bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–10–12
fifteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Mitochondrial phosphopantetheinylation is required for oxidative metabolism.
  2. Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
  3. Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
  4. STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
  5. Combining drugs that bypass p53 to treat TP53-mutated leukemias.
  6. Acidosis orchestrates adaptations of energy metabolism in tumors.
  7. PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.
  8. Creatine Kinase B promotes non-small cell lung cancer survival and metastasis.
  9. Non-canonical dihydrolipoyl transacetylase promotes chemotherapy resistance via mitochondrial tetrahydrofolate signaling.
  10. HRS sustains mitochondrial homeostasis by anchoring destabilized proteins during tumorigenesis.
  11. Imperial strategy of cancer cells through mitochondrial transfer.
  12. Targeting mitochondrial translation and OXPHOS in high-grade serous ovarian carcinoma eliminates stem-like cells.
  13. The BH3-only protein NOXA is essential for apoptosis induction by BH3-mimetics targeting BCL2 or BCL-XL in DLBCL.
  14. Mapping the evolution of mitochondrial complex I through structural variation.
  15. SLC25A10 promotes cisplatin resistance by inhibiting ferroptosis in cervical cancer.
  1. Metabolism. 2025 Oct 06. pii: S0026-0495(25)00282-3. [Epub ahead of print] 156413
    Mitochondrial phosphopantetheinylation is required for oxidative metabolism.
    Pieter R Norden, Riley J Wedan, Samuel E J Preston, Morgan Canfield, Naomi Graber, Jacob Z Longenecker, Olivia A Pentecost, Elizabeth McLaughlin, Madeleine L Hart, Sara M Nowinski.
      4'-Phosphopantetheinyl (4'PP) groups are essential co-factors added to target proteins by phosphopantetheinyl transferase (PPTase) enzymes. Although mitochondrial 4'PP-modified proteins have been described for decades, a mitochondrially-localized PPTase has never been found in mammals. We discovered that the cytoplasmic PPTase aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT) is required for mitochondrial respiration and oxidative metabolism. Loss of AASDHPPT results in failed 4'PP modification of the mitochondrial acyl carrier protein and blunted activity of the mitochondrial fatty acid synthesis (mtFAS) pathway. We found that in addition to its cytoplasmic localization, AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 20 amino acids of the protein. Our data show that this novel mitochondrial localization of AASDHPPT is required to support mtFAS activity and oxidative metabolism. We further identify five variants of uncertain significance in AASDHPPT that are likely pathogenic in humans due to loss of mtFAS activity.
    Keywords:  Electron transport chain; Fatty acid synthesis; Metabolism; Mitochondria; Phosphopantetheine; Reductive carboxylation; Respiration
    DOI:  https://doi.org/10.1016/j.metabol.2025.156413
  2. Science. 2025 Oct 09. 390(6769): 156-163
    Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
    Michele Frison, Brandon S Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D Ryall, Camilla Lyons, Stephen P Burr, Malwina Prater, Lyuba V Bozhilova, Angelos Glynos, James B Stewart, Nick S Jones, Marcos R Chiaratti, Patrick F Chinnery.
      Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.
    DOI:  https://doi.org/10.1126/science.adr5438
  3. Nat Commun. 2025 Oct 08. 16(1): 8952
    Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
    Vidhi Pareek, Stephen Benkovic.
      Cancer cells have the unique capability to upregulate the de novo nucleotide biosynthesis supporting cell survival under nucleotide deprivation. We probe the role of metabolic channeling and membrane-less metabolic compartmentalization by mitochondria-proximal dynamic de novo pyrimidine and purine biosynthesis metabolons, the pyrimidinosome and the purinosome, respectively. We designed in-cell stable isotope label incorporation assays (13C6 glucose, 15N2 glutamine) for detection of metabolic channeling, revealing the function and enzymatic composition of these complexes. Moreover, we discovered that the mitochondrially compartmentalized GOT2 dependent generation of aspartic acid feeds the channeled nucleotide synthesis instead of the bulk cytosolic pool or the GOT1 activity. While a low flux diffusive pathway generates the pathway intermediates in an accumulative process, it's the channeled pathway that successfully generates the end product nucleotides. Our results demonstrate how metabolic channeling and efficient de novo nucleotide biosynthesis is fueled by coordination of mitochondrially compartmentalized metabolic events with cytosolic metabolons in cancer cells.
    DOI:  https://doi.org/10.1038/s41467-025-64013-w
  4. Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2508809122
    STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
    Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.
      The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the alternate pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet rapid mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process have remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.
