bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–03–30
24 papers selected by
William Grey, University of York



  1. Front Cell Dev Biol. 2025 ;13 1555877
      Hematopoietic stem cells (HSCs) provide all kinds of blood cells for life while maintaining self-renewal ability. During development, HSCs are first produced in the mouse embryo around embryonic day (E) 11. At this time, only one or two transplantable HSCs can be detected per embryo. Then, HSCs migrate to the fetal liver, where the number of HSCs rapidly increases, showing enhanced self-renewal ability. After birth, a transition occurs from the rapidly proliferating fetal HSCs to the more slowly dividing adult HSCs, which ends by 3-4 weeks of age. It is known that fetal HSCs express distinct surface markers and transcriptomes and produce a variety of distinct immune cells that are not made by adult HSCs. Accumulating evidence indicates that the ontogeny of the hematopoietic system is driven by a highly conserved and developmentally regulated RNA binding protein known as Lin28b. Lin28b is predominantly expressed in the fetal hematopoietic stem and progenitor cells (HSPCs) and regulates the developmental switch from fetal to adult HSCs. In this review, we will provide an overview of how Lin28b regulates the expansion and differentiation of HSCs in early life. These insights can be taken into consideration when developing ex vivo HSC expansion utilizing such physiological characteristics of HSCs.
    Keywords:  HMGA2; HSC expansion; IGF2BP2; LIN28B; Let7; fetal and adult hematopoietic stem cells
    DOI:  https://doi.org/10.3389/fcell.2025.1555877
  2. Haematologica. 2025 Mar 27.
      Megakaryocytes (MKs) are canonically viewed as specialized hematopoietic cells merely producing platelets and generated through a series of hematopoietic stem and progenitor cells in the bone marrow (BM). Despite essential physiological functions, the generation and function of MKs remain incompletely understood. Recent studies, almost in mice, have begun to redefine the cellular hierarchy of megakaryopoiesis, and shed new light on the alternative routes and mechanisms of megakaryopoiesis. Moreover, the conception of MKs as a homogenous cell population with the sole purpose of platelet production is being challenged. Conversely, MKs are shown to be a heterogenous cell population with distinct differentiation routes and versatile functions. Especially, MKs show abilities reminiscent of immune cells, and are increasingly considered as the root dictating the hemostatic and immune functions of platelets in various physiopathological conditions. Furthermore, although been well known as a component of the BM niche maintaining hematopoietic stem cells (HSCs) during homeostasis, the newly-identified properties of MKs further make them a key supporter for stressed or diseased HSCs during myeloablative injury, aging and hematopoietic malignancy. Therefore, the generation and function of MKs are more diverse than we previously thought. Here, we review the recent literatures that expand our views of MK differentiation and heterogeneity, as well as of MK functions with special focuses on their immune functions and supporting roles for stressed or diseased HSCs.
    DOI:  https://doi.org/10.3324/haematol.2024.287236
  3. Blood. 2025 Mar 25. pii: blood.2024025776. [Epub ahead of print]
      Hematopoietic stem cells (HSCs) exhibit significant age-related phenotypic and functional alterations. Although single-cell technologies have elucidated age-related compositional changes, prospective identification of aging-associated HSC subsets has remained challenging. In this study, utilizing Clusterin (Clu)-GFP reporter mice, we demonstrated that Clu expression faithfully marks age-associated myeloid/platelet-biased HSCs throughout life. Clu-GFP expression clearly segregates a novel age-associated HSC subset that overlaps with but is distinct from those previously identified using antibodies against aging maker proteins or reporter systems of aged HSC signature genes. Clu-positive (Clu+) HSCs emerge as a minor population in the fetus and progressively expand with age. Clu+ HSCs display not only an increased propensity for myeloid/platelet-biased differentiation but also a unique behaviour in the BM, favouring self-renewal over differentiation into downstream progenitors. In contrast, Clu-negative (Clu-) HSCs exhibit lineage-balanced differentiation, which predominates in the HSC pool during development but becomes underrepresented as aging progresses. Both subsets maintain long-term self-renewal capabilities even in aged mice but contribute differently to hematopoiesis. The predominant expansion of Clu+ HSCs largely drives the age-related changes observed in the HSC pool. Conversely, Clu- HSCs preserve youthful functionality and molecular characteristics into old age. Consequently, progressive changes in the balance between Clu+ and Clu- HSC subsets account for HSC aging. Our findings establish Clu as a novel marker for identifying aging-associated changes in HSCs and provide a new approach that enables lifelong tracking of the HSC aging process.
