bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–04–19
nineteen papers selected by
William Grey, University of York
  1. Intracellular IL-23R is necessary for mitotic spindle formation and viability in AML.
  2. Comparative analysis of NSG and NBSGW mice for preclinical evaluation of gene-modified human hematopoietic stem and progenitor cells.
  3. Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia.
  4. Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models.
  5. PTP4A2 Promotes Leukemogenesis through Inhibiting the p53 Tumor Suppressor Signaling Pathway in Leukemia-initiating Cells.
  6. 8-Me-PIQ Expands Cord Blood CD34+ Hematopoietic Stem and Progenitor Cells via Metabolic Suppression and Inhibition of Ribosome Biogenesis.
  7. CRISPR-Cas9 knockout screens to identify drug resistance genes in acute myeloid leukemia.
  8. Engineered hematopoietic stem cells give rise to therapeutic antibody secreting B cells.
  9. Allosteric inhibition of RAN decreases miR-126 biogenesis in endothelial cells and controls acute myeloid leukemia growth.
  10. Don't Cut the Cord: Why Umbilical Cord Blood Still Deserves a Place in Transplantation.
  11. Aging changes cell mechanics and dynamics associated with cytoplasmic crowding.
  12. Restoration of the immune system with base editing and non-genotoxic conditioning in a Rag2 point-mutant mouse model.
  13. CHK2-USP37 axis stabilizes FOXO4 to sustain senescence and evade apoptosis.
  14. Ubiquitin ligase RCHY1 regulates autophagosome-lysosome fusion.
  15. Nrf1 coordinates proteasome activity and autophagy to maintain cardiac proteostasis.
  16. B lymphocyte protein factories produced by hematopoietic stem cell gene editing.
  17. Phosphorylation of Cullin3 by the pseudokinase ALDH18A1 disrupts KEAP1-mediated NRF2 degradation.
  18. Three-dimensional architecture of human bone marrow.
  19. The metabolic profiles of cancer stem cells.
  1. Leukemia. 2026 Apr 17.
    Intracellular IL-23R is necessary for mitotic spindle formation and viability in AML.
    Nathan Duong, Dilshad H Khan, Geethu E Thomas, Yue Feng, Rose Hurren, Jong Bok Lee, Jonathan St-Germain, Lily Drimmer, Yongran Yan, Lan Xin Zhang, Karen Kai-Lin Fang, Dakai Ling, Mary L Ma, Neil MacLean, Marcela Gronda, Vincent Rondeau, Brandon D Brown, Laura Matellán, Courtney L Jones, Hong Chang, Andrea Arruda, Stephanie Xie, Laurence Pelletier, Mark D Minden, Li Zhang, Steven M Kornblau, Brian Raught, Kevin Jacobs, Max G Jacobs, Daniel Goede, Vito Spadavecchio, Aaron D Schimmer.
      Interleukin-23 receptor (IL-23R) is a cell surface cytokine receptor classically expressed on T cells, where it regulates T cell activation. Here, we discovered a novel intracellular localization and function for IL-23R in Acute Myeloid Leukemia (AML). Compared to normal hematopoietic cells, IL-23R was increased in primary AML samples. IL-23R was predominantly localized intracellularly in AML cells. BioID mass spectrometry identified mitotic spindle proteins as top interactors with IL-23R. We confirmed interaction between endogenous IL-23R and the mitotic spindle in AML cells and primary AML samples, and this interaction was mediated by IL-23R's (S/T)x(I/L)P motif. Genetic depletion of IL-23R disrupted mitotic spindle formation and reduced proliferation and stem cell/progenitor function of AML cell lines and primary AML samples. In contrast, depletion of IL-23R spared normal hematopoietic cells and progenitors. Thus, we discovered a novel intracellular function for IL-23R where this receptor regulates mitotic spindle formation and the growth of AML cells.
    DOI:  https://doi.org/10.1038/s41375-026-02949-8
  2. Stem Cell Res Ther. 2026 Apr 15.
    Comparative analysis of NSG and NBSGW mice for preclinical evaluation of gene-modified human hematopoietic stem and progenitor cells.