    Keywords:  cholesterol; intermembrane space; lipoid congenital adrenal hyperplasia; mitochondria; steroidogenesis
    DOI:  https://doi.org/10.1073/pnas.2508809122
  5. Blood Adv. 2025 Oct 08. pii: bloodadvances.2025016683. [Epub ahead of print]
    Combining drugs that bypass p53 to treat TP53-mutated leukemias.
    Sudipta Biswas, Zeinab Zahran, Xiaorong Gu, Lisa Cardone, Remuna Marti, Nour Mouannes, Maximillian Stich, Akriti G Jain, Kateryna Fedorov, Benjamin K Tomlinson, Mendel Goldfinger, Amit Verma, Yogen Saunthararajah.
      Acute myeloid leukemias (AMLs) containing TP53 (p53) mutations are routinely treated with decitabine or 5-azacytidine which deplete DNA methyltransferase 1 (DNMT1)('hypomethylating agents', HMA). Unfortunately, resistance/relapse, characterized by preserved DNMT1, is rapid. HMA are pyrimidine analogs, and to deplete DNMT1, must compete with endogenous pyrimidines. These were substantially increased in HMA-resistant versus parental AML cells, together with upregulation of carbamoyl-phosphate-synthetase-2/aspartate transcarbamylase/dihydroorotase (CAD) that rate-limits de novo pyrimidine synthesis. Moreover, TP53-mutated AMLs appeared primed for such resistance with baseline higher CAD. Pyrimidine synthesis can be depowered by using the BCL2-inhibitor venetoclax to release BAX to depolarize mitochondrial membranes. However, BAX, a p53-target gene, was ~2-fold less expressed in TP53-mutated vs TP53-wildtype cells, and venetoclax impacts were correspondingly limited. Alternatively, pyrimidine synthesis can be inhibited directly at dihydroorotate dehydrogenase (DHODH) using the clinical drug teriflunomide. Contrasting with venetoclax, teriflunomide decreased pyrimidines several-fold, restored DNMT1-depletion, and cytoreduced HMA-resistant TP53-mutated AML cells via p53/apoptosis-independent terminal lineage-maturation. This non-cytotoxic pathway preserved viability and proliferation of normal hematopoietic stem/progenitor cells (HSPC). Inhibiting pyrimidine synthesis triggered automatic increases in pyrimidine salvage, such that schedules for teriflunomide combination with HMA, taken-up by salvage, mattered: in mice with TP53-mutated AML, teriflunomide scheduled day-before HMA was more efficacious than same-day or day-after. Chronic teriflunomide exposure paradoxically increased pyrimidines via sustained compensatory pyrimidine salvage, conferring resistance rather than sensitivity to HMA. In sum, DNMT1- and DHODH-targeting, administered by timed-intermittent (metronomic) schedules, can circumvent genetic-resistance caused by TP53-mutations, and adaptive-resistance caused by metabolic homeostasis, without cytotoxicity to normal HSPC.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016683
  6. Science. 2025 Oct 09. 390(6769): eadp7603
    Acidosis orchestrates adaptations of energy metabolism in tumors.
    Sven Groessl, Robert Kalis, Marteinn T Snaebjornsson, Leon Wambach, Jakob Haider, Florian Andersch, Almut Schulze, Wilhelm Palm, Johannes Zuber.
      Malignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal-regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.
    DOI:  https://doi.org/10.1126/science.adp7603
  7. J Cell Sci. 2025 Oct 09. pii: jcs.263903. [Epub ahead of print]
    PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.
    Sudeshna Nag, Kaitlin Szederkenyi, Christopher M Yip, G Angus McQuibban.
      Mitochondrial dynamics relies on the function of dynamin family GTPase proteins including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and dynamin-related protein 1 (DRP1). The mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) protein can regulate the phosphorylation levels and the function of both MFN2 and DRP1, however, the precise regulation of PGAM5 activity is unknown. We show that PGAM5 oligomerization and localization controls its function. Under depolarization and/or metabolic stress PGAM5 changes its association from dodecamers to dimers. These PGAM5 oligomers have differential affinity towards MFN2 and DRP1. Simultaneously, PGAM5 is cleaved by the inner mitochondrial membrane resident proteases PARL and OMA1 and a fraction of the cleaved PGAM5 translocates to the cytosol. These two events play an important role in regulating mitochondrial dynamics under depolarization and/or metabolic stress. Taken together, our results identify PGAM5 oligomerization and cleavage-induced relocalization as critical regulators of its function.