    DOI:  https://doi.org/10.1182/blood.2024025776
  4. J Immunol. 2025 Mar 27. pii: vkaf026. [Epub ahead of print]
      Increased myeloid lineage production, termed myeloid skewing, leading to decreased tumor immunity, is a hallmark of aberrant hematopoiesis associated with cancer. It is believed that myeloid skewing may occur at the hematopoietic stem and progenitor cells (HSPCs) level to elicit hematopoietic changes. However, our understanding of the underlying molecular mechanisms remains incomplete. Here, we characterize the transcriptional and chromatin accessibility landscapes of bone marrow and splenic hematopoietic progenitors in the MMTV-PyMT mouse model of breast cancer using single-cell ATAC + RNA sequencing. We show that HSPCs in the bone marrow (BM) of the tumor-bearing mice show a modest upregulation of the myeloid-bias transcriptional signature without significant chromatin accessibility changes. By contrast, dendritic cell (DC) progenitors exhibit the most prominent transcriptional and chromatin changes, showing a signature of STAT3, CEBP, and non-DC myeloid gene activation. Compared to BM, splenic HSPCs exhibit a Notch signaling signature associated with erythroid commitment rather than further upregulation of the myeloid-bias signature. In addition, we also identify a cluster of splenic HSPCs in tumor-bearing animals with a transcriptional signature of mobilization. Our paired chromatin data suggest that AP-1 factors play a crucial role in driving this HSPC mobilization signature. Overall, we provide a comprehensive dataset for understanding the hematopoietic consequences of cancer.
    Keywords:  cancer; chromatin; hematopoiesis; single-cell multiome; transcription
    DOI:  https://doi.org/10.1093/jimmun/vkaf026
  5. Pharmacol Res. 2025 Mar 23. pii: S1043-6618(25)00134-3. [Epub ahead of print]215 107709
      Glucocorticoids (GC) are cornerstone drugs in the treatment of multiple myeloma (MM). Because MM cells exploit the bone marrow microenvironment to obtain growth and survival signals, resistance to glucocorticoid-induced apoptosis emerges, yet the underlying mechanisms remain poorly characterized. Here, we identify that the chemokine receptor CCR1, together with its main ligand CCL3, plays a pivotal role in reducing the glucocorticoid sensitivity of MM cells. We show that blocking CCR1 signaling with the antagonist BX471 enhances the anti-MM effects of the glucocorticoid dexamethasone in MM cell lines, primary patient material and a myeloma xenograft mouse model. Mechanistically, the drug combination shifts the balance between pro- and antiapoptotic proteins towards apoptosis and deregulates lysosomal proteins. Our findings suggest that CCR1 may play a role in glucocorticoid resistance, as the GC-induced downregulation of CCR1 mRNA and protein is blunted in a GC-resistance onset model. Moreover, we demonstrate that inhibiting CCR1 partially reverses this resistance, providing a promising strategy for resensitizing MM cells to GC treatment.
    Keywords:  Chemokine receptor; Glucocorticoid resistance; Glucocorticoids; Multiple myeloma
    DOI:  https://doi.org/10.1016/j.phrs.2025.107709
  6. Int J Mol Sci. 2025 Mar 20. pii: 2816. [Epub ahead of print]26(6):
      Severe infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug resistance. It is therefore paramount that we better understand how the host responds to severe infection. Hematopoiesis is particularly of interest in this context because hematopoietic stem and progenitor cells (HSPCs) maintain the turnover of all blood cells, including all immune cells. Severe infections have been widely acknowledged to affect HSPCs; however, this disruption has been mainly studied during the acute phase, and the process and level of HSPC recovery remain understudied. Using a self-resolving model of natural rodent malaria, infection by Plasmodium chabaudi, here we systematically assess phenotypically defined HSPCs' acute response and recovery upon pathogen clearance. We demonstrate that during the acute phase of infection the most quiescent and functional stem cells are depleted, multipotent progenitor compartments are drastically enlarged, and oligopotent progenitors virtually disappear, underpinned by dramatic, population-specific and sometimes unexpected changes in proliferation rates. HSPC populations return to homeostatic size and proliferation rate again through specific patterns of recovery. Overall, our data demonstrate that HSPC populations adopt different responses to cope with severe infection and suggest that the ability to adjust proliferative capacity becomes more restricted as differentiation progresses.
