bims-mithem 2026-09-27 papers

Issue of 2026–09–27
five papers selected by
Tim van Tienhoven, Erasmus Medical Center

Signal Transduct Target Ther. 2026 Sep 23. pii: 404. [Epub ahead of print]11(1):

Targeting BIRC6 rejuvenates hematopoietic stem cell aging and immunosenescence.

Weinian Liao, Fangze Shao, Shaoyan Wang, Yetong Wang, Xinliang Chen, Yue Zhang, Zhang Zhang, Xiaodong Zai, Yilong Yang, Ying Yin, Youliang Wang, Jun Zhang, Junping Wang, Junjie Xu.

Immunosenescence represents a central hallmark of organismal aging, characterized by a progressive decline in immune function, which compromises host defense and accelerates systemic aging. Hematopoietic stem cell (HSC) aging is a key contributor to this process, characterized by aberrant expansion, myeloid-biased differentiation, and impaired self-renewal, culminating in hematopoietic-immune imbalance. Although the expansion and survival advantages of aged HSCs have been well-demonstrated, the underlying mechanisms remain elusive. Here, we reveal that regulatory T cells (Tregs) within the bone marrow (BM) microenvironment actively safeguard the survival of aged HSCs via a previously uncharacterized signaling pathway. We identify a novel aged HSC subpopulation characterized by high expression of Baculoviral IAP Repeat Containing 6 (BIRC6), an apoptosis inhibitor. This BIRC6-high subpopulation is markedly expanded in aged mice and recapitulates the hallmarks of HSC aging. Mechanistically, cAMP derived from BM Tregs activates the PKA-CREB pathway in HSCs, activating Birc6 transcription, which reduces apoptotic priming in aged HSCs, thereby promoting hematopoietic-immune imbalance. Strikingly, targeted BIRC6 inhibition in HSCs using antibody-conjugated lipid nanoparticle-encapsulated antisense oligonucleotides (LNP-ASOs) significantly reverses hematopoietic-immune aging phenotypes and ameliorates age-associated immune dysfunction in middle-aged mice. LNP-ASO treatment dramatically rebalances immune cell production, reduces immunosenescence markers, and enhances vaccine responses in middle-aged mice. More importantly, this strategy was also effective in HSCs from middle-aged human donors, highlighting its potential for clinical translation. These findings elucidate a key microenvironmental pathway (Treg-cAMP-PKA-CREB-BIRC6) driving HSC aging and offer a novel strategy to ameliorate the aged hematopoietic system and combat age-related immune decline.

DOI: https://doi.org/10.1038/s41392-026-02787-1

Blood. 2026 Sep 21. pii: blood.2026034660. [Epub ahead of print]

Melatonin, circadian metabolism, mitochondrial remodeling, and cell size dynamics in primitive hematopoietic stem cells.

Primitive hematopoietic stem cells (pHSCs) sustain lifelong hematopoiesis through tightly regulated transitions between quiescence and activation. Circadian oscillations influence hematopoiesis; however, the mechanisms coordinating metabolic state and stem cell function daily remain incompletely defined. Here, we show that circadian cues coordinated a program of mitochondrial remodeling, metabolic reprogramming, and structural adaptation in pHSCs. At night, peak melatonin levels were associated with reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species, and activation of DRP1 and PINK1 dependent mitophagy, resulting in enhanced long term repopulating capacity. In parallel, pHSCs exhibited increased glycolytic activity characterized by elevated glucose uptake, GLUT1 expression, AMPK phosphorylation, and HIF1α signaling. Mechanistically, mitochondrial remodeling was regulated in part by melatonin signaling, whereas glycolytic reprogramming was modulated by systemic circadian inputs, including feeding associated cues and Wnt/β-catenin signaling. FoxM1 and DRP1 contributed to mitochondrial quality control, while PGC1α dependent transcription supported compensatory mitochondrial biogenesis across the daily circadian cycle. These metabolic transitions were accompanied by dynamic changes in cell and nuclear size, linked to lamin A/C phosphorylation modulation. These coordinated processes defined a nocturnal state of enhanced stem cell fitness characterized by improved regenerative potential. Key features of glycolytic regulation were conserved in human HSCs, and in vitro melatonin treatment reduced the mitochondrial membrane potential and cell size of human pHSCs. Together, these findings establish a temporally regulated metabolic framework in which circadian cues partition mitochondrial and glycolytic programs to preserve stem cell maintenance and function, adding a new layer to pHSC metabolic physiology with clinical transplantation implications.

DOI: https://doi.org/10.1182/blood.2026034660

Aging Cell. 2026 Oct;25(10): e70715

The Role of EVs in the Aging Hematopoietic System.

Esra G Kosebent, Nathalie Havranek, Karoline Kollmann, Kristina Kirschner, Eszter Doma, Kavya Gupta.

Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that mediate intercellular communication by transferring proteins, nucleic acids, and lipids. Within the hematopoietic system, EVs orchestrate critical signaling between bone marrow (BM) niche cells and hematopoietic stem and progenitor cells (HSPCs) to regulate quiescence, proliferation, and lineage commitment. During aging, senescence and telomere attrition drive a profound remodeling of EV biogenesis and cargo. Aged EVs, particularly those released from senescent mesenchymal stromal cells (MSCs) and osteoblasts, exhibit altered microRNA profiles and reduced protective antioxidants. These changes perpetuate niche dysfunction, induce senescence in recipient cells, and promote myeloid-biased hematopoiesis. Importantly, this communication is a selective process governed by vesicle-intrinsic surface signatures, such as tetraspanins and integrins, which interact with specific receptors on distinct hematopoietic subsets to regulate signaling fidelity. Conversely, EVs from young or pluripotent stem cells deliver rejuvenating signals that can restore aged HSPC function and attenuate inflammaging. Elucidating these mechanisms of selective targeting and stress-responsive cargo remodeling provides vital insights for developing EV-based diagnostic tools and rejuvenation strategies to prevent age-related immune imbalances and hematologic malignancies.

Keywords: aging; bone marrow microenvironment; extracellular vesicles; rejuvenation

DOI: https://doi.org/10.1111/acel.70715

J Ovarian Res. 2026 Aug 29. pii: 293. [Epub ahead of print]19(1):

Restoring glucose metabolic homeostasis to attenuate ovarian aging: mechanisms and clinical prospects.

Genping Zeng, Mengyuan Chu, Jiaqi Yang, Yunfei Han, Qianyi Zhou, Han Zhang, Ying Yan.

Ovarian aging has emerged as a major challenge to female reproductive health worldwide, primarily characterized by a decline in oocyte quality and/or quantity, diminished granulosa cell function, and impairment of the surrounding microenvironment. Within this microenvironment, glucose metabolism participates in the synergistic regulation of ovarian homeostasis through specific metabolic networks and metabolite-driven signaling. Metabolic disruption can impair intercellular communication mechanisms, induce oxidative stress and mitochondrial dysfunction, and ultimately drive ovarian aging. Ovarian granulosa cells surround the oocyte and facilitate bidirectional communication via gap junctions or molecular signaling. These cells continuously supply energy substrates to support oocyte growth and maturation, while the oocyte, in turn, promotes granulosa cell proliferation and differentiation. Impairment of glycolysis in granulosa cells leads to energy deficits and triggers apoptosis. Concurrently, metabolic reprogramming in the oocyte links glucose metabolic homeostasis with mechanisms governing developmental competence. Glucose-derived metabolites drive various post-translational modifications (PTMs), including glycosylation, acetylation, phosphorylation, and succinylation, that contribute to ovarian function and intersect with pathological processes such as oxidative stress, chronic inflammation, and autophagy. Therefore, therapeutic strategies targeting glucose metabolism, such as modulating metabolic pathways, metabolite signaling, and associated PTMs, offer promising avenues for treating ovarian aging. However, the glucose metabolic network within the ovarian microenvironment is highly complex, and targeting a single node is often insufficient to restore metabolic homeostasis. A comprehensive approach that integrates multiple strategies to simultaneously intervene at different regulatory levels is needed. This review summarizes recent advances in understanding the ovarian glucose metabolic network, metabolite-driven post-translational modifications, and the interplay among various pathological mechanisms. We further explore potential regulators that could restore glucose metabolic balance and propose that future efforts should focus on developing precision strategies, guided by artificial intelligence and multi-omics data to modulate the metabolic reprogramming of both the microenvironment and functional cells, ultimately translating these insights into clinical interventions for ovarian aging.

Keywords: Glucose Metabolism; Metabolic Homeostasis; Metabolic Reprogramming; Ovarian Aging; Post-translational Modifications; Therapeutic Target

DOI: https://doi.org/10.1186/s13048-026-02244-1

iScience. 2026 Oct 16. 29(10): 117500

Levofloxacin enhances 5-fluorouracil efficacy in colorectal cancer by activating the DDR-TP53-mitochondrial apoptosis axis.

Chenmeng Huang, Chenchen Sun, Han Wang, Ying Wei, Yufei Zhang, Wenfeng Li, Aping Yue, Yajing Yang, Jiajia Wang, Jindan Guo, Zhengxi Hu, Jiangyang Chi, Yongli Fan.

5-Fluorouracil (5-FU)-based regimens are a cornerstone of colorectal cancer (CRC) chemotherapy. Levofloxacin (LVF), a widely used fluoroquinolone antibiotic, has been reported to exhibit anticancer properties. We investigated LVF's ability to enhance CRC chemosensitivity to 5-FU in cell lines, subcutaneous xenografts (Balb/c-nude mice), and spontaneous intestinal tumors (Apcmin/+ mice). LVF potentiated 5-FU-induced apoptosis in vitro and in vivo. Mechanistically, LVF induced mitochondrial dysfunction in CRC cells, marked by reactive oxygen species (ROS) accumulation, increased mitochondrial ROS, and loss of mitochondrial membrane potential. TP53 and downstream effectors NOXA and BBC3 mediate between LVF-induced mitochondrial damage and 5-FU sensitization. LVF-induced DNA damage response (DDR) and subsequent oxidative phosphorylation (OXPHOS) upregulation trigger mitochondrial damage and TP53 activation. Importantly, we confirmed that the canonical LVF target TOP2A and the reported LVF effector ribosomal S6 kinase 4 (RSK4) are dispensable for LVF-mediated sensitization. Thus, LVF acts as a non-canonical 5-FU chemosensitizer in TP53-WT CRC via DDR-TP53-mitochondrial apoptosis activation, supporting clinical repurposing.

Keywords: 5-fluorouracil; DNA damage; apoptosis; colorectal cancer; levofloxacin

DOI: https://doi.org/10.1016/j.isci.2026.117500