bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–08–03
fifteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Mitochondrial Calcium Uniporter Links Acetyl-CoA Metabolism and H3K27 Acetylation to Maintain Glioblastoma Stem Cells.
  2. Mitochondrial dysfunction mediated by ER-calcium dysregulation in neurons derived from Alzheimer's disease patients.
  3. STIM-IP3R crosstalk regulates migration of breast cancer cells.
  4. Phosphoinositides as regulators of membrane contact sites.
  5. Metabolic Adaptation of Regenerative Hematopoiesis Depends on Docking-Independent Mitochondrial Connexin-43.
  6. BAT mitochondria: whitening meets softening.
  7. Alternative Polyadenylation Contributes to Fibroblast Senescence in Pulmonary Fibrosis.
  8. Aging is growing up: celebrating the latest research in aging and senescence biology.
  9. HADHA-mediated regulation of JAK/STAT3 signaling in glioblastoma: a metabolic-epigenetic axis.
  10. Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects.
  11. Targeting Bcl-xL with Navitoclax Effectively Eliminates Senescent Tumor Cells That Appear Following CEP-1347-Induced Differentiation of Glioma Stem Cells.
  12. Mitochondrial inflexibility ignites tumor immunogenicity in postoperative glioblastoma.
  13. Endoplasmic reticulum-mitochondria coupling prompts ZBP1-mediated RPE cell PANoptosis in age-related macular degeneration.
  14. Senescence-associated lysosomal dysfunction impairs cystine deprivation-induced lipid peroxidation and ferroptosis.
  15. De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer.
  1. Cancer Res. 2025 Jul 25.
    Mitochondrial Calcium Uniporter Links Acetyl-CoA Metabolism and H3K27 Acetylation to Maintain Glioblastoma Stem Cells.
    Guangqin Liu, Haoqian Zhang, Siqi Chen, Jun Gao, Haixin Zhao, Yan Dong, Changwei Liu, Xuechen Wei, Ting Li, Chang Lu, Haizhen Zhu, Dingyi Lu, Shiyu Feng, Teng Li, Weina Zhang, Qing Xia, Jianghong Man, Tao Zhou, Jiayi Chen, Ailing Li, Xin Pan.
      Glioblastoma stem cells (GSCs) exhibit remarkable metabolic and epigenetic adaptability, contributing to therapeutic resistance and tumor recurrence. The mechanisms underlying this plasticity represent potential targetable vulnerabilities to improve glioblastoma treatment. Here, we identified a critical metabolic-epigenetic axis centered on the mitochondrial calcium uniporter (MCU) that governs GSC survival and tumor initiation. MCU was preferentially expressed in GSCs, and loss of MCU significantly impaired GSC self-renewal and viability. Mechanistically, MCU enhanced mitochondrial calcium uptake, promoting acetyl-CoA production via pyruvate dehydrogenase activation. Elevated acetyl-CoA levels drove histone H3K27 acetylation at the TRIB3 locus to maintain GSC growth. In glioblastoma patients, higher MCU expression was correlated with increased acetyl-CoA levels, elevated H3K27 acetylation, enhanced TRIB3 expression, higher tumor grade, and poorer survival. Pharmacological inhibition of MCU with berberine suppressed GSC growth and extended survival in mouse GBM models. These findings establish MCU as a critical link between mitochondrial metabolism and epigenetic regulation, highlighting its potential as a therapeutic target for glioblastoma.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0419
  2. Acta Neuropathol Commun. 2025 Jul 29. 13(1): 165
    Mitochondrial dysfunction mediated by ER-calcium dysregulation in neurons derived from Alzheimer's disease patients.
    Sarah Mustaly-Kalimi, Wacey Gallegos, Daniel Steinbrenner, Smriti Gupta, Aiden J Houcek, David A Bennett, Robert A Marr, Daniel A Peterson, Israel Sekler, Grace E Stutzmann.
