bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–06–14
seventeen papers selected by
William Grey, University of York
  1. Multiome-based identification of molecular markers for prospective identification of platelet-biased HSCs.
  2. Aging-Driven Reprogramming of CD34⁺ Hematopoietic Stem Cells in Leukemogenesis: Mechanisms and Therapeutic Implications.
  3. Organelle proteomics reveals novel metabolic vulnerabilities in FLT3-ITD cells.
  4. STING1 senses mitochondrial damage to promote mitophagy.
  5. A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
  6. Architectural fragility of gene regulatory networks underlies hematopoietic stem cell aging.
  7. Linezolid Acts as a Selective Inhibitor of the JAK2 V617F Mutation.
  8. Integrated proteogenomic and metabolomic profiling of acute myeloid leukemias to identify molecular subtypes and associated therapy targets.
  9. Synergistic cooperation between progranulin and Jak2/Stat3 signaling determines definitive myeloid cell fate.
  10. Cell size modulates ferroptosis susceptibility.
  11. SIRT3 regulates PRDX3 acetylation to support mitochondrial peroxide detoxification and limit oxidative stress-associated ferroptosis vulnerability.
  12. Cell size-dependent mRNA transcription drives proteome remodeling.
  13. Mutation-dependent responses to sleep and exercise in clonal haematopoiesis.
  14. Targeting SMC3 deacetylation synergizes with XPO1 inhibition to reprogram the epigenetic landscape and suppress NPM1-mutated acute myeloid leukemia.
  15. CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
  16. Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases.
  17. Long-range mutual activation establishes Rho and Rac polarity during cell migration.
  1. Stem Cell Reports. 2026 Jun 11. pii: S2213-6711(26)00170-0. [Epub ahead of print] 102959
    Multiome-based identification of molecular markers for prospective identification of platelet-biased HSCs.
    Bowen Zhang, Yiran Meng, Esther Rodríguez Correa, Xiying Ren, Alexandre Fagnan, Michael D Milsom, Claus Nerlov.
      Platelet-biased hematopoietic stem cells (PLT-HSCs) play key roles in normal physiology, aging, and blood cancer. However, currently, no markers allow their accurate identification or prospective isolation. We here combine single-mouse hematopoietic stem cell (HSC) gene expression, chromatin accessibility, and surface proteome profiling to identify subtype-specific markers. Using machine learning, we identified markers (CD61hiCD274hiCD357loCD27lo) that isolate PLT-HSCs to high purity, validated by single-cell transplantation. Furthermore, we develop a minimal expression marker panel that discriminates PLT- and multi-lineage (MUL-)HSCs using microfluidics-based single-cell RT-qPCR. We show that both methods detect the age-associated increase in PLT-HSCs, while poly(I-C)-induced chronic inflammation did not alter HSC lineage bias. In contrast, romiplostim treatment increased MUL-HSC prevalence. Finally, using spectral flow cytometry to simultaneously quantify cell cycle and HSC lineage bias, we show that platelet depletion selectively activates PLT-HSCs. Together, these approaches allow accurate isolation of PLT-HSCs and robust quantification of lineage bias under perturbation.
    Keywords:  hematopoietic stem cells; lineage bias; platelet-biased HSCs; single-cell multiomics
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102959
  2. Mech Ageing Dev. 2026 Jun 11. pii: S0047-6374(26)00064-3. [Epub ahead of print] 112212
    Aging-Driven Reprogramming of CD34⁺ Hematopoietic Stem Cells in Leukemogenesis: Mechanisms and Therapeutic Implications.
    Surya Nath Pandey, Muhammad Afzal, A Rekha, Mano Priya Vijayan, Prerna Uniyal, Chandana Maji, Abida Khan, Lakshmi Thangavelu, Karuppiah Nagaraj.