    Caroline Y Kuo, Sean Harrington, Beatriz Campo-Fernandez, Stacia K Wyman, Xiaomeng Wu, Ruixue Zhang, Alejandro Espinoza, Bruno J de Andrade Silva, Julie M Sanchez, Sorel Fitz-Gibbon, Chin-Hong Tseng, Matteo Pellegrini, Melissa Bonner, Zulema Romero.
      Humanized mouse models are essential for evaluating the engraftment capacity and genetic integrity of gene-modified hematopoietic stem and progenitor cells (HSPCs). Here, we compared two widely used xenotransplantation platforms, NSG and NBSGW mice, in the context of lentiviral vector (LVV) transduction and CRISPR/Cas9-mediated gene correction. HSPCs harboring high LVV copy numbers exhibited engraftment deficits in NSG mice that were not observed in NBSGW mice. This discrepancy highlights the potential for the NBSGW model to mask safety liabilities of LVV-modified products due to its higher overall levels of human chimerism. In contrast, CRISPR/Cas9 editing with a single-stranded oligodeoxynucleotide donor yielded comparable correction rates in both models, even across decreasing input cell doses, demonstrating that long-term repopulating hematopoietic stem cells (HSCs) retain equivalent engraftment capacity in each strain. Single-cell RNA-sequencing revealed distinct progenitor populations that were markedly under-represented in the NSG model but preserved in NBSGW recipients, emphasizing the greater capacity of NBSGW mice to better support multilineage human hematopoiesis. Together, these findings establish that both NSG and NBSGW mice are suitable for assessing long-term engraftment and gene modification outcomes in human HSPCs. However, the significantly higher percentage of human cell chimerism in the NBSGW model may obscure cell populations with engraftment deficits. Careful selection of in vivo models is therefore critical for rigorous preclinical evaluation of gene therapy products prior to clinical translation.
    Keywords:  CRISPR/Cas9; Hematopoietic stem and progenitor cells (HSPCs); Humanized mouse models; Lentiviral vector (LVV); Long-term engraftment
    DOI:  https://doi.org/10.1186/s13287-026-05010-8
  3. Blood Neoplasia. 2026 May;3(2): 100196
    Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia.
    Johnson Ung, Su-Fern Tan, Jeremy J P Shaw, Maansi Taori, Tess M Deddens, Giovana Venancio, McLane M Montgomery, James T Hagen, Raphael T Aruleba, Upendar R Golla, Arati Sharma, B Bishal Paudel, Irene Lee, Bhavishya Ramamoorthy, Kevin A Janes, Francine Garrett-Bakelman, Myles C Cabot, Kelsey H Fisher-Wellman, Todd E Fox, David F Claxton, Charles E Chalfant, David J Feith, Thomas P Loughran.
      Resistance to combination regimens containing the B-cell lymphoma 2 (BCL-2) inhibitor and BH3 mimetic venetoclax in acute myeloid leukemia (AML) is a growing clinical challenge for this extensively used agent. We previously established the antileukemic properties of ceramide, a tumor-suppressive sphingolipid, in AML, and demonstrated that upregulated expression of acid ceramidase (AC), a ceramide-neutralizing enzyme, supports leukemic survival and resistance to BH3 mimetics. Here, we report the antileukemic efficacy and mechanisms of cotargeting AC and BCL-2 in venetoclax-resistant AML. Analysis of the BeatAML data set revealed a positive relationship between increased AC gene expression and venetoclax resistance. Pharmacologic AC inhibition with the ceramide analog SACLAC enhanced single-agent venetoclax cytotoxicity and the venetoclax + cytarabine combination in AML cell lines with primary or acquired venetoclax resistance. SACLAC + venetoclax was synergistically lethal when evaluated ex vivo across a cohort of venetoclax-resistant (n = 21) and venetoclax-sensitive (n = 46) primary samples from patients with AML. Moreover, the SACLAC + venetoclax combination was equipotent to the combination of venetoclax + cytarabine at reducing cell viability across primary patient samples. Mechanistically, cotargeting AC and BCL-2 increased ceramide to levels that trigger a cytotoxic integrated stress response (ISR), ISR-mediated NOXA protein upregulation, mitochondrial dysregulation, and caspase-dependent cell death. Importantly, AC knockdown sensitized AML cells to venetoclax and induced NOXA protein accumulation, whereas NOXA knockdown protected against AC and BCL-2 cotargeting. Collectively, these findings demonstrate the efficacy of cotargeting AC and BCL-2, and rationalize targeting AC as a therapeutic approach for venetoclax-sensitive and -resistant AML.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100196
  4. Leukemia. 2026 Apr 15.
    Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models.