    Keywords:  DRP1; Glucose-Starvation; MFN2; Mitochondrial morphology; PGAM5
    DOI:  https://doi.org/10.1242/jcs.263903
  8. J Biol Chem. 2025 Oct 08. pii: S0021-9258(25)02657-2. [Epub ahead of print] 110805
    Creatine Kinase B promotes non-small cell lung cancer survival and metastasis.
    Mouna Tlili, Bozena Samborska, Charlotte Girondel, Afnan Abu-Thuraia, Qiaoqiao Zhang, Jakub Bunk, Mohammed F Hussain, Peter M Siegel, Lawrence Kazak.
      Creatine kinase (CK) catalyzes the reversible transfer of a phosphoryl group from ATP to creatine. There are four distinct CK genes (CKM, CKB, CKMT1 and CKMT2) with cell-type selective expression and subcellular localization. In cancer, uncontrolled cell proliferation drives aggressive migration and invasion into nearby tissues and distant organs. While creatine metabolism is known to support cancer cell survival, the specific roles of individual CK isoenzymes remain unclear. Here, we demonstrate that CKB is essential for CK enzymatic activity in several cancer cell lines, including NSCLC (H1299), osteosarcoma (143B), and ovarian adenocarcinoma (OVCAR8). Moreover, we demonstrate that CKB promotes metastasis of H1299 cells to the lung and liver in vivo, a process associated with enhanced anoikis resistance.
    Keywords:  *Creatine; *lung cancer; *metastasis; *osteosarcoma; *ovarian cancer
    DOI:  https://doi.org/10.1016/j.jbc.2025.110805
  9. Nat Commun. 2025 Oct 08. 16(1): 8932
    Non-canonical dihydrolipoyl transacetylase promotes chemotherapy resistance via mitochondrial tetrahydrofolate signaling.
    Jung Seok Hwang, JiHoon Kang, Jaehyun Kim, Kiyoung Eun, Sophia West, Hannah E Bacho, Vanessa Avalos, Sydney Shuff, Dong M Shin, Nabil F Saba, Kelly R Magliocca, Cheng-Kui Qu, Haian Fu, Suresh S Ramalingam, Andrey A Ivanov, Taro Hitosugi, Sumin Kang.
      Chemotherapy is often a primary treatment for cancer. However, resistance leads to therapeutic failure. Acetylation dynamics play important regulatory roles in cancer cells, but the mechanisms by which acetylation mediates therapy resistance remain poorly understood. Here, using acetylome-focused RNA interference (RNAi) screening, we find that acetylation induced by mitochondrial dihydrolipoyl transacetylase (DLAT), independent of the pyruvate dehydrogenase complex, is pivotal in promoting resistance to chemotherapeutics, such as cisplatin. Mechanistically, DLAT acetylates methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) at lysine 44 and promotes 10-formyl-tetrahydrofolate (10-formyl-THF) and consequent mitochondrially encoded cytochrome c oxidase II (MT-CO2) induction. DLAT signaling is elevated in cancer patients refractory to chemotherapy or chemoimmunotherapy. A decoy peptide DMp39, designed to target DLAT signaling, effectively sensitizes cancer cells to cisplatin in patient-derived xenograft models. Collectively, our study reveals the crucial role of DLAT in shaping chemotherapy resistance, which involves an interplay between acetylation signaling and metabolic reprogramming, and offers a unique decoy peptide technology to overcome chemotherapy resistance.
    DOI:  https://doi.org/10.1038/s41467-025-63892-3
  10. Int J Biol Macromol. 2025 Oct 05. pii: S0141-8130(25)08664-7. [Epub ahead of print] 148107
    HRS sustains mitochondrial homeostasis by anchoring destabilized proteins during tumorigenesis.
    Bo-Lin Xiao, Jin-Bang Li, Zhuo-Kun Chen, Ze-Chen Zhao, Yi-Man Wang, Hai-Ming Liu, Hou-Fu Xia, Qiu-Yun Fu, Shao-Xin Huang, Jun Shang, Gang Chen, Wei Zhang.