      Aging is a major driver of hematological impairment and a significant risk factor for hematologic malignancies. CD34⁺ hematopoietic stem and progenitor cells (HSPCs) represent a critical cellular compartment in which age-related changes converge to promote leukemogenesis. This review synthesizes contemporary findings on the interplay between intrinsic hallmarks of aging, including genomic instability, telomere attrition, epigenetic drift, and mitochondrial dysfunction, and extrinsic factors, including chronic inflammation and bone marrow niche remodeling, in the reprogramming of CD34⁺ cell fate. These alterations promote clonal hematopoiesis of indeterminate potential (CHIP), impair immune competence, and increase susceptibility to malignant transformation. Special attention is directed towards CD34⁺CD38⁻ subsets, which possess leukemic stem cell (LSC) functionality and demonstrate resistance to standard treatments. Emerging biomarkers, including CD123, CD96, IL1RAP, and CD133, are discussed in relation to disease progression and therapeutic targeting. We emphasize how aging-related inflammatory signaling and metabolic changes preferentially benefit pre-leukemic clones. Ultimately, we investigate therapeutic approaches designed to disrupt leukemogenesis by focusing on aging mechanisms, the senescent microenvironment, and vulnerabilities specific to leukemic stem cells (LSCs). This review contextualizes CD34⁺ cell biology within aging mechanisms, offering a cohesive view on illness onset and highlighting prospects for early intervention in older populations.
    Keywords:  Aging; CD34(+) cells; Clonal hematopoiesis; Hematopoietic stem cells; Leukemic stem cells; Leukemogenesis
    DOI:  https://doi.org/10.1016/j.mad.2026.112212
  3. Leukemia. 2026 Jun 09.
    Organelle proteomics reveals novel metabolic vulnerabilities in FLT3-ITD cells.
    Valeria Bica, Anna Francesca Pacilè, Martin Boettcher, Valentina Marano, Veronica Marabitti, Francesca Nazio, Mirko Cortese, Thomas Fischer, Livia Perfetto, Dimitrios Mougiakakos, Giorgia Massacci, Francesca Sacco.
      In acute myeloid leukemia (AML), the insertion site of internal tandem duplications (ITDs) within the FLT3 gene critically determines the sensitivity to tyrosine kinase inhibitors (TKIs). Despite recent advances, patients harboring ITDs in the tyrosine kinase domain (TKD) still lack effective therapeutic options. To elucidate the molecular basis underlying the differential TKI sensitivity of FLT3-ITD cells, we integrated high-resolution mass spectrometry-based (phospho)proteomics with subcellular fractionation. Our analysis revealed that midostaurin induces the subcellular redistribution of approximately 2500 proteins involved in crucial biological processes, including cell cycle control, autophagy, and metabolism. Functional analyses further demonstrated that the ITD insertion site determines the autophagy response to midostaurin and modulates mitochondrial metabolism, influencing organelle architecture and ATP production, even at steady state. Importantly, by integrating subcellular proteomic dataset with functional metabolic assays, we uncovered a lipid-dependent vulnerability of FLT3-ITD cells: lipid restriction enhances FLT3 trafficking to the plasma membrane, and markedly reduces cell viability, restoring midostaurin sensitivity of resistant FLT3-ITD cells. Together, our findings reveal that the FLT3-ITD insertion site orchestrates a coordinated remodeling of subcellular protein organization, autophagy, and metabolism, and identify lipid-mediated control of FLT3 compartmentalization as a therapeutically actionable mechanism to overcome TKI resistance in FLT3-ITD AML.
    DOI:  https://doi.org/10.1038/s41375-026-03000-6
  4. Autophagy. 2026 Jun 13.
    STING1 senses mitochondrial damage to promote mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Hayden Weng Siong Tan, Han-Ming Shen, Guang Lu.