      Tight regulation of mitochondrial Ca2+ is essential for neuronal bioenergetics and cellular metabolism. Ca2+ transfer from ER-localized ryanodine receptors (RyR) and inositol triphosphate receptors (IP3R) to the mitochondria maintains a steady Ca2+ source that fuels oxidative phosphorylation and ATP production. In Alzheimer's disease (AD), RyR-evoked Ca2+ release is markedly increased, contributing to synaptic deficits, protein mishandling, and memory impairment. Here, we demonstrate dysregulated RyR-Ca2+ release in neurons from familial and sporadic AD patients, and this directly compromises mitochondrial activity and contributes to AD cellular pathology. We measured an array of mitochondrial functions using fluorescent biosensors and optical imaging in RyR2-expressing HEK cells and neurons derived from AD and nonAD individuals. In neurons from AD patients, resting mitochondrial Ca2+ levels were elevated alongside increased free radical production and higher caspase-3 activity relative to nonAD neurons. RyR-evoked Ca2+ release further potentiated pathogenic mitochondrial responses in AD neurons, with increased Ca2+ uptake and exaggerated mitochondrial membrane depolarization. Additionally, clearance of damaged mitochondria was impaired in AD neurons, demonstrating consequences from dysfunctional lysosomes. Notably, impairments to mitochondria in AD neurons were largely prevented with the RyR negative allosteric modulator, Ryanodex. These findings highlight how excess RyR-Ca2+ release broadly contributes to early cellular pathology in AD which includes a cascade of ER, lysosomal, and mitochondrial deficits culminating in neuronal decline and degeneration. Additionally, pharmacological suppression of RyR-Ca2+ release preserves mitochondrial, ER and lysosomal function, thus providing a novel and effective therapeutic strategy.
    Keywords:  Alzheimer’s disease; Calcium dysregulation; Mitochondria; Ryanodine receptor; iPSC-derived neurons
    DOI:  https://doi.org/10.1186/s40478-025-02023-x
  3. J Cell Biol. 2025 Sep 01. pii: e202411203. [Epub ahead of print]224(9):
    STIM-IP3R crosstalk regulates migration of breast cancer cells.
    Ruslana Militsin, Hadas Achildiev Cohen, Maya Hershfinkel, Ofek Levi, Stavit Drori, Adi Yifat Raz, Yuval Shaked, Raz Palty.
      Calcium ions (Ca2+) are crucial second messengers involved in numerous processes including tumorigenesis and cancer cell migration. Previous studies have shown that the endoplasmic reticulum (ER) Ca2+ sensors, stromal interaction molecules STIM1 and STIM2, are key regulators of cancer cell migration. In this study, using breast cancer cells lacking one or both STIM isoforms we show that although STIM proteins are critical regulators of cell migration, they are dispensable for this cellular activity. The mechanism underlying this complex effect involves functional crosstalk between STIM proteins and inositol 1,4,5-trisphosphate receptors (IP3Rs). Our findings indicate that beyond their classical role in store-operated Ca2+ entry, STIM proteins shape the spatial dynamics of IP3R-mediated Ca2+ release. Our results suggest that following ER Ca2+ depletion, the activated STIM proteins shift the pattern of IP3R-mediated Ca2+ release from a localized signal, which promotes cell migration, to a more diffuse signal, which attenuates cell migration.
    DOI:  https://doi.org/10.1083/jcb.202411203
  4. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jul 26. pii: S1388-1981(25)00081-2. [Epub ahead of print] 159673
    Phosphoinositides as regulators of membrane contact sites.
    Håvard S Haukaas, Harald Stenmark.
      Membrane contact sites (MCSs) between the different compartments of the cell play important roles in lipid, protein and ion transfer. Phosphoinositides are crucial for the functions of many MCSs, either as membrane anchors for MCS proteins, or as part of a countertransport mechanism driven by phosphoinositide dephosphorylation in the endoplasmic reticulum. Here we review the involvement of phosphoinositides in MCSs between the endoplasmic reticulum and other organelles such as the plasma membrane, mitochondria, endosomes, lysosomes, autophagosomes and the Golgi complex. These phosphoinositide-containing MCSs mediate transfer of Ca2+, phospholipids, cholesterol, and a motor protein, and thus are of great importance for cellular physiology.
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159673
  5. Blood. 2025 Aug 01. pii: blood.2024028079. [Epub ahead of print]
    Metabolic Adaptation of Regenerative Hematopoiesis Depends on Docking-Independent Mitochondrial Connexin-43.
    Abhishek K Singh, Angelo D'Alessandro, Ashley Wellendorf, Daniel Gonzalez-Nieto, Matthew Kofron, Monika Dzieciatkowska, Leo Mejia, Luis Barrio, Marie-Dominique Filippi, Jose A Cancelas.