    Malathi Kandarpa, Luke F Peterson, Harish Potu, Megha Ramappan, Yihong Liu, Avery Polk, Shaomeng Wang, Moshe Talpaz.
      MDM2 is an E3 ubiquitin ligase that promotes p53 tumor suppressor degradation and has emerged as a therapeutic target in the treatment of wild-type (wt) TP53 tumors. In acute myeloid leukemia (AML), TP53 mutations are infrequent (15-20%), but wt-p53 is often inactivated through overexpression of MDM2. Thus, MDM2 inhibitors are currently in clinical trials for AML. However, p53 stabilization with inhibitors upregulates MDM2, which limits their clinical efficacy. Proteolysis-targeting chimeric (PROTAC) molecules that degrade MDM2 may overcome this feedback. MD-265 is a PROTAC that recruits CRBN, degrades MDM2, restores p53 and induces apoptosis. We tested MD-265 in ex vivo cultures of 105 primary leukemic stem cells (LSCs). The median cytotoxic IC50 for MD-265 was 16 nM, median IC50 for MI-1061 was 150-fold higher. LSCs with IC50 > 1 µM were classified as MD-265 resistant and harbored mutations in TP53. Normal hematopoietic stem cells showed 100-fold higher IC50 (818 nM) than LSCs. AML patient-derived xenograft (PDX) models in NSG-SGM3 mice were treated with MD-265 or an oral MDM2 inhibitor. In PDX models, MD-265 was not toxic and prolonged survival. MD-265 is a potent and specific MDM2 degrader with broad pre-clinical activity and a promising drug candidate for the treatment of leukemias.
    DOI:  https://doi.org/10.1038/s41375-026-02957-8
  5. Blood Adv. 2026 Apr 15. pii: bloodadvances.2025018908. [Epub ahead of print]
    PTP4A2 Promotes Leukemogenesis through Inhibiting the p53 Tumor Suppressor Signaling Pathway in Leukemia-initiating Cells.
    Shiyu Xiao, Michihiro Kopbayashi, Yunpeng Bai, Wenjie Cai, Sergio Barajas, Mohammed Abdullahel Amin, Sasidhar Vemula, Chonghua Yao, Yuxia Yang, Christopher Borchers, Tiffany M Mays, Magdalena Sotelo, Hao Pan, Yuzhi Jia, Jian Shen, Sophie Kimiko Kuriyama Hu, Moiez Ali, Sophia Veranga, Jayme Ogino, Sydney G Eggleston, Huiping Liu, Harris Perlman, Loretta Li, Jessica K Altman, Yasmin Abaza, Elizabeth A Eklund, Peng Ji, Christine R Zhang, Irum Khan, Lindsey D Mayo, James C Mulloy, Madina Sukhanova, Yali Dou, Leonidas C Platanias, Zhong-Yin Zhang, Hongxia Chen, Yan Liu.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy that is sustained by leukemia-initiating cells (LICs). While PTP4A2 phosphatase, as known as PRL2, is highly expressed in AML, the mechanisms by which PTP4A2 promotes leukemogenesis are largely unexplored. In this study, we demonstrate that PTP4A2 promotes AML by inhibiting the p53 tumor suppressor pathway in LICs. Using KMT2A-MLLT3-driven AML as a model, we found that PTP4A2 deficiency activates p53 and induces LIC apoptosis and senescence, thereby extending the survival of recipient mice repopulated with Ptp4a2-/- LICs. Mechanistically, PTP4A2 directly interacts with p53 and dephosphorylates it at serine 392, decreasing p53 stability and activity to enhance LIC proliferation and survival. Collectively, our findings identify p53 as a potential PTP4A2 substrate in leukemia cells and uncover a novel mechanism by which PTP4A2 enhances LIC maintenance.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018908
  6. Stem Cell Rev Rep. 2026 Apr 17.
    8-Me-PIQ Expands Cord Blood CD34+ Hematopoietic Stem and Progenitor Cells via Metabolic Suppression and Inhibition of Ribosome Biogenesis.