    Keywords:  hematopoietic stem and progenitor cells; malaria; recovery from infection
    DOI:  https://doi.org/10.3390/ijms26062816
  7. Leukemia. 2025 Mar 27.
      The nuclear export protein XPO1 interacts with nucleoporin 214 (NUP214) and has been implicated in the pathogenesis of SET::NUP214 acute myeloid leukemia (AML). We evaluated DEK::NUP214 (DN), characterizing a distinct AML entity, for its dependency on XPO1 in human AML models. Deletion of XPO1 in DN-positive FKH-1 cells revealed a strong dependency on XPO1. Pharmacologic inhibition of XPO1 by the second-generation selective inhibitor of nuclear export, eltanexor, in primary human and FKH-1 cells reduced XPO1 expression, disrupted co-localization of XPO1 and DN, and induced apoptosis and cell cycle arrest. Functionally, XPO1 and DN co-localized at chromatin, and this co-localization was strongly reduced by XPO1 inhibition. Loss of chromatin binding resulted in downregulation of DN target genes and pathways related to cell cycle and self-renewal. Eltanexor treatment of a patient-derived DN-AML xenograft model disrupted leukemia development, showing molecular clearance in bone marrow after a median of 377 days in eltanexor-treated mice, while control mice succumbed after a median of 244 days. In summary, XPO1 stabilizes DN at chromatin to allow the activation of its oncogenic gene signature, while targeting XPO1 treats leukemia successfully in vivo. These findings establish XPO1 as a molecular target in DEK::NUP214 AML.
    DOI:  https://doi.org/10.1038/s41375-025-02570-1
  8. Cell Rep. 2025 Mar 24. pii: S2211-1247(25)00205-0. [Epub ahead of print]44(4): 115434
      Adaptation to changes in amino acid availability is crucial for cellular homeostasis, which requires an intricate orchestration of involved pathways. Some cancer cells can maintain cellular fitness upon amino acid shortage, which has a poorly understood mechanistic basis. Leveraging a genome-wide CRISPR-Cas9 screen, we find that superoxide dismutase 2 (SOD2) has a previously unrecognized dismutase-independent function. We demonstrate that SOD2 regulates global proteasomal protein degradation and promotes cell survival under conditions of metabolic stress in malignant cells through the E3 ubiquitin ligases UBR1 and UBR2. Consequently, inhibition of SOD2-mediated protein degradation highly sensitizes different cancer entities, including patient-derived xenografts, to amino acid depletion, highlighting the pathophysiological relevance of our findings. Our study reveals that SOD2 is a regulator of proteasomal protein breakdown upon starvation, which serves as an independent catabolic source of amino acids, a mechanism co-opted by cancer cells to maintain cellular fitness.
    Keywords:  CP: Cancer; CP: Molecular biology; SOD2; UBR1; UBR2; amino acid starvation; cancer; drug resistance; leukemia; protein degradation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115434
  9. Mol Ther Methods Clin Dev. 2025 Mar 13. 33(1): 101438
      In vivo gene therapy targeting hematopoietic stem cells (HSCs) holds significant therapeutic potential for treating hematological diseases. This study uses adeno-associated virus serotype 6 (AAV6) vectors and Cre recombination to systematically optimize the parameters for effective in vivo HSC transduction. We evaluated various genetic architectures and delivery methods of AAV6, establishing an optimized protocol that achieved functional recombination in more than two-thirds of immunophenotypic HSCs. Our findings highlight that second-strand synthesis is a critical limiting factor for transgene expression in HSCs, leading to significant under-detection of HSC transduction with single-stranded AAV6 vectors. We also demonstrate that HSCs in the bone marrow (BM) are readily accessible to transduction, with neither localized injection nor mobilization of HSCs into the bloodstream, enhancing transduction efficacy. Additionally, we observed a surprising preference for HSC transduction over other BM cells, regardless of the AAV6 delivery route. Together, these findings not only underscore the potential of AAV vectors for in vivo HSC gene therapy but also lay a foundation that can inform the development of both in vivo AAV-based HSC gene therapies and potentially in vivo HSC gene therapies that employ alternative delivery modalities.
