bims-meract 2026-08-02 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–08–02
sixteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

The PON1-NDUFA4 axis maintains mitochondrial respiratory fitness and drives lenvatinib tolerance in hepatocellular carcinoma.
Targeting the CTBP1-CETP axis overcomes ferroptosis resistance in non-small cell lung cancer by altering lipid accumulation.
The TFDP2-PDK3 axis drives glucose metabolic reprogramming to promote radioresistance in nasopharyngeal carcinoma.
Inhibition of PGC1β-dependent mitochondrial biogenesis enhances EGFR-targeted therapy in lung cancer.
70 Years of DON and Beyond: Glutaminase Inhibition as a Synergistic Strategy in Cancer Combination Therapy.
Naringin sensitizes nasopharyngeal carcinoma cells to paclitaxel by inducing AKR1C3 expression.
TKTL1 mediates metabolic adaptation and stress resistance in pancreatic cancer cells under nutrient-deprived conditions.
Enhancing the efficacy of B7-H3-targeting antibody-drug conjugate DS-7300a in TP53-deficient tumors by inducing ferroptosis.
Combined inhibition of de novo pyrimidine synthesis and ATR promotes ATF4-mediated cell death in TP53-deficient ALL.
Protocol to study the antitumor and metabolic effects of intermittent fasting plus cisplatin and metformin in ovarian cancer PDX models.
Targeting ACSF2 overcomes Ara-C resistance in acute myeloid leukemia via the cholesterol metabolism-ERK signaling axis.
USP15-mediated deubiquitination of FIS1 impairs mitochondrial function and sensitizes bladder cancer cells to radiotherapy.
Inhibition of mitochondrial protein translation sensitizes tumor cells to death receptor 5 agonistic antibody.
HMGB1-Induced Metabolic Rewiring of Macrophages via RAGE/MAPK Fosters Endocrine Resistance in Breast Cancer.
The Zuo Jin Wan Formula Reverses Cisplatin Resistance in Gastric Cancer by Inhibiting the Mitochondrial Translocation of Dynamin-Related Protein 1 and Its Mediated Mitochondrial Fission and Mitophagy.
The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.

Mol Cancer Res. 2026 Jul 28.

The PON1-NDUFA4 axis maintains mitochondrial respiratory fitness and drives lenvatinib tolerance in hepatocellular carcinoma.

Shi-Lin Lin, Yue Wang, Yi-Min Zheng, Ai-Wu Ke, A-Ying Ma, Chao Gao.

Metabolic plasticity driven by mitochondrial oxidative phosphorylation (OXPHOS) is increasingly recognized as a key determinant of therapeutic tolerance in hepatocellular carcinoma (HCC), but the upstream regulators that preserve electron transport chain stability during treatment remain poorly defined. In this study, we identified paraoxonase-1 (PON1) as a clinically relevant regulator of mitochondrial metabolism and lenvatinib response in HCC. PON1 was markedly upregulated in HCC and independently associated with poor overall and recurrence-free survival. Functionally, PON1 promoted tumor growth and conferred robust tolerance to lenvatinib. Mechanistically, PON1 directly interacted with and stabilized NDUFA4, a key component required for complex IV assembly, thereby maintaining mitochondrial membrane potential, complex IV integrity, and OXPHOS-dependent adenosine triphosphate production while limiting reactive oxygen species accumulation. Genetic silencing of PON1 or NDUFA4 impaired mitochondrial respiration, increased oxidative stress, and restored lenvatinib sensitivity in HCC cells and xenograft models. Structure-guided virtual screening identified the Food and Drug Administration-approved CFTR corrector lumacaftor as a potent modulator of PON1 that disrupted the PON1-NDUFA4 interaction and enhanced the antitumor efficacy of lenvatinib in vivo. These findings identify the PON1-NDUFA4 axis as a previously unrecognized metabolic vulnerability that sustains mitochondrial respiratory fitness and lenvatinib resistance in HCC. Targeting mitochondrial protein-stabilizing mechanisms such as PON1-NDUFA4 may offer a broadly applicable strategy for overcoming therapy resistance in liver cancer and other aggressive malignancies. Implications: These findings establish mitochondrial protein stabilization as an actionable therapeutic vulnerability and provide a rationale for combination strategies to overcome targeted therapy resistance in HCC.

DOI: https://doi.org/10.1158/1541-7786.MCR-26-0121
Clin Transl Med. 2026 Aug;16(8): e70749

Targeting the CTBP1-CETP axis overcomes ferroptosis resistance in non-small cell lung cancer by altering lipid accumulation.