      Hematopoietic stem cells (HSC) exhibit a distinctive antioxidant profile during steady-state and stress hematopoiesis. HSC and multipotential progenitors (HSC/MPP) are metabolically coupled to bone marrow (BM) mesenchymal stromal cells through mitochondrial transfer, a process dependent on hematopoietic connexin 43 (Cx43) and low AMP-activated protein kinase (AMPK) activity. However, the mechanism by which Cx43 preserves mitochondrial functionality in HSC remains elusive. Here, through integrated transcriptomic, proteomic, metabolomic, phenotypic, and functional analyses of HSC and their isolated mitochondria, we identified that Cx43 is present on inner and outer mitochondrial membranes of HSC/MPP, where it primarily regulates mitochondrial metabolism and ATP synthesis by preserving the mitochondrial cristae, activation of mitochondrial AMPK and 2-oxoglutarate dehydrogenase (OGDH)-a rate liming enzyme in TCA cycle and electron transfer chain. During replicative stress, Cx43 deficient HSC/MPP fail to adapt metabolically, accumulate mitochondrial Ca2+, increase mitochondrial AMPK activity, mitochondrial fission, mitophagy, and production of reactive oxygen species, thereby limiting HSC/MPP regeneration potential. Disruption of hyper mitochondrial fragmentation and mitophagy by Drp1 dominant negative mutant (Drp1K38A) or restoration of mitochondrial function through ex vivo heteroplasmy prevent the harmful effects of Cx43 deficiency on mitochondrial metabolism and restore HSC activity in serial transplantation experiments. Re-expression analysis of Cx43 structure function mutants indicate that Cx43 hemichannels are sufficient to reset HSC mitochondrial metabolism, dynamics, Ca2+ levels, and regeneration capacity. This report defines the cell-autonomous mechanism of action behind the role of Cx43 in HSC activity and opens a venue to translational applications in transplantation.
    DOI:  https://doi.org/10.1182/blood.2024028079
  6. Nat Metab. 2025 Aug 01.
    BAT mitochondria: whitening meets softening.
    Mateus Prates Mori, Oswaldo A Lozoya, Janine H Santos.
      
    DOI:  https://doi.org/10.1038/s42255-025-01319-5
  7. Aging Cell. 2025 Jul 30. e70179
    Alternative Polyadenylation Contributes to Fibroblast Senescence in Pulmonary Fibrosis.
    Jingjing Huang, Maria Jose Gacha-Garay, Yu Wang, Scott D Collum, Rene A Girard, Hydia Puente, Seung-Hee Yoo, Rahat Hussain, Jayeshkumar Patel, Manish Patel, Eric J Wagner, Hari KrishnaYalamanchili, Harry Karmouty-Quintana, Zheng Chen, Tingting Mills.
      Idiopathic pulmonary fibrosis (IPF) is a prevalent and deadly age-related disease characterized by chronic, progressive, and irreversible fibrosis. A key effector cell population in the fibroproliferative response is the fibroblasts. Fibroblast cell senescence gradually worsens during aging, and the acquisition of a senescence-associated secretory phenotype (SASP) turns senescent fibroblasts into pro-inflammatory cells. However, the mechanism promoting senescence in IPF, especially at the post-transcriptional level, is poorly understood. We recently discovered that Nudix Hydrolase 21 (NUDT21, also named CFIm25), an RNA-binding protein, plays a critical role in regulating the expression of SASP factors through alternative polyadenylation (APA). APA allows adding poly(A) tail at different sites of 3' UTR and generates transcript isoforms with different 3' UTR lengths. We found that NUDT21 was downregulated in aging and fibrotic lungs, particularly at the fibrotic foci of IPF lungs known to have abundant senescent myofibroblasts and collagens. NUDT21 knockdown in normal lung fibroblasts promoted the 3' UTR shortening of several STAT3 signaling components and enhanced STAT3 phosphorylation and the expression of several SASPs, including interleukins, collagens, and matrix metalloproteinases (MMPs). Moreover, NUDT21 downregulation may be associated with increased fibroblast senescence and abnormal mitochondrial function. Importantly, mice with Nudt21 deletion in Col1a1 expressing cells aggravated bleomycin-induced pulmonary fibrosis. Taking together, our study demonstrated an important role of NUDT21-mediated APA in regulating SASP expression and fibroblast senescence that could contribute to the pathogenesis of IPF.
