]

Mutant p53 promotes clonal hematopoiesis through generating a chronic inflammatory microenvironment.

Sisi Chen, Sergio Barajas, Sasidhar Vemula, Yuxia Yang, Ed Simpson, Hongyu Gao, Rudong Li, Farzaneh Behzadnia, Sarah C Nabinger, David A Schmitz, Hongxia Chen, Wenjie Cai, Shiyu Xiao, Ruyue Luo, Mohammed Abdullahel Amin, Maegan L Capitano, James P Ropa, Aidan Fahey, Shuyi Zhou, Tiffany M Mays, Magdalena Sotelo, Hao Pan, Sophie K Hu, Sophia Veranga, Moiez Ali, Maria Shumilina, Reuben Kapur, Kehan Ren, Yuzhi Jia, Huiping Liu, Irum Khan, Yasmin Abaza, Jessica K Altman, Elizabeth A Eklund, Lucy A Godley, Christine R Zhang, Peng Ji, Seth L Masters, Ben A Croker, H Scott Boswell, George E Sandusky, Zhonghua Gao, Lindsey D Mayo, Sharon A Savage, Stephanie Halene, Yali Dou, Leonidas C Platanias, Madina Sukhanova, Yunlong Liu, Omar Abdel-Wahab, Yan Liu.

  Aged individuals with somatic TP53 mutations manifest clonal hematopoiesis (CH) and are at high risk of developing myeloid neoplasms. However, the underlying mechanisms are not fully understood. Here we show that inflammatory stress confers a competitive advantage to p53 mutant hematopoietic stem and progenitor cells (HSPCs) by activating the NLRP1 inflammasome and increasing the secretion of pro-inflammatory cytokines such as IL-1β, inhibiting wild type (WT) HSPC fitness in a paracrine fashion. During aging, mutant p53 dysregulates pre-mRNA splicing in HSPCs, leading to enhanced NF-κB activation and increased secretion of IL-1β and IL-6, thereby generating a chronic inflammatory bone marrow microenvironment. Furthermore, blocking IL-1β with IL-1β neutralizing antibody or inhibiting IL-1β secretion using gasdermin D (GSDMD) inhibitor decreases the fitness of p53 mutant HSPCs. Thus, our findings uncover an important role for mutant p53 in regulating inflammatory signaling in CH and suggest that curbing inflammation may prevent the progression of TP53-mutant clonal hematopoiesis to myeloid neoplasms.

Keywords:  Cytokines; Hematology; Hematopoietic stem cells; Inflammation; NF-kappaB

DOI:  https://doi.org/10.1172/JCI184285
Exp Hematol. 2025 Dec 25. pii: S0301-472X(25)00642-3. [Epub ahead of print] 105363

Laminin Receptor Characterization in Acute Myeloid Leukemia: Integrin α7β1 Defines leukemic cells with Migratory Potential.

Elsa Görsch, Saskia Rudat, Marlon Arnone, Hildegard Keppeler, Nandini Asokan, Jan C Schröder, Taylor Scott Mills, Lucas Mix, Lea Kramer, Jan Pauluschke-Fröhlich, Maksim Klimiankou, Jan Weller, Gerd Klein, Claudia Lengerke.

  Interactions with the bone marrow (BM) niche are crucial for promoting self-renewal and survival of acute myeloid leukemia (AML) cells. Consequently, AML cells express a variety of surface receptors to engage with BM niche cells and extracellular matrix proteins, including laminins. Despite the association of laminin receptors with stemness in healthy hematopoiesis, their role in AML remains poorly understood. In this study, we present a comprehensive examination of the laminin receptors integrin α3β1, α6β1, α7β1 and basal cell adhesion molecule (BCAM) in AML. We demonstrate that high mRNA expression of all four laminin receptors correlates with poor overall survival. Notably, integrin α6 and α7 display the highest cell surface density among the examined laminin receptors and are higher expressed on AML cells compared to healthy controls. Moreover, our results indicate that the absence of integrin α7 expression can identify cells with increased colony forming potential, even in patients that are negative for the stem cell marker CD34 usually used to enrich LSC. Re-analyzing survival data from the TCGA-AML cohort, integrin α7 expression further allows refinement of the risk stratification based on the LSC score where low LSC and integrin α7 levels confer superior survival. Lastly, integrin α7 appears to mark leukemic cells with enhanced migratory potential, which can be inhibited by the anti-integrin α7 blocking antibody in vitro and in vivo. Together, our results confirm the association of high laminin receptor expression with poor prognosis, and establish integrin α7 as marker of high migratory leukemic cells. TEASER ABSTRACT: Acute myeloid leukemia (AML) cells engage with supportive bone marrow niche cells and extracellular matrix (ECM) proteins through surface receptors. Here, we demonstrate that high mRNA expression of the laminin receptors integrin α3β1, α6β1, α7β1 and BCAM correlates with poor overall survival. Moreover, integrin α7 expression marks leukemic cells displaying enhanced migratory potential. Together, we believe that our study significantly advances our understanding of AML-ECM interactions, and provides important insights that might be instrumental in the development of future therapies addressing therapy resistance in AML.