Yanjie Chen, Heng Wang, Ximin Tan, Chenxi Yan, Fangfang Liu, Shuxuan Deng, Chengyan Wang, Yangchen Xia, Zhaolin Xu, Kongming Wu, Shanshan Huang, Qian Chu.

   BACKGROUND: Non-small cell lung cancer (NSCLC) remains a leading cause of global cancer mortality. Increasing evidence implicates aberrant cholesterol metabolic reprogramming as a key facilitator of tumour malignancy; however, the mechanistic connections between lipoprotein metabolism and NSCLC pathogenesis remain elusive. Here, we investigate the unrecognised oncogenic role of cholesteryl ester transfer protein (CETP), a central lipid exchange mediator.
METHODS: Serum lipid profiles from 151 NSCLC patients were analysed, and CETP mRNA expression level was evaluated in normal lung (n = 47) and NSCLC tissue (n = 54) and paired NSCLC tissue microarrays (n = 113). Integrated ChIP-seq/RNA-seq analyses, ChIP-qPCR, dual-luciferase reporter and ubiquitination assays were performed to investigate CTBP1-mediated CETP transcription. Functional studies in NSCLC cells, xenograft models and eight patient-derived organoids evaluated the role of the CTBP1-CETP axis in lipid remodelling, ferroptosis and the therapeutic efficacy of obicetrapib alone or combined with RSL3.
RESULTS: CETP was significantly up-regulated in NSCLC tissues and predicted poor overall survival in both LUAD (HR = 1.46, 95% CI 1.13-1.87, p = .0033) and LUSC (HR = 1.51, 95% CI 1.12-2.01, p = .0067). CTBP1 activated CETP transcription, and CTBP1 ubiquitination further enhanced its transcriptional activity. The CTBP1-CETP axis promoted ferroptosis resistance by lipid accumulation. Obicetrapib phenocopied CETP depletion and synergised with RSL3 to inhibit tumour growth in NSCLC cells, xenografts and patient-derived organoids.
CONCLUSIONS: Our study delineates a novel CTBP1-CETP-lipid droplet-MAPK signalling cascade that couples metabolic rewiring with ferroptosis evasion. These insights establish the CTBP1-CETP axis as a critical cell fate determinant, positioning pharmacological CETP inhibition (e.g., obicetrapib) as a translatable therapeutic vulnerability in lipid-dependent, ferroptosis-resistant NSCLC.

Keywords:  CETP; CTBP1; ferroptosis; lipid accumulation; non‐small cell lung cancer; obicetrapib

DOI:  https://doi.org/10.1002/ctm2.70749
Radiother Oncol. 2026 Jul 28. pii: S0167-8140(26)00547-5. [Epub ahead of print] 111708

The TFDP2-PDK3 axis drives glucose metabolic reprogramming to promote radioresistance in nasopharyngeal carcinoma.

Qi Yang, Jianbo Fang, Cuiying Chen, Chunyan Zhang, Shulu Hu, Qiong Lv, Xuechun Li, Xiang Liu, Hui Meng, Weitao Shen, Jian Zhang.

   BACKGROUND: Although nasopharyngeal carcinoma (NPC) is highly radiosensitive, tumor radioresistance inevitably leads to local recurrence and distant metastasis, posing a major clinical challenge for NPC treatment.
MATERIALS AND METHODS: By integrating single-cell RNA sequencing data from eight local NPC samples, mRNA sequencing data from pre-established radioresistant cell models, and phenotype-associated gene sets shared across heterogeneous tumor cells, we identified the potential central role of Transcription Factor Dimerization Partner 2 (TFDP2) in radioresistance. After demonstrating the critical role of TFDP2 in radioresistance through comprehensive in vitro and in vivo experiments, we performed transcriptome sequencing on TFDP2-silenced cells and conducted bioinformatic analysis to explore the potential mechanism. Finally, using a series of functional assays, including examination of key metabolic indicators, immunofluorescence, immunohistochemistry, chromatin immunoprecipitation (ChIP)-qPCR, and dual-luciferase reporter assays, we elucidated the precise molecular mechanism by which TFDP2 mediates radioresistance.
RESULTS: TFDP2 plays a pivotal role in the process of radioresistance in NPC: its elevated expression not only enhances radiation resistance but also predicts worse clinical outcomes in publicly available NPC cohorts. Mechanistically, TFDP2 promotes radioresistance by activating PDK3 transcription, which reprograms metabolism from oxidative phosphorylation to glycolysis.
CONCLUSIONS: This work establishes TFDP2-mediated metabolic reprogramming as a critical mechanism of radioresistance, offering mechanistic insights and a potential therapeutic target for improving radiotherapy outcomes in NPC.