    Keywords:  AAV; HSC; adeno-associated virus; bone marrow transduction; genetic hematological disease; in vivo gene therapy; second-strand synthesis; self-complementary; systemic delivery; targeted integration
    DOI:  https://doi.org/10.1016/j.omtm.2025.101438
  10. Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2416771122
      In native extracellular matrices (ECM), cells utilize matrix metalloproteinases (MMPs) to degrade and remodel their microenvironment. Accordingly, synthetic matrices have been engineered to permit MMP-mediated cleavage, facilitating cell spreading, migration, and interactions. However, the interplay between matrix degradability and mechanical properties remains underexplored. We hypothesized that MMP activity induces immediate mechanical alterations in the ECM, which are subsequently detected by cells. We observed that both fibrillar collagen and synthetic degradable matrices exhibit enhanced stress relaxation following MMP exposure. Cells responded to these variations in relaxation by modulating their spreading and focal adhesions. Furthermore, we demonstrated that stress relaxation and cell spreading can be precisely controlled through the rational design of matrix degradability. These findings establish a fundamental link between matrix degradability and stress relaxation, with potential implications for a broad spectrum of biological applications.
    Keywords:  collagen; degradability; extracellular matrix; matrix metalloproteinase; stress relaxation
    DOI:  https://doi.org/10.1073/pnas.2416771122
  11. Vox Sang. 2025 Mar 25.
       BACKGROUND AND OBJECTIVES: Maximizing the potency of cord blood (CB) units (CBU) is a goal of all CB banks. Low transplant cell dose in CB transplantation is one of several contributors to the slower engraftment. Processing delays could also be at play because CBU can be stored at room temperature (RT) for up to 48 h before cryopreservation. We hypothesized that prolonged storage at RT reduces the potency and engraftment activities of CBU due to the loss of haematopoietic stem cells (HSCs) and progenitor cells.
    MATERIALS AND METHODS: CBU were split in half, with one half processed shortly after collection and the other half after 40 h of storage at RT. Viabilities and potencies were compared post thaw, and engraftment activity was tested in xenotransplants. Bioinformatic analysis was carried out to identify pathways modulated by prolonged storage at RT.
    RESULTS: Prolonged storage at RT reduced the viability of CB cells and potency of grafts based on in vitro and in vivo assays. Transcriptomic analyses revealed that paracrine factors released in CBU induce several changes in gene expression programmes in CD34+ cells. These included the activation of the senescence gene CDKN1B and down-regulation of cell cycle and autophagy genes. Supplementation of CBU with trehalose prevented the loss in cell viability and potency. The latter was associated with the restoration of autophagy and suppression of the senescence gene CDKN1B.
    CONCLUSION: These results stress the importance of rapid processing of CBU and support further investigations on trehalose as a natural supplement to protect CBU' potency during storage.
    Keywords:  haematopoietic stem cells; potency; processing delay; storage; trehalose; umbilical cord blood; viability
    DOI:  https://doi.org/10.1111/vox.70012
  12. Nat Commun. 2025 Mar 24. 16(1): 2496
      Protein ubiquitylation is maintained by a dynamic balance of the conjugation and deconjugation of ubiquitin. It remains unclear how deubiquitylation-stabilized substrates are directed for degradation. Branched ubiquitin chains promote substrate degradation through the proteasome. TRIP12 and UBR5 are HECT-type E3 ubiquitin ligases, which are specific for lysine 29 (K29) and lysine 48 (K48) linkages, respectively. Here, we show that the deubiquitylase (DUB) OTUD5 is cooperatively modified by TRIP12 and UBR5, resulting in conjugation of K29/K48 branched ubiquitin chains and accelerated proteasomal degradation. TRIP12-OTUD5 antagonism regulates TNF-α-induced NF-κB signaling. Mechanistically, OTUD5 readily cleaves K48 linkages, but does not affect K29 linkages. Consequently, K29 linkages overcome OTUD5 DUB activity to facilitate UBR5-dependent K48-linked chain branching. This mechanism is applicable to other OTUD5-associated TRIP12 substrates. Thus, the combination of DUB-resistant and proteasome-targeting ubiquitin linkages promotes the degradation of deubiquitylation-protected substrates, underscoring the role of branched ubiquitin chains in shifting the ubiquitin conjugation/deconjugation equilibrium.