Keywords:  acute myeloid leukemia; bone marrow niche; integrin α7β1; laminin receptors; leukemic stem cells; migration and homing

DOI:  https://doi.org/10.1016/j.exphem.2025.105363
bioRxiv. 2025 Dec 15. pii: 2025.12.11.693143. [Epub ahead of print]

Deep learning predicts haematopoietic stem cell ageing from 3D chromatin images.

Pablo Iáñez Picazo, Eva Mejía-Ramírez, Dario Di Bari, Elena Vitali, M Carolina Florian, Paula Petrone.

The functional decline of the haematopoietic system during ageing propagates detrimental effects on the whole organism, ultimately eroding life and healthspan. Quantifying haematopoietic ageing holds great scientific and clinical relevance. Alterations in chromatin architecture are a well-established hallmark of ageing that encode rich and informative signatures of the ageing process, yet they remain largely unexplored as quantitative markers. Here, we present an interpretable deep learning approach based on convolutional neural networks, ChromAgeNet, that learns changes in the spatial features of chromatin architecture during natural aging of Hematopoietic Stem Cells (HSCs). We trained our algorithm on 3D microscope images of DAPI-stained HSC nuclei to discriminate between young and aged murine HSCs, achieving and AUROC of 0.77 ± 0.03. This approach outperforms classical machine learning models trained on handcrafted chromatin features from the same dataset. We then applied explainable artificial intelligence techniques, identifying chromatin entropy, peripheral heterochromatin and chromatin condensates as predictive markers. As a proof of concept, we evaluated the potential of our model as a phenotypic screening tool for aged HSCs treated with epigenetic drugs to detect rejuvenation. Altogether, we demonstrate that changes in chromatin organization can be modeled via machine learning to predict cellular ageing in the hematopoietic compartment. Our developed framework, ChromAgeNet, serves as an interpretable algorithm to unravel the intricate relationship between chromatin changes and cellular ageing, and advance high throughput drug screening for rejuvenation therapies.

DOI: https://doi.org/10.64898/2025.12.11.693143
Nat Aging. 2026 Jan 02.

Shear stress governs hematopoietic stem cell fate to promote inflammation-induced aging.

Tongyao Shang, Li Zhao, Shibo Ying, Lida Su, Yue Yang, Jiadong Liu, Yingying Wang, Jipeng Xue, Cheng Cheng, Yixin Wu, Shiyao Chen, Hongmei Dong, Xuequn Chen, Hailin Ma, Qi Zhang, Tingbo Liang, Wei Yang, Ye Feng, Marong Fang, Xinjiang Lu.

Hematopoietic stem cells (HSCs) reside in the bone marrow in a quiescent state, but can be mobilized into the blood in response to inflammation, cytokine stimulation, nervous activity or hypoxia. Chronic inflammation, a hallmark of aging, accelerates HSC aging by promoting myeloid-biased differentiation and reducing self-renewal capacity, yet the role of mechanical stimulation in regulating these processes remains poorly understood. Here, we found that PIEZO1 senses shear stress in blood flow to induce HSC proliferation and myelopoiesis. We show that shear stress induces PIEZO1-mediated ion currents and Ca2+ influx in both mouse and human HSCs, with downstream effects on proliferation and myeloid differentiation mediated via JAM3 and CAPN2 pathways. GsMTx4, a PIEZO1 antagonist, attenuated inflammation-induced aging in mice by inhibiting HSC activation. These findings link the mechanical sensor PIEZO1 to HSC proliferation and myeloid differentiation via multi-tiered signaling, highlighting its role in accelerating inflammation-induced aging.