    Keywords:  NUDT21; alternative polyadenylation; fibroblast; pulmonary fibrosis; senescence
    DOI:  https://doi.org/10.1111/acel.70179
  8. Genes Dev. 2025 Aug 01. 39(15-16): 909
    Aging is growing up: celebrating the latest research in aging and senescence biology.
    Andrew Dillin.
      
    DOI:  https://doi.org/10.1101/gad.353136.125
  9. Cell Death Discov. 2025 Aug 01. 11(1): 361
    HADHA-mediated regulation of JAK/STAT3 signaling in glioblastoma: a metabolic-epigenetic axis.
    Kan Wang, Yifei Xiao, Jinxin Wan, Yuanqi Chu, Ruipeng Zheng, Fengjun Lv, Guang Yang, Mingchun Yang, Haitao Ge, Yuwen Song, Yu Cheng.
       ASTRACT: Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain cancer, characterized by rapid growth and resistance to conventional therapies. This study investigates the role of HADHA, a key enzyme in fatty acid β-oxidation, in the progression of GBM. we show that the overexpression of HADHA in GBM correlates with a poor prognosis in patients and plays a role in promoting tumor growth and invasion. Mechanistically, HADHA regulates the JAK/STAT3 signaling pathway through modulation of H3K27ac histone acetylation. Knockdown of HADHA results in decreased acetyl-CoA levels, leading to reduced H3K27ac modification and subsequent inhibition of JAK/STAT3 activation. Furthermore, we show that the small molecule JIB-04, which targets HADHA, inhibits GBM cell proliferation and invasion both in vitro and in vivo. Our findings highlight the importance of targeting metabolic enzymes in cancer therapy and suggest that HADHA could represent a potential new therapeutic target for GBM. By targeting the metabolic-epigenetic pathway, this strategy presents a promising approach for treating this devastating disorder.
    DOI:  https://doi.org/10.1038/s41420-025-02660-0
  10. Nat Commun. 2025 Jul 30. 16(1): 6613
    Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects.
    Ritobrata Ghose, Fabio Pezzano, Rémi Badia, Savvas Kourtis, Ilir Sheraj, Shubhamay Das, Antoni Gañez Zapater, Upamanyu Ghose, Sara Musa-Afaneh, Lorena Espinar, Albert Coll-Manzano, Katja Parapatics, Saška Ivanova, Paula Sànchez-Fernàndez-de-Landa, Dragana Radivojevikj, Valeria Venturini, Stefan Wieser, Antonio Zorzano, André C Müller, Verena Ruprecht, Sara Sdelci.
      The physical tissue microenvironment regulates cell state and behaviour. How mechanical confinement rewires the subcellular localisation of organelles and affects cellular metabolism is largely unknown. In this study, proteomics analysis revealed that cellular confinement induced a strong enrichment of mitochondrial proteins in the nuclear fraction. Quantitative live cell microscopy confirmed that mechanical cell confinement leads to a rapid re-localisation of mitochondria to the nuclear periphery in vitro, reflecting a physiologically relevant phenomenon in patient-derived tumours. This nucleus-mitochondria proximity is mediated by an endoplasmic reticulum-based net that entraps the mitochondria in an actin-dependent manner. Functionally, the nucleus-mitochondria proximity results in a nuclear ATP surge, which can be regulated by the genetic and pharmacological modulation of mitochondrial ATP production or via alterations of the actin cytoskeleton. The confinement-induced nuclear ATP surge has physiologically significant long-term effects on cell fitness, driven by changes in chromatin state, enhanced DNA damage repair, and cell cycle progression during mechanical cell deformation. Together, our data describe a confinement-induced metabolic adaptation that is required to enable prompt DNA damage repair and cell proliferation under mechanical confinement stress by facilitating chromatin state transitions.
    DOI:  https://doi.org/10.1038/s41467-025-61787-x
  11. Int J Mol Sci. 2025 Jul 20. pii: 6984. [Epub ahead of print]26(14):
    Targeting Bcl-xL with Navitoclax Effectively Eliminates Senescent Tumor Cells That Appear Following CEP-1347-Induced Differentiation of Glioma Stem Cells.
    Senri Takenouchi, Yasufumi Ito, Kazuki Nakamura, Yurika Nakagawa-Saito, Yuta Mitobe, Keita Togashi, Shuhei Suzuki, Asuka Sugai, Yukihiko Sonoda, Chifumi Kitanaka, Masashi Okada.