    DOI:  https://doi.org/10.1038/s41467-025-57873-9
  13. Leukemia. 2025 Mar 27.
      Unbiased kinome-wide CRISPR screening identified DYRK1A as a potential therapeutic target in KMT2A-rearranged (KMT2A-R) B-acute lymphoblastic leukemia (ALL). Mechanistically, we demonstrate that DYRK1A is regulated by the KMT2A fusion protein and affects cell proliferation by regulating MYC expression and ERK phosphorylation. We further observed that pharmacologic DYRK1A inhibition markedly reduced human KMT2A-R ALL cell proliferation in vitro and potently decreased leukemia proliferation in vivo in drug-treated patient-derived xenograft mouse models. DYRK1A inhibition induced expression of the proapoptotic factor BIM and reduced the expression of BCL-XL, consequently sensitizing KMT2A-R ALL cells to BCL2 inhibition. Dual inhibition of DYRK1A and BCL2 synergistically decreased KMT2A-R ALL cell survival in vitro and reduced leukemic burden in mice. Taken together, our data establishes DYRK1A as a novel therapeutic target in KMT2A-R ALL and credential dual inhibition of DYRK1A and BCL2 as an effective translational therapeutic strategy for this high-risk ALL subtype.
    DOI:  https://doi.org/10.1038/s41375-025-02575-w
  14. Mol Ther Nucleic Acids. 2025 Jun 10. 36(2): 102495
      Nanoblades are viral particles loaded with the Cas9 protein complexed with gRNA, which allowed efficient gene editing in hematopoietic stem and progenitor cells (HSPCs). Combined with recombinant adeno-associated vector (rAAV) 6 containing two homologous arms to a gene locus resulted in 50% of expression cassette knockin into HSPCs. However, high effective doses of rAAV6 induced HSPC cell death. Here, we demonstrated that, at high doses, rAAV2 was much less toxic for template DNA delivery and allowed transduction levels in HSPCs equivalent to rAAV6. To improve donor template delivery, rAAV2 and rAAV6 were chemically bio-conjugated with a mannose ligand, via the lysine or tyrosine amino acid residues exposed at the adeno-associated vector (AAV) capsid surface. High-level transduction of HSPCs with mannose-coupled rAAV6 vectors accompanied by a remarkable lower toxicity was achieved as compared to control rAAV6 in correlation with highly reduced p53 pathway activation. Mannose-conjugated rAAV6 combined with nanoblades allowed efficient gene knockin and increased survival of HSPCs from 10% to 80% as compared to the unmodified rAAV6 even in the most immature CD34+CD38lowCD90+ hematopoietic stem cell (HSC) population. Summarizing, mannose-conjugated rAAV6 maintained high-level donor mediated gene knockin when combined with nanoblades without inducing significant toxicity for the HSPCs, an important feature for clinical translation of HSPC gene-editing strategies.