DOI: https://doi.org/10.1038/s43587-025-01039-1
Int J Biol Macromol. 2025 Dec 29. pii: S0141-8130(25)10514-X. [Epub ahead of print] 149957

Biomacromolecule driven ex vivo expansion of hematopoietic stem cells: Molecular mechanisms and engineering strategies.

Langyu He, Jingjing Zhu, Huan Fang, Hongxi Liu, Yuen Yee Cheng, Shuo Wu, Yiming Zhong, Bo Pan, Kedong Song.

  With the advancement of regenerative medicine and precision healthcare, ex vivo expansion of hematopoietic stem cells (HSCs) holds significant promise for clinical transplantation, gene therapy, and drug screening. However, achieving large-scale expansion while preserving stemness and long-term repopulating capacity remains a substantial challenge. This review summarizes recent advances in multimodal strategies for HSCs expansion from both molecular and engineering perspectives, with a particular emphasis on biomacromolecular regulation. At the molecular level, we discuss how cytokines and stromal cell co-culture systems mediate niche-derived biomacromolecular signals that preserve HSCs stemness. At the engineering level, we emphasize recent modifications in biomaterial structures, such as porous scaffolds, nanofibers, and hydrogels-that improve the presentation and delivery of biomacromolecular cues. These innovations significantly improve the precision and scalability of HSCs expansion. We further examine bioreactor systems that regulate microenvironmental conditions and molecular gradients to support consistent, large-scale expansion. We propose an integrated evaluation framework that combines ex vivo and in vivo biomacromolecular readouts to assess stemness preservation and translational potential of expanded HSCs. Future expansion platforms are expected to integrate smart biomaterials, artificial intelligence, and organ-on-a-chip technologies to enable programmable control of biomacromolecular signaling. These advances may help overcome current limitations in efficiency, consistency, and cost, ultimately providing customizable clinical-grade HSCs products.

Keywords:  Biomacromolecules; Biomimetic materials; Bioreactor; Cytokine; Ex vivo expansion; Hematopoietic stem cell; Hydrogels and nanofiber scaffolds; Stromal cell

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149957
Stem Cell Reports. 2025 Dec 26. pii: S2213-6711(25)00355-8. [Epub ahead of print] 102751

Hsp70-Bim interaction mediated mitophagy as a potential therapeutic target for CML stem cells.

Ting Song, Yang Song, Hong Zhang, Zhiyuan Hu, Fangkui Yin, Maojun Jiang, Yanxin Zhang, Ziqian Wang, Zhichao Zhang.

  In chronic myeloid leukemia (CML), disease persistence in patients is maintained by leukemic stem cells (LSCs), which drive tyrosine kinase inhibitor (TKI) resistance. Autophagy has been proposed as a potential therapy to eradicate CML LSCs. Here, using a small-molecule inhibitor of Hsp70 (heat shock protein 70)-Bim (Bcl-2-interacting mediator of cell death) interaction, S1-10, we demonstrate that Hsp70-Bim is a target for CML stemness maintenance. Hsp70-Bim is driven by Bcr-Abl and mediates particularly stronger mitophagy in CML LSCs than differentiated CML cells and HSCs. The more selective mitophagy regulation of Hsp70-Bim than ULK1 (unc-51-like autophagy activating kinase 1) is illustrated. Pharmacological inhibition of Hsp70-Bim blocks mitophagy, leading to the differentiation of CML LSCs, loss of quiescence, and loss of LSC self-renewal potential. In the patient-derived xenograft (PDX) CML models, S1g-10 reduces the number of LSCs by more than 80% after two weeks of injection, without obvious toxicity on normal red blood cells.

Keywords:  Hsp70-Bim; chronic myeloid leukemia; leukemia stem cells; mitophagy; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.stemcr.2025.102751
Front Oncol. 2025 ;15 1713174

Overcoming the sorafenib resistance mechanism in FLT3-mutated acute myeloid leukemia: molecular basis and new targets.

Hui Peng, Min Li, Yuan Yuan Peng, Xiao Lan Li, Jing Yang, Qiang Ge Sun, Kui Song.