      The cGAS-STING1 pathway is essential for innate immunity, while its functions beyond immune activation have emerged as a key research topic. Recent studies have revealed the non-canonical roles of this pathway in autophagy. However, whether it participates in organelle quality control through selective autophagy processes such as mitophagy remains largely unexplored. In our study, we identify the cGAS-STING1 pathway as an essential upstream regulator of PINK1-PRKN-dependent mitophagy. We demonstrate that upon mitochondrial damage, STING1 is recruited to damaged mitochondria in a process requiring PINK1- and VCP/p97-mediated degradation of outer mitochondrial membrane proteins. STING1 at damaged mitochondria then activates TBK1, which phosphorylates the mitophagy receptor OPTN at Ser177, enhancing its recruitment to damaged mitochondria and driving efficient mitophagy. Disruption of the STING1-TBK1-OPTN axis impairs mitophagy and shifts the cellular response from pro-survival mitophagy to apoptosis. Our findings therefore uncover a non-canonical, pro-survival function of the cGAS-STING1 pathway in mitophagy, extending its role beyond innate immunity to the regulation of selective autophagy and cell fate decisions. Abbreviations: BafA1: bafilomycin A1; cGAS: cyclic GMP‑AMP synthase; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; NAC: N-Acetylcysteine; Nec-1: Necrostatin-1; OMM: outer mitochondrial membrane; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RIPK1: receptor interacting serine/threonine kinase 1; ROS: reactive oxygen species; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; VCP/p97: valosin containing protein; Z-VAD-FMK: benzyloxycarbony (Cbz)-l-ValAla-Asp (OMe)-fluoromethylketone.
    Keywords:  Cell death; OPTN; PINK1-PRKN-dependent mitophagy; cGAS-STING1 pathway; innate immunity; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2026.2689463
  5. Nat Commun. 2026 Jun 10.
    A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
    Sarin Segev-Nakar, Itay Koren.
      Peroxisomes are essential organelles involved in lipid and reactive oxygen species metabolism, and their function requires proper targeting of peroxisomal membrane proteins (PMPs). When peroxisome biogenesis fails, as occurs in peroxisome biogenesis disorders, PMP levels decrease markedly, yet the underlying mechanisms remain unclear. Here, using quantitative proteomics and transcriptomics in peroxisome-deficient cells, we observe widespread post-transcriptional downregulation of PMPs driven by increased protein turnover via ubiquitination and proteasomal degradation. An unbiased CRISPR screen uncovers a mitochondrial quality control axis. PMPs that fail to reach their native peroxisomal destination are rerouted to mitochondria, where the mitochondrial outer membrane E3 ligases MUL1 and MARCH5 act redundantly to promote their degradation. Importantly, the transmembrane domain of PMPs is sufficient to drive their mitochondrial turnover. Functionally, simultaneous loss of peroxisomes and mitochondrial E3 ligases severely impairs cell proliferation, underscoring the essential role of this pathway. Together, these findings provide insight into the pathology of organelle dysfunction and reveal an inter-organelle quality control axis in which mitochondria act as a surveillance hub to clear PMPs and maintain cellular proteostasis when peroxisomes are absent.
    DOI:  https://doi.org/10.1038/s41467-026-74117-6
  6. bioRxiv. 2026 Jun 04. pii: 2026.06.03.729976. [Epub ahead of print]
    Architectural fragility of gene regulatory networks underlies hematopoietic stem cell aging.
    Harlan P Stevens, Ali Doğa Yücel, Russell A Gould, George Cai, Vadim N Gladyshev, Alexandru M Plesa, George M Church.
      Hematopoietic stem and progenitor cell (HSPC) aging contributes to immune dysfunction and age-associated disease, but its regulatory mechanisms remain unclear. Here, we present the largest single-cell multiome atlas of human circulating HSPCs to date, with >380,000 paired RNA and ATAC profiles across 77 donors. Beyond recapitulating established hallmarks of HSPC aging, we reconstructed a high-resolution gene regulatory network and identified a global rewiring in which stress-response and myeloid transcription factor (TF) programs expand, while self-renewal and lymphoid lineage-defining circuitry collapses. We associate these phenotypes with increased cis-regulatory entropy, including elevated transcriptomic noise, weakened peak-to-gene coupling, and chromatin peak broadening. This rewiring is selective, where TFs with GC-rich, promoter-proximal architectures are preserved or amplified, and complex, distal enhancer-dependent identity networks are eroded. Thus, these findings suggest that progressive entropic destabilization of gene regulatory architecture simultaneously drives stress hyperactivation, myeloid bias, and identity loss in aging HSPCs.
