This study aims to explore the effects of silencing Zic family member 5 (ZIC5) on glucose metabolism and disulfidptosis in lung adenocarcinoma (LUAD) cells.
Data from The Cancer Genome Atlas (TCGA) was used to analyze ZIC5 expression in LUAD and its association with patient outcomes. ZIC5 was silenced in A549 and H1299 cells using siRNA. The expression of ZIC5 mRNA and protein was assessed by qRT-PCR and Western blot. Cell proliferation was evaluated through CCK-8 and 5-ethynyl-2'-deoxyuridine (EdU) assays, while glucose uptake, lactate production, and ATP levels were measured to assess energy metabolism. Seahorse XF analysis was used to evaluate extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Disulfidptosis was assessed through NADP+/NADPH ratio, glutathione (GSH) content, GSSG/GSH ratio, and immunofluorescence staining.
ZIC5 is highly expressed in LUAD and is associated with poor patient prognosis. Silencing ZIC5 significantly reduced its mRNA and protein levels in A549 and H1299 cells, markedly inhibited cell proliferation, and led to significant decreases in glucose uptake, lactate production, ATP levels, ECAR, and OCR. Additionally, silencing ZIC5 resulted in an increased NADP+/NADPH ratio, decreased GSH levels, and a reduced GSSG/GSH ratio, alongside classic disulfidptosis features.
ZIC5 plays a crucial role in promoting LUAD cell proliferation and energy metabolism while inhibiting disulfidptosis. Silencing ZIC5 markedly suppresses these processes, indicating its potential as a therapeutic target in LUAD.

Despite the great promise of human pluripotent stem cell (hPSC)-based cell therapy, safety concerns arise from genetic aberrations during in vitro culture, due to their uncertain consequences. Notably, these genetic aberrations confer a survival trait known as "culture-adaptation", allowing aberrant hPSCs to evade apoptosis and outcompete normal cells. Thus, it is crucial to develop strategies for selectively eliminating aberrant hPSCs to ensure the safety of therapeutic applications. Herein, we discovered that hPSCs with genetic variations exhibited increased glycolysis and active fatty acid biosynthesis. Surprisingly, these variants, showing resistance to stress-induced apoptosis, were paradoxically susceptible to ferroptosis by the treatment of RAS-selective lethal 3 (RSL3), a glutathione peroxide 4 inhibitor. The selective sensitivity to RSL3 resulted from elevated levels of polyunsaturated fatty acids containing phospholipids, driven by the up-regulation of acyl-coenzyme A synthetase long-chain family member 4 through Yes1-associated protein 1 activity. Importantly, the distinct sensitivity of normal hPSCs and metabolic variants to ferroptosis enabled the targeted removal of genetically aberrant hPSCs through RSL3 treatment, while normal hPSCs transiently exposed to RSL3 maintained their pluripotency and normal differentiation capacity. These findings hold important promise for the maintenance of genetically normal hPSCs during extended in vitro culture, thereby ensuring the safety and efficacy of hPSC-based cell therapies.
Copyright © 2024 Yun-Jeong Kim et al.