  Acute myeloid leukemia (AML) originates from myeloid hematopoietic stem cells. Approximately 30% of patients exhibit FMS-like tyrosine kinase 3 (FLT3) mutations clinically, which is associated with a poor prognosis. FLT3 tyrosine kinase inhibitors (FLT3-TKIs), including sorafenib, demonstrate efficacy in FLT3-mutated AML, but resistance remains a significant challenge. However, various mechanisms have led to the rapid development of resistance to sorafenib treatment, including both primary and secondary drug resistance. Primary resistance refers to sorafenib's initial treatment failure due to redundant signaling pathways and tumor heterogeneity, while secondary resistance develops after prolonged therapy through new genetic mutations or activation of alternative pathways. This study systematically examines mechanisms of sorafenib resistance in AML, including tumor genetic changes and the bone marrow microenvironment. It outlines classic mechanisms, such as FLT3 functions, kinase mutations, and cellular signaling pathways, while also addressing gaps in knowledge regarding resistance driven by metabolic factors and the bone marrow environment. Furthermore, the paper explores novel FLT3 inhibitors and combination therapies, while outlining future directions for precision intervention through dynamic monitoring of clonal evolution. This review provides a comprehensive framework for understanding and addressing sorafenib resistance, offering insights into future therapeutic strategies for FLT3-mutated AML.

Keywords:  AML; FLT3 inhibitors; FLT3 mutations; sorafenib resistance; targeted therapy

DOI:  https://doi.org/10.3389/fonc.2025.1713174
Cell Rep Med. 2025 Dec 29. pii: S2666-3791(25)00599-3. [Epub ahead of print] 102526

CDK4/6 inhibition overcomes venetoclax resistance mechanisms with enhanced combination activity in acute myeloid leukemia.

Melissa L Stewart, Jessica Gibbs, Kevin Watanabe-Smith, Ariel Nguyen, Isabel Kenna, Karina Thiel-Klare, Andy Kaempf, Daniel Bottomly, Stephen E Kurtz, Christopher A Eide, Nicola Long, Jennifer N Saultz, Luca Sax, Ariane Huang, Shannon K McWeeney, Bill H Chang, Jeffrey W Tyner.

  Venetoclax (ven) combined with azacytadine is a widely used therapy for acute myeloid leukemia (AML). However, most patients develop resistance. To identify more effective combinations, we analyze 302 AML patient samples and find ven plus palbociclib (ven+palbo), a cyclin dependent kinase (CDK)4/6 inhibitor, to be highly effective. Ven+palbo shows synergistic activity in AML cell lines and patient-derived xenograft mouse models. Patient samples exhibiting a synergistic response to ven+palbo show downregulation of genes involved in protein synthesis. Genome-wide (CRISPR) screening shows that loss of translational genes uniquely confers sensitivity to ven but not to ven+palbo. AML cells exposed to ven exhibit an adaptive increase of protein synthesis that is overcome by ven+palbo through regulation of translational machinery. Additionally, ven+palbo mitigates resistance mechanisms observed with single-agent ven (BAX loss) and palbo (RB1 loss). Finally, we identify the loss of IKZF1 as a mechanism of resistance to ven+palbo and show that targeting AXL is effective in IKZF1-mutated AML.

Keywords:  cell state; monocytic; progenitor; targeted therapy

DOI:  https://doi.org/10.1016/j.xcrm.2025.102526
Methods Mol Biol. 2026 ;2983 143-158

Methods for Measuring TNFα-Induced Autophagy in Cancer Cells.

Sheyda Najafi, Ehab M Abo-Ali, Vikas V Dukhande.

  Autophagy is an evolutionarily conserved cellular mechanism in eukaryotes that plays an important role in the maintenance of cellular homeostasis. The autophagy process maintains protein homeostasis by recycling damaged organelles and degrading many long-lived or damaged proteins through lysosomes in coordination with the ubiquitin-proteasome system. Cytokines are low molecular weight secreted proteins that regulate a broad range of biological activities. For instance, pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα) induce inflammation, autophagy, and apoptotic cell death. In this chapter, we discuss experimental techniques such as immunoblotting and fluorescence microscopy that can be utilized to measure autophagy in response to TNFα treatment.