    Yu Li, Mengmeng Li, Bin Guo, Rongzhen Jiang.
      
    Keywords:   Ex-vivo expansion; Cord blood; Hematopoietic stem cells; Small molecule compounds
    DOI:  https://doi.org/10.1007/s12015-026-11115-7
  7. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00006-3. [Epub ahead of print]205 199-216
    CRISPR-Cas9 knockout screens to identify drug resistance genes in acute myeloid leukemia.
    Xin Yang, Jiaqi Cai, Jiayi Wang, Yanyu Meng, Yufang Shi, Huan Cai.
      Acute Myeloid Leukemia (AML) is a hematopoietic malignancy characterized by the uncontrolled proliferation of aberrant myeloid blasts within the bone marrow, resulting in disrupted hematopoiesis and severe clinical consequences. Drug resistance represents a major barrier in AML treatment, frequently manifesting as relapse following initial remission with conventional chemotherapeutic agents such as cytarabine and venetoclax. The underlying mechanisms of drug resistance include enhanced drug efflux, altered drug metabolism, and activation of pro-survival signaling pathways, necessitating the elucidation of specific genetic determinants to enable the development of effective therapeutic strategies. The advent of CRISPR/Cas9 system has facilitated precise genomic modifications, permitting the generation of cell libraries with targeted gene knockouts in AML cells. This approach can identify genes whose disruption alters drug sensitivity, implicating their involvement in survival and resistance to cell death. This protocol outlines a systematic strategy to uncover genes associated with drug resistance in AML cells by leveraging CRISPR/Cas9-mediated functional genomic screening. By employing this methodology, genes conferring drug susceptibility upon knockout are noted as potential drivers of drug resistance, offering valuable insights for the rational design of targeted therapies.
    Keywords:  Acute myeloid leukemia; CRISPR-Cas9 screen; Cytarabine; Drug resistance; Venetoclax
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.006
  8. Res Sq. 2026 Apr 06. pii: rs.3.rs-9269825. [Epub ahead of print]
    Engineered hematopoietic stem cells give rise to therapeutic antibody secreting B cells.
    Matthew Porteus, Sofia Luna, William Feist, Ashley Utz, Jumana Afaghani, Masashi Miyauchi, Hana Ghanim, Freja Ekman, Anais Amaya, Sridhar Selvaraj, Norman Russkamp, Ludwig Schmiderer.
      Monoclonal antibodies represent half of the top ten selling drugs. Their proven efficacy, however, generally requires repeated administration for prolonged periods of time. In contrast, cell-based therapies offer a different set of pharmacokinetics and pharmacodynamics than traditional medicines, including the potential to have lifetime durability after a single infusion. Here, we describe a genome-engineered stem cell-based platform for continuous antibody production from a single dose. Using CRISPR/Cas9 homology-directed repair mediated editing, we precisely integrated therapeutic antibody expression cassettes into a safe-harbor locus of hematopoietic stem and progenitor cells (HSPCs). Upon differentiation, these gene-targeted HSPCs generate B cells that secrete monoclonal antibodies. We validated this platform using two clinically approved antibodies, achieving efficient targeted integration of the gene-targeted antibodies (GT-Ab) in human HSPCs that successfully engraft in immunodeficient mice. Direct engineering of human B cells demonstrated robust secretion of therapeutic antibodies. To evaluate in vivo antibody production, we transplanted engineered GT-Ab murine HSPCs into immunocompetent mice, achieving durable serum antibody concentrations within the therapeutic range over several months. Lastly, by fusing the antibody to a destabilization domain, we enabled tunable antibody secretion via small molecule regulation. This modular platform establishes a potentially curative approach for chronic diseases currently reliant on repeated antibody administration, offering durable antibody production from a single treatment.
    DOI:  https://doi.org/10.21203/rs.3.rs-9269825/v1
  9. Commun Biol. 2026 Apr 14.
    Allosteric inhibition of RAN decreases miR-126 biogenesis in endothelial cells and controls acute myeloid leukemia growth.