      The role of the endosomal sorting complex required for transport (ESCRT) in tumorigenesis remains controversial and context-dependent, with its subunits often exhibiting opposing functions across cancer types. The ESCRT-0 component HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) has been linked to both tumor-suppressive and pro-oncogenic processes, yet its impact on tumor initiation and metabolic adaptation is poorly understood. Here, using a transgenic melanoma model, we demonstrate that melanocyte-specific deletion of HRS delays tumor onset, suppresses tumor growth, and prolongs survival. HRS-deficient tumor cells exhibit a shift toward glycolytic metabolism and impaired proliferation under energy stress. We further show that HRS loss leads to mitochondrial dysfunction, marked by disrupted morphology, reduced tricarboxylic acid (TCA) cycle metabolites, and decreased respiratory enzyme levels. Mechanistically, HRS deficiency disrupts the FYVE- and UIM domain-dependent endosomal clearance of ubiquitinated misfolded proteins, leading to their translocation into mitochondria. This aberrant accumulation triggers a mitochondrial unfolded protein response (mtUPR) and compromises mitochondrial function. Clearance of misfolded proteins from mitochondria rescues these defects. Our study reveals a non-canonical role for HRS in maintaining mitochondrial proteostasis and supporting tumor metabolic plasticity, highlighting HRS as a potential target for disrupting tumor metabolic adaptation.
    Keywords:  HRS; Mitochondrion; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148107
  11. Mol Oncol. 2025 Oct 05.
    Imperial strategy of cancer cells through mitochondrial transfer.
    Takamasa Ishino, Yosuke Togashi.
      Mitochondria are essential organelles that regulate various biological processes including metabolism. Beyond their intracellular functions, intercellular mitochondrial transfer has emerged as a novel mechanism of intercellular communication. Notably, an increasing number of studies have reported its occurrence in the tumor microenvironment (TME), where it contributes to tumor progression. While previous studies largely characterized cancer cells as recipients of mitochondria, Cangkrama et al. demonstrated that cancer cells donate their mitochondria to fibroblasts via tunneling nanotubes. The mitochondrial transfer to fibroblasts reprogrammed them into cancer-associated fibroblasts exhibiting combined myofibroblastic and inflammatory characteristics, with enhanced oxidative metabolism and pro-tumorigenic activity. Our group has identified mitochondrial 'hijack' from cancer cells to tumor-infiltrating lymphocytes, leading to an impaired antitumor immunity. These insights underscore the need to recognize cancer cells as mitochondrial donors in the TME capable of reshaping the TME to their own advantage, resembling a dynastic expansion strategy that exerts influence by strategically placing lineages.
    Keywords:  cancer‐associated fibroblast; mitochondrial transfer; tumor microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.70142
  12. Cell Death Dis. 2025 Oct 06. 16(1): 676
    Targeting mitochondrial translation and OXPHOS in high-grade serous ovarian carcinoma eliminates stem-like cells.
    Aravindan Narayanan, Souvik Guha, Avinash Mali, Sharmila A Bapat.
      Ex vivo stem cell self-renewal and maintenance is supported by absence of serum-derived mitogens. In the present study, we sought to elucidate the proteomes of stem-like cells grown in serum-free media across a panel of high-grade serous ovarian cancer cell lines, which encompass a gradient from epithelial, intermediate and mesenchymal cell phenotypes to recapitulate the heterogeneity of the disease. MaxQuant-based label-free quantification of proteins identified that despite their different cellular and molecular architectures, all phenotypes exhibited mitochondria- and stemness-related pathways under conditions of serum starvation, although the specific proteins involved were discrete to each phenotype. This suggests that common cellular programs in a disease can be mediated through variable biological networks that generates molecular heterogeneity. We further explored if these pathways are inter-related, co-regulated or just incidentally associated in response to an environment depleted of growth factors and mitogens. Irrespective of their phenotype, cell lines on serum-starvation displayed an increased amount of mitochondrial DNA, mitochondrial biogenesis and mitochondrial activity with a switch from glycolysis to oxidative phosphorylation fuelled by the fatty acid oxidation. Ultra-structural studies implicated this metabolic fluctuation was regulated by dynamic mitochondrial remodelling. This also led us to explore a possible therapeutic strategy of targeting mitochondrial function to restrict tumor regenerative potential and disease recurrence. Conclusively, these new avenues contribute to a more comprehensive understanding of ovarian cancer.
    DOI:  https://doi.org/10.1038/s41419-025-07987-1
  13. Br J Haematol. 2025 Oct 05.
    The BH3-only protein NOXA is essential for apoptosis induction by BH3-mimetics targeting BCL2 or BCL-XL in DLBCL.
    Nahide Yildirim, Marius Anders, Victoria M Smith, Sandrine Jayne, Moritz Assmann, Rebekah Jukes-Jones, Martin J S Dyer, Meike Vogler.