    DOI:  https://doi.org/10.64898/2026.06.03.729976
  7. bioRxiv. 2026 Jun 03. pii: 2026.05.31.729063. [Epub ahead of print]
    Linezolid Acts as a Selective Inhibitor of the JAK2 V617F Mutation.
    Anisa Azatovna Gumerova, Christoph Schaniel, Zixing Huang, Althea Agdamag, Shuhui Liu, Alessandro Principi, Jacob Kazmi, Francisco Fueyo Gonzalez, Jihong Cui, Georgii Pevnev, Caliana Yang, Zehra Tumoglu, Xin Gao, Tony Yuen, Yelena Ginzburg, Jeffrey Glassberg, Shozeb Haider, Mone Zaidi, Ronald Hoffman, Huihui Li.
      The JAK2 V617F (JAK2 VF ) driver mutation is found in 95% of patients with polycythemia vera (PV), a progressive myeloproliferative neoplasm. Current treatments suppress excessive hematopoiesis but lack specificity for targeting JAK2 VF cells, are unable to deplete mutant stem/progenitor cells and ultimately result in drug resistance. We discovered that the FDA-approved antibiotic, linezolid (LZD), ameliorates the PV phenotype across multiple model systems. LZD suppressed cell proliferation and STAT5 signaling, altered the cell cycle, and increased apoptosis of JAK2 VF -harboring human erythroleukemia cells, but not in wild-type acute leukemia cells. Computational modelling indicated that LZD interacts specifically with mutant JAK2 VF but not with wild-type JAK2 protein. We further showed that, in JAK2 VF mice that faithfully recapitulate human PV, LZD mitigates disease burden by selectively targeting JAK2 VF stem cells thereby normalizing spleen size and blood counts. LZD also inhibited hematopoietic colony formation by patient-derived peripheral blood mononuclear cells, with the more primitive progenitors being preferred targets. Importantly, LZD selectively decreased JAK2 VF+ colony numbers, without impacting wild-type JAK2 colonies. In all, the data provide a firm foundation for evaluating LZD-like molecules as an effective therapy for PV and other myeloproliferative neoplasms.
    Key points: Linezolid acts as a JAK2 V617F IZselective inhibitor in PV mouse models and PV patient samples while sparing wildIZtype hematopoiesis. Linezolid acts directly on JAK2 V617F hematopoietic stem cells.
    DOI:  https://doi.org/10.64898/2026.05.31.729063
  8. Nat Cancer. 2026 Jun 12.
    Integrated proteogenomic and metabolomic profiling of acute myeloid leukemias to identify molecular subtypes and associated therapy targets.
    Clinical Proteomic Tumor Analysis Consortium
      Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous hematological malignancy. Here, to better define this clinically taxing and translationally challenging malignancy, we applied a multiomics approach, consisting of 13 modalities to analyze 173 treatment-naive individuals with AML. By integrating these 'omes', we identified distinct AML subtypes, genotype-phenotype associations, biomarkers and pathobiological mechanisms. Across the spectrum of primitive and committed AML, we found extensive metabolomic and lipidomic reprogramming driven by divergent MYC and mTOR activity. We linked metabolic changes to striking hyperacetylation of mitochondrial proteins in CEBPA-mutant AML. Protein-centric subtyping revealed a distinct NPM1-mutant subset characterized by outlier expression of FOXC1 and HOXB8/9. To nominate therapeutic targets across subtypes, we developed a multiomic machine-learning approach and validated MTA1 as a contributor to panobinostat resistance. Altogether our findings underscore the complex nature of AML and provide a clinically and translationally informed unified view that reveals coalescent phenotypes across multiomic layers.
    DOI:  https://doi.org/10.1038/s43018-026-01175-6
  9. Cell Rep. 2026 Jun 10. pii: S2211-1247(26)00555-3. [Epub ahead of print]45(6): 117477
    Synergistic cooperation between progranulin and Jak2/Stat3 signaling determines definitive myeloid cell fate.
    Abbigail McCune, Masuma Khatun Usha, Inga Baldus, C J Willett, Noemi Ferrito, Radwa Barakat, Emilee Clemensen, Elizabeth Snella, Mark Morton, Jesus Lacal, Giulia Pavani, Clyde A Campbell, Raquel Espin-Palazon.