    Keywords:  CD34+ cells; CRISPR-Cas9; HSPCs; MT: Delivery Strategies; bio-conjugation; gene editing; rAAV; rAAV2; rAAV6; virus like particles
    DOI:  https://doi.org/10.1016/j.omtn.2025.102495
  15. Cell Signal. 2025 Mar 25. pii: S0898-6568(25)00180-9. [Epub ahead of print]131 111767
      Multiple myeloma (MM) is a common yet incurable hematological malignancy characterized by bone marrow infiltration. A major clinical challenge is the resistance to chemotherapy, highlighting the urgent need to better understand the molecular mechanisms underlying chemotherapeutic resistance to available drugs. Recent studies have emphasized the role of micropeptides in solid tumors and leukemia, but their functions in MM remain unclear. In this study, we identified a novel micropeptide, altKLF4, derived from the transcription factor KLF4, which is highly expressed in newly diagnosed myeloma patient samples. We found that ectopic expression of altKLF4 interfered with chemotherapy sensitivity induced by proteasome inhibitors in myeloma cells. Additionally, confocal microscopy and transcriptome sequencing revealed that altKLF4 co-localizes with the mitochondrial inner marker TOMM20 and participates in mitochondria-related biological processes, suggesting that altKLF4 partially localizes to the mitochondria. Mitochondria may also play a role in regulating ferroptosis. Our results further demonstrated that altKLF4 inhibited drug sensitivity and ferroptosis induced by the GPX4 inhibitor RSL3 in multiple myeloma cells through a direct interaction with GPX4. In vivo experiments showed that RSL3 significantly suppressed primary myeloma growth, which could be rescued by the micropeptide altKLF4. Taken together, our study identifies altKLF4 as a novel micropeptide that serves as a potential biomarker for chemotherapeutic resistance in multiple myeloma, offering insights for diagnosis and management of drug-resistant MM.
    Keywords:  Chemotherapeutic sensitivity; Ferroptosis; KLF4; Micropeptide; Myeloma
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111767
  16. Nat Commun. 2025 Mar 24. 16(1): 2749
      Red blood cell development from erythroid progenitors requires profound reshaping of metabolism and gene expression. How these transcriptional and metabolic alterations are coupled is unclear. Nprl3 (an inhibitor of mTORC1) has remained in synteny with the α-globin genes for >500 million years, and harbours most of the a-globin enhancers. However, whether Nprl3 serves an erythroid role is unknown. We found that while haematopoietic progenitors require basal Nprl3 expression, erythroid Nprl3 expression is further boosted by the α-globin enhancers. This lineage-specific upregulation is required for sufficient erythropoiesis. Loss of Nprl3 affects erythroblast metabolism via elevating mTORC1 signalling, suppressing autophagy and disrupting glycolysis. Broadly consistent with these murine findings, human NPRL3-knockout erythroid progenitors produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Therefore, we propose that the anciently conserved linkage of NprI3, α-globin and their associated enhancers has coupled metabolic and developmental control of erythropoiesis.
    DOI:  https://doi.org/10.1038/s41467-025-57683-z
  17. Cell Death Discov. 2025 Mar 26. 11(1): 120
      Adoptive cell therapy (ACT) can address an unmet clinical need for patients with relapsed/refractory acute myeloid leukemia (AML), but its effect is often modest in the setting of high tumor burden. In this study, we postulated that strategies to lower the AML apoptotic threshold will augment T cell killing of AML cells. BH3 mimetics, such as venetoclax, are a clinically approved class of compounds that predispose cells to intrinsic apoptosis by inhibiting anti-apoptotic mitochondrial proteins. We explored the anti-leukemic efficacy of BH3 mimetics combined with WT1-specific CD8+ T cells on AML cell lines and primary samples from patients with a diverse array of disease characteristics to evaluate if lowering the cellular apoptotic threshold via inhibition of anti-apoptotic mitochondrial proteins can increase leukemic cell sensitivity to T cell therapy. We found that the combination approach of BH3 mimetic and CD8+ T cells led to significantly increased killing of established AML lines as well as of adverse-risk primary AML leukemic blast cells. In contrast to the hypothesis that enhanced killing would be due to combined activation of the intrinsic and extrinsic apoptotic pathways, our data suggests that CTL-mediated killing of AML cells was accomplished primarily through activation of the intrinsic/mitochondrial apoptotic pathway. This highly effective combinatorial activity due to convergence on the mitochondrial apoptotic pathway was conserved across multiple AML cell lines and primary samples, suggesting that mitochondrial priming may represent a novel mechanism of optimizing adoptive cell therapy for AML patients.