      Cellular senescence is a state of the durable cell cycle arrest of dysfunctional cells, which has been associated with the promotion of tumor cell reprogramming into a stem cell state. We previously reported that the mixed lineage kinase (MLK) inhibitor CEP-1347 promotes the differentiation of glioma stem cells (GSCs)-key contributors to glioblastoma recurrence and therapy resistance-into non-stem tumor cells. However, we also noted that CEP-1347-treated GSCs exhibited a morphological change suggestive of senescence. Therefore, we herein investigated whether CEP-1347 induces senescence in GSCs and, consequently, if senescent GSCs may be eliminated using senolytics. Cell death induced by CEP-1347 in combination with senolytic agents or with the knockdown of anti-apoptotic BCL2 family genes, as well as the effects of CEP-1347 on the expression of senescence markers and anti-apoptotic Bcl-2 family proteins, were examined. The results obtained showed that CEP-1347 induced senescence in GSCs accompanied by the increased expression of Bcl-xL. Among the panel of senolytic agents tested, navitoclax, a BH3 mimetic, efficiently induced cell death in GSCs when combined with CEP-1347 at concentrations clinically achievable in the brain. The knockdown of Bcl-xL resulted in more pronounced GSC death in combination with CEP-1347 than that of Bcl-2. These results suggest that combining CEP-1347 with the targeting of Bcl-xL, the expression of which increases with CEP-1347-induced senescence, is a rational approach to ensure the elimination of GSCs, thereby improving the outcomes of glioblastoma treatment.
    Keywords:  drug repositioning; glioblastoma multiforme; stem cell capacity; tumor-initiating cells
    DOI:  https://doi.org/10.3390/ijms26146984
  12. Nat Commun. 2025 Jul 28. 16(1): 6946
    Mitochondrial inflexibility ignites tumor immunogenicity in postoperative glioblastoma.
    Lulu Cheng, Zezheng Fang, Junpeng Wang, Kaiyan Xi, Yi Zhang, Fan Feng, Le Yu, Myla Santiago, Jingjing Wang, Zimei Wu, Kang-Nan Wang, Thomas Daubon, Shilei Ni, Yanrong Zhang, Yulin Zhang.
      Cellular and molecular heterogeneity contributes to the insufficient immunogenicity of glioblastoma multiforme (GBM), a lethal malignancy characterized by post-resection relapse, ultimately leading to limited immune cell infiltration. Here, we report a strategy to boost tumor immunity by activating the endogenous cGAS-STING signaling pathway through in-situ manipulation of the mitochondrial electron transport chain (ETC), thereby augmenting the immune responsiveness of GBM. Under white light irradiation, the synthetic butterfly-shaped photosensitizer B-TTPy disrupts the mitochondrial ETC by producing excessive reactive oxygen species. Synergistically, inhibition of checkpoint kinase 1 amplifies ETC dysfunction, thus enhancing the cytotoxicity of B-TTPy against tumor cells. Our results demonstrate that the in-house-customized Mitochondrial Electron Alteration Nanoparticles in Glioblastoma (MEANING) efficiently activate innate and adaptive immune response by recruiting antigen-presenting cells and cytotoxic T cells to the surgical margin. Moreover, biodegradable hydrogel-medicated surgical cavity treatment with MEANING can reshape the immunosuppressive tumor microenvironment and eliminate residual GBM cells. In sum, our findings establish a local immune activation approach for GBM, to prevent postoperative tumor recurrence and identify ETC blockade as a promising therapeutic strategy for low-immunogenic tumors.
    DOI:  https://doi.org/10.1038/s41467-025-62244-5
  13. Commun Biol. 2025 Jul 29. 8(1): 1118
    Endoplasmic reticulum-mitochondria coupling prompts ZBP1-mediated RPE cell PANoptosis in age-related macular degeneration.
    Ao Zhang, Ting-Ting Wei, Honglin Yin, Cheng-Ye Tan, Cheng Han, Yong Yao, Lingpeng Zhu.