      Perturbations in cell fate disrupt tissue homeostasis and drive diseases such as cancer. The JAK/STAT pathway is central to hematopoietic malignancies, yet its regulators in cell fate decisions remain poorly defined. Here, we identify progranulin (GRN) as a critical determinant of myeloid fate through the regulation of JAK2/STAT3 signaling. Using inducible stat3 and grna zebrafish models, knockout approaches, FACS, transcriptomics, and CUT&RUN, we show that Stat3 induces grna, which in turn amplifies stat3 expression, reinforcing myeloid over erythroid commitment. Lineage tracing and live imaging reveal that this Grna/Stat3 feedback operates during definitive, but not primitive, myelopoiesis. Functionally, definitive myeloid cells drive tissue repair, whereas primitive counterparts are less effective. Myeloid differentiation in a human leukemia line required GRN co-stimulation of JAK2/STAT3, highlighting its conserved role in fate determination. These findings uncover a regulatory axis controlling hematopoietic commitment and identify GRN as a potential therapeutic target in diseases with aberrant JAK2/STAT3 activation.
    Keywords:  CP: developmental biology; CP: stem cell research; JAK2/STAT3; developmental hematopoiesis; embryonic macrophages; leukemia; myeloid differentiation; progranulin; tissue regeneration; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2026.117477
  10. Elife. 2026 Jun 10. pii: RP111544. [Epub ahead of print]15
    Cell size modulates ferroptosis susceptibility.
    Evgeny Zatulovskiy, Magdalena B Murray, Shuyuan Zhang, Scott J Dixon, Jan M Skotheim.
      Size is a fundamental property of cells that influences many aspects of their physiology. This is because cell size sets the scale for all subcellular components and drives changes in the composition of the proteome. Given that large and small cells differ in their biochemical composition, we hypothesized that they should also differ in how they respond to signals and make decisions. Here, we investigated how cell size affects the susceptibility of human cells to cell death. We found that large cells are more resistant to ferroptosis caused by system xc- inhibition. Ferroptosis is a type of cell death characterized by the iron-dependent accumulation of toxic lipid peroxides. This process is opposed by cysteine-dependent lipid peroxide detoxification mechanisms. We found that larger cells exhibit higher concentrations of the cysteine-containing metabolite glutathione and lower concentrations of membrane lipid peroxides. Mechanistically, this can be explained by the fact that larger cells had lower concentrations of an enzyme that enriches cellular membranes with peroxidation-prone polyunsaturated fatty acids, ACSL4, and increased concentrations of the glutathione-producing enzymes glutamate-cysteine ligase and glutathione synthetase, the iron-chelating protein ferritin, and the lysosomal protease cathepsin B, which can catabolize cysteine-rich extracellular proteins to produce additional cystine for fueling the synthesis of glutathione. Taken together, our results highlight the significant impact of cell size on cellular function and survival, revealing a size-dependent vulnerability to ferroptosis that could influence therapeutic strategies based on this cell death pathway.
    Keywords:  biochemistry; cell biology; cell death; cell size; chemical biology; erastin2; ferroptosis; glutathione; heterogeneous response; human; scaling
    DOI:  https://doi.org/10.7554/eLife.111544
  11. Free Radic Biol Med. 2026 Jun 11. pii: S0891-5849(26)00876-2. [Epub ahead of print]
    SIRT3 regulates PRDX3 acetylation to support mitochondrial peroxide detoxification and limit oxidative stress-associated ferroptosis vulnerability.
    Tiange Wang, Jun Tu, Xiangyun Wei, Zi Liang, Rong Cai, Qiuju Fan, Jianli He, Tianshi Wang, Jinke Cheng.