    DOI:  https://doi.org/10.1038/s41420-025-02375-2
  18. Cell Calcium. 2025 Mar 18. pii: S0143-4160(25)00023-5. [Epub ahead of print]127 103014
      The homeostasis of cellular reactive oxygen species (ROS) and calcium (Ca2+) are intricately linked. ROS signaling and Ca2+ signaling are reciprocally regulated within cellular microdomains and are crucial for transcription, metabolism and cell function. Tumor cells often highjack ROS and Ca2+ signaling mechanisms to ensure optimal cell survival and tumor progression. Expression and regulation of Ca2+ channels and transporters at the plasma membrane, endoplasmic reticulum, mitochondria and other endomembranes are often altered in tumor cells, and this includes their regulation by ROS and reactive nitrogen species (RNS). Likewise, alterations in cellular Ca2+ levels influence the generation and scavenging of oxidants and thus can alter the redox homeostasis of the cell. This interplay can be either beneficial or detrimental to the cell depending on the localization, duration and levels of ROS and Ca2+ signals. At one end of the spectrum, Ca2+ and ROS/RNS can function as signaling modules while at the other end, lethal surges in these species are associated with cell death. Here, we highlight the interplay between Ca2+ and ROS in cancer progression, emphasize the impact of redox regulation on Ca2+ transport mechanisms, and describe how Ca2+ signaling pathways, in turn, can regulate the cellular redox environment.
    Keywords:  Ca(2+); ROS; Redox signaling; cancer
    DOI:  https://doi.org/10.1016/j.ceca.2025.103014
  19. Sci Immunol. 2025 Mar 28. 10(105): eadk5041
      Pulmonary fibrosis is an incurable disease that manifests with advanced age. Yet, how hematopoietic aging influences immune responses and fibrosis progression remains unclear. Using heterochronic bone marrow transplant mouse models, we found that an aged bone marrow exacerbates lung fibrosis irrespective of lung tissue age. Upon lung injury, there was an increased accumulation of monocyte-derived alveolar macrophages (Mo-AMs) driven by cell-intrinsic hematopoietic aging. These Mo-AMs exhibited an enhanced profibrotic profile and stalled maturation into a homeostatic, tissue-resident phenotype. This delay was shaped by cell-extrinsic environmental signals such as reduced pulmonary interleukin-10 (IL-10), perpetuating a profibrotic macrophage state. We identified regulatory T cells (Tregs) as critical providers of IL-10 upon lung injury that promote Mo-AM maturation and attenuate fibrosis progression. Our study highlights the impact of an aging bone marrow on lung immune regulation and identifies Treg-mediated IL-10 signaling as a promising target to mitigate fibrosis and promote tissue repair.
    DOI:  https://doi.org/10.1126/sciimmunol.adk5041
  20. Sci Adv. 2025 Mar 28. 11(13): eado3923
      Relapsed/refractory acute myeloid leukemia (rrAML) is a malignant blood cancer with an extremely poor prognosis, largely ascribed to the drug-resistant leukemia stem cells (LSCs). Most patients suffer from a risk of difficult-to-cure as well as severe systemic toxicity when receiving standard chemotherapies. As hyaluronic acid (HA) is a specific ligand of CD44 highly expressed by LSCs, we had HA self-assembled with cisplatin and daunorubicin to form a dual chemodrug nanogel (HA/Cis/Dau) to afford the targeted therapeutic interventions of rrAML. HA/Cis/Dau displayed an extra therapeutic function of inducing the granulocyte-monocyte differentiation in CD44+ rrAML cells, an rrAML mouse model, and primary blasts isolated from patients with AML. Unlike free drugs directly diffusing and killing rrAML cells, HA/Cis/Dau transported the drugs into lysosomes, causing lysosomal membrane permeabilization, ROS accumulation, and thus a metabolic reprogramming of the rrAML cells. Moreover, HA/Cis/Dau was featured with alleviated side effects, ease of preparation, and cost effectiveness, therefore holding great promises for the targeted treatment of rrAML.