      BCL2 inhibitors (BCL2i) have transformed the management of chronic lymphocytic leukaemia (CLL), but their use in more aggressive B-cell malignancies such as diffuse large B-Cell lymphoma (DLBCL) is complicated by the more heterogeneous nature of the disease. Successful responses are limited to a subset of patients, highlighting the need for robust biomarkers predicting sensitivity. Here, we investigated the underlying mechanisms of inherent resistance to the BCL2i ABT-199 and BCL-XL inhibitor A1331852, focusing on the roles of the principal pro-apoptotic BH3-only proteins NOXA and BIM. We show that NOXA deletion, but not BIM deletion, in BCL2 and BCL-XL-dependent DLBCL cells both in vitro and in vivo resulted in a highly significant enhanced resistance to both BCL2i and BCL-XL inhibitors. In contrast, NOXA deletion did not result in alteration of sensitivity to MCL1 inhibitors. NOXA loss was associated with increased stability and binding capacity of MCL1; binding of BIM to MCL1 was associated with resistance to ABT-199. Resistance to BCL2i and BCL-XL inhibitors was abrogated by suppression of MCL1 expression. In conclusion, we show that NOXA is essential for the effectiveness of BH3-mimetics targeting BCL2/BCL-XL; in the absence of NOXA, BIM displaced from BCL2/BCL-XL can be bound by MCL1.
    Keywords:  BCL2 proteins; BH3‐mimetics; DLBCL; apoptosis; venetoclax
    DOI:  https://doi.org/10.1111/bjh.70192
  14. FEBS Lett. 2025 Oct 10.
    Mapping the evolution of mitochondrial complex I through structural variation.
    Dong-Woo Shin, Tingting Chen, James A Letts.
      Respiratory complex I (CI) is a multi-subunit membrane protein complex important for the production of ATP via the oxidative phosphorylation pathway. The structure of CI is roughly conserved across species and is composed of subunits that are either embedded in the membrane or are exposed to the aqueous environment that together form an overall L-shaped 'boot'. The conserved core of CI is generally composed of 14 subunits. Across species, various less conserved 'supernumerary' or 'accessory' subunits have been added. Accessory subunits vary in number across species and can include proteins that are unique to specific lineages. Additionally, there are structural variations in the core subunits between clades. In this Review, we compare seven representative CI structures from divergent eukaryotic lineages to identify what aspects of the CI core subunits are susceptible to variation and classify eukaryotic accessory subunits into those conserved from the last eukaryotic common ancestor (LECA) or those that are lineage specific. Impact statement Understanding the biodiversity and evolution of mitochondrial complex I will reveal patterns that may reflect metabolic niche and can be used to constrain quantitative models of molecular evolution.
    Keywords:  OXPHOS; bioenergetics; cellular respiration; complex I; cryoEM structures; evolution; last eukaryotic common ancestor; metabolism; mitochondria
    DOI:  https://doi.org/10.1002/1873-3468.70181
  15. Cell Death Discov. 2025 Oct 07. 11(1): 447
    SLC25A10 promotes cisplatin resistance by inhibiting ferroptosis in cervical cancer.
    Chenglei Ma, Xiaoyi Lu, Chen Ni, Yu Gao, Fei Yang, Shiwen Chen, Yi Du, Fang Zhao, Ying Cao, Haiwei Huang.
      Cisplatin (DDP)-based chemotherapy is the standard first-line treatment for cervical cancer (CC). However, many patients with CC develop resistance to DDP, either initially or over time. This resistance significantly limits the effectiveness of treatment. Therefore, identifying new therapeutic targets and combination therapies to overcome DDP resistance is a critical need. In this study, we investigated the expression of SLC25A10 in cervical cancer tissues using bioinformatics analysis and partial tissue analysis. We found that SLC25A10 expression was significantly higher in human cervical cancer tissues compared to normal tissues, based on data from The Cancer Genome Atlas (TCGA) and clinical samples. Moreover, increased SLC25A10 expression was associated with adverse clinicopathological characteristics of cervical cancer patients. To explore the functional role of SLC25A10, we conducted a series of in vitro and in vivo experiments. Our results demonstrated that SLC25A10 promotes cervical cancer cell growth, migration, and resistance to DDP. Mechanistically, we found that inhibiting SLC25A10 expression restricted the transport of glutathione (GSH) and reduced the expression of glutathione peroxidase 4 (GPX4). This led to increased intracellular lipid peroxidation and accumulation of reactive oxygen species (ROS), ultimately promoting iron-mediated cell death (ferroptosis) in cervical cancer cells. In conclusion, our findings suggest that SLC25A10 may serve as a novel therapeutic target to overcome cisplatin resistance and enhance the efficacy of chemotherapy in CC. Future studies should focus on further elucidating the role of SLC25A10 in CC and exploring its potential as a therapeutic target in combination with other treatments.
    DOI:  https://doi.org/10.1038/s41420-025-02712-5
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒12 at 0:40.