      Oxidative stress disrupts mitochondrial redox homeostasis and contributes to ferroptosis-associated vulnerability, yet the molecular link between impaired mitochondrial peroxide detoxification and ferroptosis-associated vulnerability remains incompletely defined. Here, we identify PRDX3 as a candidate SIRT3-regulated effector of mitochondrial peroxide control. In AML12 cells, oxidative stress reduced mitochondrial SENP1, increased SIRT3 SUMOylation and elevated mitochondrial protein acetylation. Mitochondrial acetylome profiling identified PRDX3 K92 as a SIRT3-responsive acetylation site. Genetic activation of SIRT3 reduced PRDX3 acetylation and was associated with enhanced PRDX3 dimerization, improved peroxide clearance and reduced mitochondrial H2O2, lipid peroxidation, iron accumulation and other ferroptosis-associated changes. Conversely, an acetylation-mimetic PRDX3 mutant impaired peroxide clearance and attenuated the protective phenotype associated with SIRT3 activation, whereas a deacetylation-mimetic mutant improved redox balance and cell viability under oxidative stress. In vivo, activation of the SIRT3-PRDX3 axis mitigated paraquat-induced liver injury. Collectively, these data support a model in which SIRT3-dependent regulation of PRDX3 acetylation helps sustain mitochondrial peroxide detoxification and limits oxidative injury during stress.
    Keywords:  PRDX3; SIRT3; ferroptosis; lysine acetylation; mitochondrial peroxide detoxification; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.021
  12. Cell Rep. 2026 Jun 10. pii: S2211-1247(26)00566-8. [Epub ahead of print]45(6): 117488
    Cell size-dependent mRNA transcription drives proteome remodeling.
    Dong Shin You, Christopher H Bohrer, Purva H Rumde, Ioannis Sanidas, Matthew P Swaffer, Daniel R Larson, Josh E Elias, Michael C Lanz, Jan M Skotheim.
      Increasing cell size drives proteomic changes that impact cell physiology. However, the molecular basis of size-dependent proteome remodeling has remained unclear. Here, we develop an inducible Cyclin D1 expression system in human cells to generate proliferating cells spanning over a 2-fold size range. We use this system to make comprehensive genome-wide measurements of mRNA and protein concentrations and stability. We find that protein and mRNA turnover rates are weakly related to cell size but that mRNA concentrations are strongly size-dependent. This establishes that transcriptional regulation is the basis of proteome remodeling. Live-cell imaging of nascent mRNAs using the MS2 system is used to measure how transcriptional dynamics change with cell size. Larger cells prolong transcriptional bursts but maintain similar burst amplitudes to achieve transcriptional scaling. Together, our results show how transcription is modulated by cell size to remodel the proteome and alter cell physiology.
    Keywords:  CP: molecular biology; bursting; cell biology; cell size; homeostasis; lysosome; scaling; single-molecule imaging; transcription; turnover
    DOI:  https://doi.org/10.1016/j.celrep.2026.117488
  13. Nature. 2026 Jun 10.
    Mutation-dependent responses to sleep and exercise in clonal haematopoiesis.
    Teresa Gerhardt, Walter Jacob, Lena Gaebel, Merlin Heiser, Christopher Wolfram, Pacific Huynh, Tetsushi Nakao, Bernardo Gindri Dos Santos, Pamela Toh, Aaron Douglas, Niki F Brisnovali, Emir Radkevich, Md Mesbah Uddin, Abi G Yates, Annie Khamhoung, Nader Yatim, Matteo Gianeselli, Máté G Kiss, Sukanya Goswami, Daniella Nelson, Rachel Chen, Darwin D'Souza, Zhihong Chen, Seunghee Kim-Schulze, Trevor Fidler, Daniel Ezzat, Shaan Khurshid, Alexander G Bick, Pradeep Natarajan, Patrick T Ellinor, Abha K Rajbhandari, Miriam Merad, Filip K Swirski, Oren Cohen, Leigh Goedeke, Michael C Honigberg, Cameron S McAlpine.