Keywords:  Apoptosis; Autophagy; Bafilomycin A1; Chloroquine; Fluorescence microscopy; Immunoblotting; LC3; TNFα; p62

DOI:  https://doi.org/10.1007/978-1-0716-4901-5_14
Aging Cell. 2026 Jan;25(1): e70347

PRKN-Mediated Ubiquitin-Proteasome Degradation of METTL3 Promotes Cellular Senescence.

Liping Chen, Canfeng Zhang, Yuanlong Ge, Haoxian Zhou, Shenglong Yang, Wenjing Wei, Qinghua Zhou, Kaizhen Xiao, Guangyu Huang, Xiaocui Li, Jia Wang, Jinping Zheng, Ronghe Gu, Zhenyu Ju, Shu Wu.

  N6-methyladenosine (m6A) methylation, a dynamic and reversible modification of eukaryotic mRNAs, plays critical roles in diverse cellular processes. Although METTL3-mediated m6A deposition has been implicated in cellular senescence, the mechanisms controlling METTL3 stability and activity during senescence remain poorly defined. Here, we demonstrate that both m6A levels and METTL3 protein abundance are significantly reduced in replication-induced and stress-induced senescence models. METTL3 depletion promotes senescence by inducing telomere dysfunction via diminished expression of shelterin components TRF2 and POT1. Mechanistically, we identify PRKN (Parkin) as a senescence-associated E3 ubiquitin ligase that promotes METTL3 proteasomal degradation through K48-linked polyubiquitination at lysine 164. Genetic PRKN inhibition in pre-senescent cells rescues METTL3 expression, restores TRF2/POT1 levels, reduces telomere dysfunction-induced foci (TIFs), and attenuates senescence-associated β-galactosidase (SA-β-gal) activity. Crucially, PRKN overexpression accelerates telomere dysfunction and senescence in wild-type METTL3-expressing cells but not in cells expressing the ubiquitination-resistant K164R METTL3 mutant. Our findings establish METTL3 ubiquitination as a pivotal regulator of telomere integrity and senescence progression, unveiling a therapeutic target for age-related pathologies.

Keywords:  METTL3; PRKN; m6A; senescence; telomere

DOI:  https://doi.org/10.1111/acel.70347
Autophagy. 2025 Dec 31. 1-3

PEX14 powers OPTN (optineurin) to drive peroxisome turnover.

Hongli Li, Jorge E Azevedo, Marc Fransen.

  Cells maintain organelle integrity and metabolic balance through tightly coordinated quality control systems. Autophagy plays a central role by recycling damaged and unnecessary cellular components, with selective pathways providing specificity through dedicated receptors. Although OPTN is well-established as a receptor for mitophagy, aggrephagy, and xenophagy, its role in pexophagy, the selective autophagic degradation of peroxisomes, has only recently been recognized. Our recent work identifies the peroxisomal membrane protein PEX14 as a critical docking platform for OPTN, enabling recruitment of autophagic machinery and initiation of pexophagy. How PEX14 engages OPTN, what triggers this interaction, and how it drives the autophagic engulfment of peroxisomes remain unclear. In this punctum, we contextualize our findings and highlight unresolved questions that must be addressed to understand the physiological and pathological relevance of this process.

Keywords:  Autophagy receptors; TBK1; organelle quality control; peroxisome biogenesis; pexophagy; phosphorylation; ubiquitination

DOI:  https://doi.org/10.1080/15548627.2025.2610452
Commun Biol. 2025 Dec 30.

Simultaneous single-cell proteomics and epigenetic analysis of histone deacetylase inhibition in human cells.

Benjamin C Orsburn.

Single-cell proteomics by mass spectrometry (SCP) is an emerging technology in which hundreds or thousands of proteins can be directly quantified in typical human cells. As the proteins detected and quantified by SCP are heavily biased toward proteins of highest abundance, chromatin proteins are an attractive target for analysis. To this end, I applied SCP to the analysis of cancer cells treated with mocetinostat, a class specific histone deacetylase inhibitor. I find that 16 PTMs can be confidently identified and localized with high site specificity in single cells. Drug treatment reveals apparent heterogeneity in the abundance and distribution of the accumulated acetylation sites in histone tails. While other techniques exist to measure histone modifications in single human cells, the approach presented here allows simultaneous quantification of hundreds of proteins, allowing phenotypic insight as well as epigenetic inferences in each individual cell. All raw and processed data described in this study has been made publicly available through the ProteomeXchange/MASSIVE repository system as MSV000093434.