    Melissa Valerio, Wenyuan Wei, Hyunjun Kang, Ning Ma, Supriyo Bhattacharya, Genevieve Baker, Weidong Hu, Lianjun Zhang, Dinh Hoa Hoang, Jia Feng, Hongyu Zhang, Bin Zhang, J Jefferson P Perry, Nagarajan Vaidehi, Le Xuan Truong Nguyen, Guido Marcucci.
      The small GTPase RAN plays a role in the biogenesis of mature miR-126, which is supplied by the bone marrow arterioles to leukemic stem cells (LSCs). MiR-126 supports the homeostasis of LSCs that initiate and maintain acute myeloid leukemia (AML). While therapeutic targeting of RAN has been difficult due to its structural features, through molecular dynamics simulations and docking studies, we have identified MAR-3.6.2 as a novel allosteric inhibitor that binds in a cryptic pocket in the C-terminal domain of RAN. We showed that MAR-3.6.2 disrupted RAN interaction with its guanine nucleotide exchange factor RCC1 and prevented the nuclear switch of RAN-GDP to RAN-GTP. This in turn led to RAN nuclear retention and reduced the RAN/XPO5-mediated export of pre-miR-126, thereby limiting mature miR-126 biogenesis in endothelial cells and their exogenous supply of mature miR-126 to LSCs. In a MllPTD/WT/Flt3ITD/ITD AML murine model, MAR-3.6.2 reduced leukemia burden, prolonged survival, and decreased LSC frequency in secondary transplants. These findings highlight MAR-3.6.2 and future, potential derivatives as a promising small molecule-based approach to eradicate AML LSCs via inhibition of RAN/XPO5 trafficking and block of miR-126 biogenesis.
    DOI:  https://doi.org/10.1038/s42003-026-10026-0
  10. Int J Immunogenet. 2026 Apr 15. e70050
    Don't Cut the Cord: Why Umbilical Cord Blood Still Deserves a Place in Transplantation.
    Jenna Nunn, Kay Poulton, Robert Wynn.
      The use of umbilical cord blood (UCB) as a stem cell source in haematopoietic stem cell transplant (HSCT) has greatly declined in recent years. It has largely been replaced by mismatched unrelated and family donors, facilitated by advances in transplant technologies, including post-transplant cyclophosphamide to prevent graft-versus-host disease (GVHD). UCB remains a distinctive source of haematopoietic stem cells (HSCs) with unique immunologic and practical advantages, including for those with malignant and non-malignant diseases. Compared to other cell sources, UCB transplantation (UCBT) offers comparable survival with reduced chronic GVHD (cGVHD) and with a potent graft-versus-leukaemia (GVL) effect. These outcomes likely reflect the biology of cord-derived lymphocytes-particularly naïve, adaptable CD8+ T-cells capable of rapid differentiation and tumour-directed cytotoxicity without sustained alloreactivity. UCB permits greater human leukocyte antigen (HLA) mismatch tolerance, especially when transplant is performed T-cell replete and can be accessed immediately, reducing time to transplant for high-risk leukaemia. In addition, recent advances in ex vivo expansion technologies have overcome historical limitations of low cell dose and delayed engraftment, expanding UCB's applicability to older paediatric and adult recipients. This review discusses the evidence of using UCB as a preferred stem cell source in patients with relapsed/refractory haematological malignancies and how we may interrogate the properties of UCB to improve outcomes in these high-risk cohorts.
    Keywords:  T‐lymphocytes; cord blood; graft‐versus‐host disease; leukaemia; relapse bone marrow transplant
    DOI:  https://doi.org/10.1111/iji.70050
  11. PNAS Nexus. 2026 Apr;5(4): pgag089
    Aging changes cell mechanics and dynamics associated with cytoplasmic crowding.
    Lani D Lee, Yuechuan Lin, Krishna C Penumatsa, Peter T C So, Ming Guo.