      Clonal haematopoiesis (CH) activates inflammation and increases the risk of atherosclerosis1,2. Whether lifestyle alters CH clone expansion or the phenotypic programming of CH mutant cells, thereby affecting atherosclerosis, is unknown. Here, in humans and mice and across mutations in Jak2, Tet2, Trp53 and Dnmt3a, we demonstrate mutation-dependent responses to sleep and exercise in CH and show that mutant cells are uniquely sensitive to lifestyle. In two human datasets, moderate-to-vigorous physical activity was associated with lower prevalence of non-DNMT3A-driven CH. In atherogenic mice with Jak2V617F or Tet2 loss of function (LOF), but not Trp53 LOF or Dnmt3aR878H CH, uninterrupted sleep or exercise curtails clone expansion. In CH with the Jak2V617F mutation, sleep and exercise reduces clone expansion by selectively reprogramming mutant, but not cohabitant wild type, haematopoietic progenitor cells towards antiproliferative and metabolically healthy phenotypes by tempering bone marrow macrophage-haematopoietic progenitor cell IL-1β signalling. Sleep or exercise also lessens Jak2V617F-driven, Tet2 LOF-driven and Trp53 LOF-driven, but not Dnmt3aR878H-driven, atherosclerosis by locally reprogramming mutant vascular macrophages, independent of peripheral clone dynamics. In Jak2V617F, but not adjacent wild type, aortic macrophages, uninterrupted sleep blunts CLEC4E-dependent inflammasome activation, consequently diminishing lesions. Exercise, meanwhile, activates PAC1+ neurons in the locus coeruleus, raising the levels of peripheral noradrenaline, which signals through adrenergic receptor β2 (ADRβ2) whose expression is preserved by exercise in Jak2V617F, but not cohabitant wild type, aortic macrophages, selectively repressing their inflammatory programming and atherosclerosis. Our findings establish that healthy lifestyles gene-specifically diminish CH and selectively reprogram mutant haematopoietic progenitor cells and macrophages to maintain cardiovascular health.
    DOI:  https://doi.org/10.1038/s41586-026-10634-0
  14. Nat Commun. 2026 Jun 11.
    Targeting SMC3 deacetylation synergizes with XPO1 inhibition to reprogram the epigenetic landscape and suppress NPM1-mutated acute myeloid leukemia.
    Jianfeng Fu, Huilin Xu, Xinying Zhao, Mengge Gao, Yonglu Tian, Yingjun Chang, Xiaofeng Zheng.
      Acute myeloid leukemia (AML) is a prevalent hematologic malignancy. Mutations in Nucleophosmin (NPM1c) is the most frequent genetic alterations in AML. However, the epigenetic regulatory mechanisms of this AML subtype remain unclear. The cohesin complex, regulated by the acetyltransferase ESCO2, orchestrates chromatin organization and regulates gene expression. Here, we show that loss of ESCO2 promotes the progression of NPM1-mutated AML by destabilizing cohesin and the NuRD complex on chromatin, thereby enhancing the expression of genes associated with leukemia self-renewal capacity. Pharmacological HDAC8 inhibition restores SMC3 binding and induces differentiation and apoptosis in NPM1-mutated AML cells. Simultaneously targeting HDAC8 and nuclear exporter XPO1 reverses aberrant epigenetic landscape and represses self-renewal gene expression induced by ESCO2 deficiency. The combined treatment effectively eliminates NPM1-mutated AML cell lines and primary human AML cells in vitro and in vivo. This study reveals an ESCO2 deficiency-induced aberrant epigenetic landscape via SMC3 hypoacetylation and identifies a potential therapeutic strategy for NPM1-mutated AML.
    DOI:  https://doi.org/10.1038/s41467-026-74343-y
  15. Nat Commun. 2026 Jun 09. pii: 5072. [Epub ahead of print]17(1):
    CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
    Chengquan Huang, Yixue Zhang, Han Gao, Yuxin Song, Shunchang Hu, Chaoyue Sun, Shiwen Duan, Dongxiao Ma, Xiumei Jiang, Gang Liu.