DOI: https://doi.org/10.1038/s42003-025-09452-3
FEBS Lett. 2026 Jan 03.

Highlights from the Susan Lindquist School on Proteostasis-EMBO|FEBS Lecture Course, 16-19 September, 2025, Espoo, Finland.

Emile van Weert, Chiara Giacomelli, Ioanna Stefani, Maria Li Lopez-Bautista, Antonia-Viktoria Neumeier, Pubali Paul, Anushka Das, Chetan Hari, Ahmet Sadik Gulgec.

  The maintenance of protein homeostasis is a fundamental premise for the survival of all life. The synthesis, folding, localization, and degradation of thousands of proteins must be organized according to various conditions. To ensure such a stable and functional proteome, the proteostasis network evolved. Dedicated to this, the fourth School on Proteostasis, a co-funded EMBO|FEBS Lecture Course in memory of Susan Lindquist, took place in Espoo, Finland on 16-19 September 2025, with 59 early career researchers (PhD students or postdoctoral fellows), 18 leading scientists, and two editors attending and discussing the current state of the field. From basic principles to the latest therapeutic developments, this meeting provided a comprehensive overview of proteostasis. This report summarizes the lecture course and highlights selected presentations.

Keywords:  aging and disease; molecular chaperones; protein degradation; protein quality control; proteostasis; stress responses

DOI:  https://doi.org/10.1002/1873-3468.70261
Discov Oncol. 2026 Jan 02.

A multi-scale feature fusion of deep learning network for classifying acute leukemia genetic subtypes from blood smear images.

Wuchen Yang, Li Ma, Jigang Xiao, Shuiqing Liu, Zhiwen Luo, Yi Wang, Xingqin Huang, Jingya Liu, Cong Han, Tinglu Tao, Xing Qiang, Hongyang Zhang, Yang Gou, Yimei Feng, Cheng Zhang, Ting Huang, Xiangui Peng, Jing Wen, Xi Zhang.



Keywords:  Acute leukemia; Acute lymphoblastic leukemia; Acute myeloid leukemia; Deep learning; DropBlock; Efficient multi-scale attention; Genetic subtypes; ResNet50

DOI:  https://doi.org/10.1007/s12672-025-03985-z
Blood. 2026 Jan 02. pii: blood.2025029996. [Epub ahead of print]

Genomic mechanisms of resistance to venetoclax in multiple myeloma with t(11;14)(CCND1;IGH).

Marcella Kaddoura, Julia Erin Wiedmeier-Nutor, Vikas A Gupta, Tomas Jelinek, Bachisio Ziccheddu, Suganti Shivaram, Hongwei Tang, Rebecca W Owens, Tereza Ševčíková, Rodrigo Fonseca, Michael A Durante, Benjamin T Diamond, Logan Zhao, Yuan Xiao Zhu, Chang-Xin Shi, Shannon M Matulis, Constantine S Mitsiades, Carl Ola Landgren, Saad Z Usmani, Roman Hajek, Marta Chesi, P Leif Bergsagel, Esteban Braggio, Lawrence H Boise, Rafael Fonseca, Shaji K Kumar, Francesco Maura, Linda B Baughn.

Multiple myeloma (MM) with t(11;14)(CCND1;IGH) remains the only subset sensitive to the BCL2 inhibitor venetoclax. Not all t(11;14)(CCND1;IGH) patients respond to treatment and some progress early after initial response. To investigate this, we interrogated 44 whole genome and exome sequencing data from 34 patients with t(11;14) MM treated with venetoclax. The presence of mutations in the RAS pathway was strongly associated with shortened progression-free survival (PFS) and was validated in an independent cohort of 21 MM patients. Presence of 1q gain was also associated with shorter PFS in patients without RAS mutations. In 10 patients with paired, pre- and post-venetoclax treatment samples, post-venetoclax progression was recurrently driven by the selection of genomic events in BCL2/MCL1 and RAS pathways and of high-risk features (e.g., loss of TP53 and CDKN2C). Overall, our study shows that comprehensive genomic profiling can identify most mechanisms underlying resistance to BCL2 inhibition in t(11;14)(CCND1;IGH) MM.

DOI: https://doi.org/10.1182/blood.2025029996