Millions of platelet units are needed each year to manage thrombocytopenia and other conditions linked to excessive bleeding. These life-saving treatments still depend entirely on donated platelets, despite the numerous shortcomings associated with them, such as limited shelf life, supply shortages, unpredictable functionality, potential for infection, as well as immune-incompatibility issues. These challenges could be overcome with universal donor platelets generated from human induced pluripotent stem cell (hiPSC)-derived megakaryocytes (MKs). We recently developed expandable hiPSC-derived megakaryocytic cell lines (imMKCLs) as a potentially unlimited source for platelet production. imMKCL-derived platelets are functional and have already been tested in patients. In this study, we demonstrate through single-cell time-course imaging that imMKCL maturation is heterogeneous and asynchronous, with only a few imMKCLs generating platelets at any given time under static culture conditions. Using a chemical screen, we identify microtubule (MT) destabilizing agents, including vincristine (VCR), as promising hits, with a larger proportion of VCR-exposed imMKCLs developing proplatelet extensions and more platelets being produced per imMKCL. VCR use reduces the MT content of imMKCLs and results in the production of platelets with a diminished peripheral MT ring structure. Nevertheless, these platelets are functional, as evidenced by their normal response to agonists, their ability to attach to and spread on fibrinogen-coated surfaces, and their capacity to restore hemostasis in vivo. Interestingly, we also observed a negative correlation between the MT content of imMKCLs and platelet yields when we compared imMKCLs differentiated under static conditions (MThigh, low yield) to our turbulence-optimized VerMES™ bioreactor (MTlow, high yield). Taken together, our findings highlight the importance of MT dynamics in megakaryocyte biology, provide a possible explanation for the still poorly understood link between vinca alkaloid in vivo use and thrombocytosis, and bring us closer to realizing the clinical potential of affordable, off-the-shelf hiPSC-derived platelets.
Copyright: © 2025 Nakamura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Leptin, a key adipokine secreted by adipose tissue (AT), has emerged as a critical mediator linking obesity and breast cancer, both of which are major global health concerns. Elevated leptin levels are detected in the circulation and in extracellular vesicles (EVs) released by adipose tissue, particularly in cases of obesity. These leptin-enriched EVs have been implicated in various stages of tumor progression. In this study, we investigated the effects of leptin within extracellular vesicles (EVs) secreted by obese adipose tissue on the functional properties and metabolism of MDA-MB-231 breast cancer cells, a model for triple-negative breast cancer (TNBC).
MDA-MB-231 cells were treated with EVs derived from the subcutaneous adipose tissue of eutrophic (EUT EVs) and obese (OB EVs) individuals.
Our findings revealed that OB EVs induced significant phosphorylation of STAT3, a key signaling molecule in cancer progression, and promoted increased cell migration, dependent on fatty acid oxidation (FAO). This effect was reversed in the presence of a leptin receptor antagonist, highlighting leptin's pivotal role in these processes. Additionally, OB EVs caused metabolic changes, including reduced lactate levels and decreased pyruvate kinase (PK) activity, while increasing glucose-6-phosphate dehydrogenase (G6PDH) activity, suggesting metabolic reprogramming that supports tumor cell survival and proliferation. In addition to metabolic alterations, OB EVs also impacted mitochondrial dynamics. We observed an upregulation of fusion and fission markers and a redistribution of mitochondria toward the cell periphery, which supports migration. Moreover, OB EVs increased the invasive capacity of MDA-MB-231 cells, an effect mediated by matrix metalloproteinase-9 (MMP-9).
Overall, our results highlight how obese adipose tissue modulates breast cancer cell behavior, with leptin-enriched EVs playing a central role in driving migration, metabolic reprogramming, and invasiveness, thereby promoting tumor malignancy. This study underscores the importance of EVs in the obesity-cancer link and offers new insights for therapeutic strategies targeting leptin signaling and EV-mediated communication in breast cancer.
Copyright © 2025 Encarnação, Amorim, Franco, Botelho, dos Santos, Ramos-Andrade, Kraemer-Aguiar, Barja-Fidalgo, Moraes and Renovato-Martins.

Sarcopenia, the age-related decline in muscle mass and function, poses a major health risk to the elderly population. Although dietary advanced glycation end-products (AGEs) have been implicated in worsening sarcopenia, the precise molecular mechanisms remain unclear.
A sarcopenia animal model was established by feeding a high AGE diet to C57BL/6 mice. Muscle function and mass were assessed using grip strength tests, and rotarod tests. Proteomic analysis was used to identify differentially expressed proteins. Immunoprecipitation, mass spectrometry, and co-immunoprecipitation were employed to investigate protein interactions both in vivo and in vitro. Quantitative reverse transcription PCR and Western blotting were conducted to measure gene and protein expression levels.
Our results revealed that dietary AGEs accelerated the onset of sarcopenia in mice by triggering apoptosis. Proteomic analysis showed a marked upregulation of protein arginine methyltransferase 1 (PRMT1) in the muscle tissues of mice fed a high AGE diet. PRMT1 mediated the arginine methylation of CREB-regulated transcription coactivator 3 (CRTC3) at the R534 site within its transactivation domain, leading to CRTC3 activation. The activated CRTC3, together with Forkhead box O3a (FOXO3a), transactivated the BAX (BCL2 associated X) gene, initiating Bax downstream signaling, promoting apoptosis in muscle cells, and contributing to muscle atrophy. Inhibition of PRMT1 prevented CRTC3 methylation and suppressed Bax-mediated apoptotic signaling in vitro. Moreover, in vivo treatment with PRMT1 and Bax inhibitors significantly attenuated AGE-induced sarcopenia in mice.
PRMT1-mediated CRTC3 arginine methylation plays a critical role in AGE-induced sarcopenia and suggests potential therapeutic targets for preventing sarcopenia progression.
© 2025. The Author(s).