      Aging induces physical changes in organisms, many of which are at the cellular level, but the mechanisms underlying these changes are poorly understood. While the cytoplasm provides a crucial physical environment to host essential cellular processes, how its properties change in aging remains largely unknown. Here, using cells from well-established aging mice models, we first investigate the morphological and dynamic changes of aging cells and how they relate to the physical state of the cytoplasm. We find that aged cells spread larger and rounder and migrate slower than young cells. Using particle fluctuation, optical tweezers, and force spectrum microscopy, we demonstrate that aging increases cytoplasmic stiffness and reduces intracellular movement, even while active intracellular forces increase. In addition, using tomographic phase microscopy, we observe a higher refractive index in aged cells which indicates a denser cytoplasm, hinting that aging causes a more crowded cell interior. This crowding behavior underlines the increased cytoplasmic stiffness and the decreased intracellular movement, thereby influencing the altered cell behavior. Our results imply a crucial physical mechanism behind cellular-level changes due to aging. Though mechanisms behind these observations remain unclear, this understanding of cells' physical nature may support fundamental biological functions explored in aging research.
    Keywords:  aging; cell mechanics; cytoplasm; intracellular crowding
    DOI:  https://doi.org/10.1093/pnasnexus/pgag089
  12. Mol Ther. 2026 Apr 11. pii: S1525-0016(26)00275-3. [Epub ahead of print]
    Restoration of the immune system with base editing and non-genotoxic conditioning in a Rag2 point-mutant mouse model.
    Carla Dib, Jack A Queenan, Hana Willner, Leah Swartzrock, Carsten T Charlesworth, Morgane Denis, Jessie R Davis, Rina Mepani, Katie Ho, Madalena Castro, Ross C Wilson, Hiromitsu Nakauchi, David R Liu, Agnieszka Czechowicz.
      Transplantation of donor hematopoietic stem and progenitor cells (HSPCs) is a well-established curative treatment for various blood and immune diseases including severe combined immunodeficiency (SCID). However, it comes with significant toxicities including graft-versus-host disease (GvHD) and tissue damage resulting from use of genotoxic chemotherapy-containing conditioning regimens. Autologous transplantation using gene-modified HSPCs eliminates GvHD but currently still relies on genotoxic conditioning. Further, gene-modification of HSPCs has commonly utilized integrating viruses which carry risk of oncogenesis. The ideal therapy would eliminate the risks associated with current HSC gene-modification and conditioning approaches. Here, we combined base editors (BE), engineered virus-like particles (eVLPs) and non-genotoxic αCD117 antibody drug conjugate (ADC) conditioning to explore optimal curative treatment of SCID. We generated a Rag2 SCID mouse model with a single point mutation (pm) and corresponding BE. Rag2pm/pm HSPCs were corrected using SpCas9NG-ABE-eVLPs without off-target effects detected. Even in settings of low editing, transplantation of BE-corrected HSPCs into αCD117-ADC conditioned mice led to efficient immune cell production in peripheral blood with normal B-cell progenitors in the bone marrow. Combining αCD117-ADC conditioning with transplantation of HSPCs that were base edited using eVLPs successfully reversed the SCID phenotype in mice, showcasing a significant advancement in reducing treatment-related toxicities while enabling disease correction.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.04.010
  13. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2526252123
    CHK2-USP37 axis stabilizes FOXO4 to sustain senescence and evade apoptosis.
    Jiahui Sun, Anke Geng, Zhiwei Song, Lingjiang Chen, Zhen-Ning Zhang, Ying Jiang, Zhiyong Mao.
      Cellular senescence, a state of permanent cell cycle arrest, contributes to tissue dysfunction and aging through the accumulation of apoptosis-resistant senescent cells. Although the transcription factor FOXO4 is known to enhance senescent cell survival, the mechanisms regulating its stability have remained unclear. Here, we identify a DNA damage response (DDR)-driven CHK2-USP37-FOXO4 axis essential for maintaining the apoptotic resistance of senescent cells. We demonstrate that FOXO4 protein stability is elevated in stress-induced senescent cells, resulting from reduced ubiquitin-proteasomal degradation. A deubiquitinase screen identified USP37 as the key enzyme stabilizing FOXO4 through direct interaction and removal of K48-linked polyubiquitin chains. Depletion of USP37 destabilizes FOXO4 and sensitizes senescent cells to apoptosis. Mechanistically, persistent DDR signaling during senescence activates CHK2, which phosphorylates USP37 at Thr589, thereby enhancing its binding to FOXO4. Importantly, ablation of USP37 in senescent cells increases the rate of apoptosis, a phenotype that is rescued by FOXO4 reexpression. Together, our work unveils USP37 as a CHK2-regulated stabilizer of FOXO4 that maintains the apoptotic resistance of senescent cells, suggesting the CHK2-USP37-FOXO4 axis as a therapeutic target for age-related pathologies.