      Age-related macular degeneration (AMD) is the leading cause of central vision impairment among the elderly. Geographic atrophy is a defining characteristic of AMD, but the detailed mechanism for massive loss of retinal pigment epithelium (RPE) cells is not fully understood. In this study, we found that Z-DNA binding protein 1 (ZBP1), a sensor for dsDNA, is able to induce RPE cell PANoptosis. Silencing ZBP1 efficiently alleviates RPE degeneration and AMD symptoms. Mechanistically, mitochondrial permeability transition pore (mPTP) opening stimulated by Ca2+ overload can trigger the releasing of mtDNA, which leads to ZBP1 activation and PANoptosis. Importantly, our findings reveal a significant role of aberrant formation of mitochondria-associated ER membranes (MAMs) in AMD. MAMs act as conduits for transferring Ca2+ from the ER to mitochondria through the VDAC1/GRP75/IP3R1 complex. Furthermore, our results indicate that GRP75 O-GlcNAcylation is involved in MAM formation. Genetic suppression of GRP75 attenuates PANoptosis and AMD progression. In summary, our study sheds light on the intricate organelle interplay underlying AMD and presents insights into potential avenues for AMD intervention.
    DOI:  https://doi.org/10.1038/s42003-025-08565-z
  14. Nat Commun. 2025 Jul 29. 16(1): 6617
    Senescence-associated lysosomal dysfunction impairs cystine deprivation-induced lipid peroxidation and ferroptosis.
    Tze Mun Loo, Xiangyu Zhou, Yoko Tanaka, Sho Sugawara, Shota Yamauchi, Hiroko Kawasaki, Yuta Matsuoka, Yuki Sugiura, Shinya Sakuma, Yoko Yamanishi, Satoshi Yotsumoto, Kosuke Dodo, Yoshitaka Shirasaki, Takashi Kamatani, Akiko Takahashi.
      Senescent cells, characterized by irreversible cell cycle arrest and inflammatory factor secretion, promote various age-related pathologies. Senescent cells exhibit resistance to ferroptosis, a form of iron-dependent cell death; however, the underlying mechanisms remain unclear. Here, we discovered that lysosomal acidity was crucial for lipid peroxidation and ferroptosis induction by cystine deprivation. In senescent cells, lysosomal alkalinization causes the aberrant retention of ferrous iron in lysosomes, resulting in resistance to ferroptosis. Treatment with the V-ATPase activator EN6 restored lysosomal acidity and ferroptosis sensitivity in senescent cells. A similar ferroptosis resistance mechanism involving lysosomal alkalinization was observed in pancreatic cancer cell lines. EN6 treatment prevented pancreatic cancer development in xenograft and Kras mutant mouse models. Our findings reveal a link between lysosomal dysfunction and the regulation of ferroptosis, suggesting a therapeutic strategy for the treatment of age-related diseases.
    DOI:  https://doi.org/10.1038/s41467-025-61894-9
  15. Nat Commun. 2025 Jul 30. 16(1): 6987
    De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer.
    Huan Zhang, Naiara Santana-Codina, Qijia Yu, Clara Poupault, Claudia Campos, Xingping Qin, Nicole Sindoni, Marina Ciscar, Aparna Padhye, Miljan Kuljanin, Junning Wang, Matthew J Dorman, Peter Bross, Andrew J Aguirre, Stephanie K Dougan, Kristopher A Sarosiek, Joseph D Mancias.
      Oncogenic KRAS induces metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC) characterized, in part, by dependency on de novo pyrimidine biosynthesis. Pharmacologic inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, delays pancreatic tumor growth; however, limited monotherapy efficacy suggests that compensatory pathways may drive resistance. Here, we use an integrated metabolomic, proteomic and in vitro and in vivo DHODH inhibitor-anchored genetic screening approach to identify compensatory pathways to DHODH inhibition (DHODHi) and targets for combination therapy strategies. We demonstrate that DHODHi alters the apoptotic regulatory proteome thereby enhancing sensitivity to inhibitors of the anti-apoptotic BCL2L1 (BCL-XL) protein. Co-targeting DHODH and BCL-XL synergistically induces apoptosis in PDAC cells and patient-derived organoids. The combination of DHODH inhibition with Brequinar and BCL-XL degradation by DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits PDAC tumor growth. These data define mechanisms of adaptation to DHODHi and support combination therapy targeting BCL-XL in PDAC.
    DOI:  https://doi.org/10.1038/s41467-025-61242-x
This page is being maintained by Thomas Krichel. It was last updated on 2025‒08‒03 at 17:12.