      Mitochondrial proteostasis-maintaining mechanisms are crucial for protecting cells from the toxicity of misfolded protein accumulation. Although excessive stress is known to inactivate these mechanisms and thereby induce mitophagy in cancer cells, the detailed molecular mechanisms coordinating these mitochondrial quality control processes remain unclear. Herein, we identify CLPX, a mitochondrial protease subunit, as an iron-sulfur protein, which requires a [4Fe-4S] cluster to bind with CLPP to exert proteolysis function. Iron chelation impairs the assembly of the [4Fe-4S] cluster onto CLPX, thereby disrupting mitochondrial proteostasis maintenance and inducing mitophagy. Furthermore, cysteine deprivation caused by excessive reactive oxygen species accumulation hinders iron-sulfur cluster biosynthesis, thereby undermining CLPX function and inducing mitophagy. Our research elucidates an iron-sulfur cluster-dependent mechanism sustaining mitochondrial proteostasis.
    DOI:  https://doi.org/10.1038/s41467-026-74080-2
  16. Signal Transduct Target Ther. 2026 Jun 09. pii: 224. [Epub ahead of print]11(1):
    Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases.
    Ankush Borlepawar, Marco Neu, Ziqi Ma, Anushka Deshpande, Hannah Bühringer, Parvana Hajieva, Norbert Frey, Ashraf Yusuf Rangrez.
      Cellular protein homeostasis, or proteostasis, underpins the integrity, adaptability, and survival of all cells by balancing protein synthesis, folding, trafficking, and degradation. This multilayered network is sustained by coordinated actions of molecular chaperones, the ubiquitin‒proteasome system, autophagy-lysosomal pathways, and organelle-specific quality control programs. When this equilibrium collapses, misfolded, aggregated, or damaged proteins accumulate, driving organelle dysfunction, maladaptive stress signaling, and disease progression. Disruption of proteostasis is now recognized as a unifying pathological hallmark linking neurodegenerative disorders, cancer, cardiovascular and metabolic diseases, and autoimmune conditions. This is particularly consequential in post-mitotic organs such as the heart and brain, which possess limited regenerative capacity and are exceptionally vulnerable to proteotoxic stress. Rapid advances now reveal proteostasis as a multicomponent, cross-compartmental, and dynamically adaptable system, rather than isolated pathways. We frame this complexity through the concept of proteostasis resilience, defined as the ability of cells and tissues to maintain proteome stability under stress, and use it to unify disease mechanisms with therapeutic opportunity. This review integrates mechanistic insights with translational advances, outlining how dysregulation of chaperones, autophagy-mitophagy, the ubiquitin‒proteasome system, and ER stress pathways drive human diseases, while highlighting emerging therapeutic platforms, from pharmacological chaperones and autophagy modulators to targeted protein degradation technologies, CRISPR screens, spatial biology, and AI-guided drug discovery. Together, this systems-level perspective positions proteostasis resilience as a foundational paradigm for understanding disease vulnerability and designing precision proteostasis-based therapies.
    DOI:  https://doi.org/10.1038/s41392-026-02714-4
  17. Nat Cell Biol. 2026 Jun 10.
    Long-range mutual activation establishes Rho and Rac polarity during cell migration.
    Henry De Belly, Andreu F Gallén, Evelyn Strickland, Dorothy C Estrada, David Sanchez Godinez, Eric Neiva, Patrick J Zager, Tamas L Nagy, Janis K Burkhardt, Hervé Turlier, Orion D Weiner.
      In migrating cells, the GTPase Rac organizes a protrusive front, whereas Rho organizes a contractile back. How these GTPases are positioned at opposite poles remains unclear. We leverage optogenetics, mechanical perturbations, and mathematical modelling to reveal a surprising mechanochemical long-range mutual activation between front and back polarity programmes that complements their well-known local mutual inhibition. Rac-based protrusions elevate membrane tension, stimulating an mTORC2-dependent activation of Rho at the opposite side of the cell. Conversely, Rho-mediated contractility induces cortical-flow-based regulation of phosphoinositide signalling that triggers Rac activation distally. We develop a minimal mechanochemical model to explain how long-range facilitation, together with local inhibition, enables robust Rho and Rac partitioning. Our findings demonstrate how the actin cortex and plasma membrane interact as an integrated mechanochemical system for long-range Rac-Rho patterning. This circuit is required for efficient polarity and migration in primary human T cells and is conserved in epithelial cells, highlighting the generality of this mechanism.
    DOI:  https://doi.org/10.1038/s41556-026-01965-1
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