    Keywords:  DNA damage response (DDR); FOXO4; USP37; apoptosis; cellular senescence
    DOI:  https://doi.org/10.1073/pnas.2526252123
  14. Cell Death Discov. 2026 Apr 15.
    Ubiquitin ligase RCHY1 regulates autophagosome-lysosome fusion.
    Ruchi Umargamwala, Jantina Manning, Julian M Carosi, Donna Denton, Sharad Kumar.
      Autophagy is a fundamental cellular recycling process that maintains homeostasis during animal development and under nutrient-limiting conditions. In our previous work, we employed autophagy-dependent cell death (ADCD) in the obsolete Drosophila larval midgut as a model to identify the enzymes involved in protein modification via ubiquitination with potential roles in autophagy regulation. From a genetic screen we identified RING E3 ligase RCHY1 as a candidate regulator. Here, we demonstrate that RCHY1 is essential for autophagy regulation during larval midgut ADCD in Drosophila and promotes autophagic flux in HeLa cells. Loss of Rchy1 impaired autophagosome-lysosome fusion and led to the accumulation of amphisomes in larval midgut cells. Similarly, depletion of RCHY1 in HeLa cells disrupted autophagic flux and reduced autolysosome formation, indicating evolutionary conservation of its function. Collectively, our findings identify RCHY1 as a putative regulator of autophagy that facilitates autophagosome-lysosome fusion.
    DOI:  https://doi.org/10.1038/s41420-026-03088-w
  15. Commun Biol. 2026 Apr 17.
    Nrf1 coordinates proteasome activity and autophagy to maintain cardiac proteostasis.
    Lakindu P Kankanamge, Hyunji An, Qin Guo, Maksymillian Prondzynski, Soon Ho Kwon, Durgesh Anil Bonde, William T Pu, Eric N Olson, Miao Cui.
      Proteolytic stress frequently arises during disease and aging, particularly in long-lived, post-mitotic cells such as cardiomyocytes. To maintain proteostasis, cardiomyocytes depend on coordinated protein quality control pathways, including the ubiquitin-proteasome system and autophagy. Mechanisms that activate these pathways hold therapeutic potential for heart disease. Here, we demonstrate that transient activation of nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1), a transcriptional regulator of proteasome activity, in cardiomyocytes during ischemia/reperfusion injury improves cardiac function. In addition to regulating the proteasome, we identify a critical role for Nrf1 in activating autophagy, which is essential for its cardioprotective effects. Through multi-omics analyses, we define both transcriptional and post-transcriptional functions of Nrf1 that underlie its cardioprotective activity. Loss-of-function studies in mice demonstrate that Nrf1, but not its homolog Nrf2, is required for autophagy and baseline cardiac function. Together, our findings establish a dual function of Nrf1 in promoting cardiac proteostasis by regulating both proteasomal and autophagic protein quality control pathways. Activating Nrf1 thus offers a therapeutic strategy for treating ischemic heart disease.
    DOI:  https://doi.org/10.1038/s42003-026-10067-5
  16. Science. 2026 Apr 16. 392(6795): eadz8994
    B lymphocyte protein factories produced by hematopoietic stem cell gene editing.
    Harald Hartweger, Chiara Ruprecht, Kai-Hui Yao, Philippe Laffont, Gabriella Lima Dos Reis, Pengcheng Zhou, Thomas Hägglöf, Laurine Binet, Maximilian Loewe, Jun P Hong, Tianli Xiao, Esen Sefik, Brianna Hernandez, Anna Gazumyan, Mila Jankovic, Michael S Seaman, Giulia Costa, Sean A Nelson, Jordan Clark, Sachie Kanatani, Patrick C Wilson, Florian Krammer, Elena A Levashina, Jean-Philippe Julien, Hedda Wardemann, Photini Sinnis, Leonidas Stamatatos, Richard A Flavell, Michel C Nussenzweig.