    DOI:  https://doi.org/10.1126/sciadv.ado3923
  21. Cells. 2025 Mar 10. pii: 404. [Epub ahead of print]14(6):
      RhoA is a major regulator of the actin cytoskeleton. Its function in the nucleus, however, is unclear. Fusing wildtype, fast cycling, constitutively active, and dominant negative forms of RhoA with tags promoting nuclear or cytoplasmic location and allowing specific detection, we established a platform to distinguish the functions of nuclear and cytoplasmic RhoA. Our data show that nuclear but not cytoplasmic activation of RhoA regulates DNA amount and nuclear size. This is mediated by sequential nuclear activation of the RhoA effector ROCK and Erk, a major cell cycle regulating kinase. The inhibition of ROCK or Erk activation in untransfected cells reduced DNA amounts to a similar extent, suggesting that endogenous activation levels of nuclear RhoA-ROCK-Erk signaling are sufficient for regulation. We reveal, furthermore, that GDP-bound, but not activated RhoA, translocates to the nucleus, indicating relatively separated cytoplasmic and nuclear RhoA signaling. Moreover, even the massive nuclear activation of RhoA does not cause an obvious increase in nuclear F-actin, indicating that RhoA activation is not critical for nuclear F-actin formation.
    Keywords:  ROCK; RhoA; nuclear F-actin
    DOI:  https://doi.org/10.3390/cells14060404
  22. Nat Commun. 2025 Mar 24. 16(1): 2863
      Gut microbiome influences tumorigenesis and tumor progression through regulating the tumor microenvironment (TME) and modifying blood metabolites. However, the mechanisms by which gut microbiome and blood metabolites regulate the TME in multiple myeloma (MM) remain unclear. By employing16S rRNA gene sequencing coupled with metagenomics and ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry, we find that Lachnospiraceae are high and phosphatidylcholine (PC) are low in MM patients. We further show that Lachnospiraceae inhibits PC production from MM cells and enhances cytotoxic CD8 T cell function. Mechanistically, PC promotes Sb9 mRNA maturation in MM cells by LIN28A/B via lysophosphatidic acid, thus enhances exosamal Sb9 production. Exosamal Sb9 then reduces GZMB expression by suppressing tumor protein p53 (TP53) UFMylation via the competitive binding of TP53 with the ubiquitin-fold modifier conjugating enzyme 1 in CD8 T cells. We thus show that Lachnospiraceae and PC may be potential therapeutic targets for MM treatment.
    DOI:  https://doi.org/10.1038/s41467-025-57966-5
  23. Trends Mol Med. 2025 Mar 21. pii: S1471-4914(25)00054-1. [Epub ahead of print]
      Recent reports of gene therapy using autologous hematopoietic stem cell transplantation (HSCT) have addressed protein deficiencies of extra-hematopoietic origin. In a recent study, Srivastava et al. report that patients with hemophilia A receiving F8 lentiviral HSCT gene therapy achieved lasting factor VIII restoration and clinical improvement, marking an advance that could enable broader applications of HSCT.
    Keywords:  gene therapy; hematopoiesis; hematopoietic stem cell; hemophilia; lineage-specific
    DOI:  https://doi.org/10.1016/j.molmed.2025.03.003
  24. Ther Adv Hematol. 2025 ;16 20406207251326802
      Acute myeloid leukemia (AML), the most common type of leukemia in adults, is a highly heterogeneous and aggressive hematologic malignancy. Since the 20th century, the combination of cytosine arabinoside and anthracyclines has been the most common chemotherapy drug used to treat patients with AML. Although, new targeted medicines have emerged, such as midostaurin and gilteritinib targeting FMS-like tyrosine kinase 3 (FLT3), ivosidenib (isocitrate dehydrogenase 1 (IDH1) inhibitor) and enasidenib (IDH2 inhibitor) targeting IDH, and gemtuzumab ozogamicin targeting CD33, which have changed the treatment strategies of AML. But, until now, hematopoietic stem cell transplantation remains the best treatment option in most cases. However, treatment resistance and relapse are still the major consequences of disease progression in AML, highlighting the urgent need for novel therapeutic approaches. As an alternative, chimeric antigen receptor (CAR)-T cells are engineered T-cells developed as a breakthrough in cancer therapy in recent years, and explored and used in various tumor types. In particular, it has achieved remarkable efficacy in the field of relapsed and refractory B lymphocyte tumors. This review mainly summarizes and discusses the research progress and the clinical application of CAR-T cell immunotherapy in AML in recent years.
    Keywords:  acute myeloid leukemia; chimeric antigen receptor T cells; immunotherapy; target antigen
    DOI:  https://doi.org/10.1177/20406207251326802