      Long-term in vivo production of therapeutic proteins and development of vaccines that elicit protective levels of broadly neutralizing antibodies (bNAbs) against major pathogens face challenges. In this study, we report on an alternative gene editing approach using small numbers of hematopoietic stem and progenitor cells (HSPCs) to direct long-term, high-level expression of antibodies or cargo proteins. In mice, edited B lymphocytes derived from transplanted HSPCs were activated by cognate antigen, underwent clonal expansion, and developed into specific antibody-synthesizing or cargo protein-synthesizing plasma cells. These cells produced long-lasting, therapeutic levels of serum antibody against HIV-1, malaria, or an anti-influenza virus bNAb that mediated universal protection from heterologous lethal challenge. Our data provide a paradigm for cell therapy approaches to prevent or treat disease using self-amplifying B cell protein factories.
    DOI:  https://doi.org/10.1126/science.adz8994
  17. Biochem Biophys Res Commun. 2026 Apr 14. pii: S0006-291X(26)00526-7. [Epub ahead of print]817 153762
    Phosphorylation of Cullin3 by the pseudokinase ALDH18A1 disrupts KEAP1-mediated NRF2 degradation.
    Yunhao Chang, Qiao Chen, Xinlong Wan, Bo Chen, Zhigang Sun, Jianqing Wu, Shuhong Huang.
      The decline of the transcription factor NRF2 during aging contributes to impaired oxidative stress defense, yet the underlying mechanisms remain incompletely understood. Here we show that ALDH18A1 (P5CS) is downregulated in parallel with NRF2 in the airway epithelial cells of aged mouse lungs. Mechanistically, P5CS directly binds to Cullin3 and promotes its phosphorylation-a previously unrecognized post-translational modification of Cullin3-in a manner dependent on its kinase-like activity. This phosphorylation inhibits Cullin3 neddylation and disrupts its interaction with KEAP1, thereby impairing the ubiquitin ligase activity of the Cullin3-KEAP1 complex and leading to NRF2 stabilization. A kinase-dead mutant (T299I) or pharmacological inhibition of P5CS kinase-like activity abolishes this regulatory effect. Our findings identify Cullin3 phosphorylation as a novel regulatory mechanism controlling NRF2 stability and provide a molecular explanation for the age-related decline of NRF2 downstream of P5CS downregulation.
    Keywords:  ALDH18A1; Aging; Cullin3 phosphorylation; NRF2
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153762
  18. Nat Biomed Eng. 2026 Apr 17.
    Three-dimensional architecture of human bone marrow.
      
    DOI:  https://doi.org/10.1038/s41551-026-01644-4
  19. Stem Cell Res Ther. 2026 Apr 13.
    The metabolic profiles of cancer stem cells.
    Zuzana Tylichova, Borivoj Vojtesek, Philip J Coates.
      Cancer stem cells (CSCs) represent a minor but highly adaptable subpopulation within tumors that drives long-term growth, metastasis, and therapy resistance. Their ability to survive and regenerate under metabolic and therapeutic stress relies on a unique integration of energy flexibility, redox balance, and proteostatic programs. While bulk tumor cells typically favor aerobic glycolysis and high protein turnover, CSCs often exhibit elevated mitochondrial activity, fatty acid oxidation, and selective suppression of proteasome function. These metabolic features support quiescence, stress tolerance, and self-renewal. Beyond energy production, metabolic intermediates such as acetyl-CoA, succinate, and lactate serve as epigenetic cofactors, linking nutrient availability to chromatin remodeling and transcriptional plasticity. Reactive oxygen species and antioxidant responses further tune this balance, shaping the transition between glycolytic and oxidative CSC states. These intrinsic programs are continuously influenced by the tumor microenvironment, where hypoxia, cytokine-driven signaling, and metabolic coupling with stromal and immune cells modulate CSC metabolism and reinforce stemness. Despite rapid progress, major conceptual and methodological gaps still limit our understanding of CSC metabolism and this review highlights these unresolved issues and further outline key contextual factors-including tumor-intrinsic, microenvironmental, systemic, and metastatic cues-that shape CSC metabolism and help explain the divergent observations reported across studies. Understanding this network will be essential for designing combinatorial therapies that target CSC metabolism while accounting for their heterogeneity and plasticity.
    Keywords:  Cancer stem cells; Glucose; Glycolysis; Metabolism; Mitochondria; Proteasome
    DOI:  https://doi.org/10.1186/s13287-026-05014-4
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