Keywords:  Glucose metabolic reprogramming; Nasopharyngeal carcinoma; Radioresistance

DOI:  https://doi.org/10.1016/j.radonc.2026.111708
EMBO Mol Med. 2026 Jul 30.

Inhibition of PGC1β-dependent mitochondrial biogenesis enhances EGFR-targeted therapy in lung cancer.

Zhen Chen, Dongsheng Wang, Songqing Fan, Qiming Wang, Yong Huang, Pan Du, Shidong Jia, Suresh S Ramalingam, Shi-Yong Sun.

Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, show robust clinical efficacy in EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), yet acquired resistance remains inevitable. Here, we demonstrate that osimertinib and other EGFR-TKIs suppress PPARGC1B expression and its regulated mitochondrial biogenesis in EGFRm NSCLC cells through a previously unrecognized FOSL1/AP-1-mediated transactivation mechanism. Upon acquisition of osimertinib resistance, PPARGC1B expression and its encoded protein PGC1β rebound and become refractory to osimertinib-mediated suppression. Enforced overexpression of PPARGC1B confers resistance to osimertinib in sensitive EGFRm NSCLC cells, whereas PPARGC1B knockdown restores drug sensitivity in resistant cells. Moreover, combining osimertinib with the mitochondria-targeting agent CPI-613 synergistically suppresses mitochondrial biogenesis, induces apoptosis, and inhibits the growth of osimertinib-resistant cells and tumors. Collectively, these findings identify PGC1β-dependent mitochondrial biogenesis as a critical determinant of therapeutic response to osimertinib and suggest co-targeting mitochondrial metabolism as a potential strategy to overcome acquired resistance in EGFRm NSCLC.

DOI: https://doi.org/10.1038/s44321-026-00493-7
Pharmaceutics. 2026 Jul 13. pii: 850. [Epub ahead of print]18(7):

70 Years of DON and Beyond: Glutaminase Inhibition as a Synergistic Strategy in Cancer Combination Therapy.

José A Campos-Sandoval, Juan De Los Santos-Jiménez, Javier Márquez, José M Matés.

  Personalized oncology seeks to selectively block specific dysregulated pathways to arrest cancer development. Increased glutamine metabolism is a hallmark of cancer, and 6-diazo-5-oxo-L-norleucine (DON), a structural analog of L-glutamine, was the first compound used to target the exacerbated nitrogen metabolism observed in cancer cells. However, its clinical application was limited by unacceptable toxicity. With the same goal of blocking glutamine metabolism, several specific glutaminase inhibitors have been characterized in recent decades, showing promising antitumor activity. Nevertheless, this strategy frequently induces adaptive metabolic resistance that must be counteracted. In this context, glutaminase has become a key target in combination therapies for several tumor types aimed at restricting anabolic adaptation when single metabolic therapy fails, emerging as a possible synergistic therapeutic intervention. Consequently, combination therapies that include glutaminase inhibition alongside additional agents to counteract the metabolic plasticity of cancer have emerged as a promising approach in personalized antitumor pharmacology. This review provides a historical-to-translational overview of glutamine-targeted therapies, with particular emphasis on glutaminase inhibitors, including compound 968, BPTES, CB-839, and next-generation inhibitors, as well as DON-derived prodrugs. We discuss their mechanisms of action and their integration with chemotherapy, targeted therapies, radiotherapy, and immunotherapy, highlighting how glutamine metabolism targeting influences tumor metabolic adaptation, redox homeostasis, therapy resistance, and tumor-immune interactions. Finally, we examine current clinical developments, emerging therapeutic combinations, and the challenges that must be addressed for the incorporation of glutamine metabolism targeting into precision oncology.

Keywords:  BPTES; CB-839; DON; DRP-104; combination therapy; glutaminase; synergistic effects

DOI:  https://doi.org/10.3390/pharmaceutics18070850
J Int Med Res. 2026 Jul;54(7): 3000605261470618

Naringin sensitizes nasopharyngeal carcinoma cells to paclitaxel by inducing AKR1C3 expression.

Zhenhe Huang, Yumei Qiu, Fangchu Liu, Xiaoli Chen, Xintao Wang.

  ObjectiveTo investigate whether naringin enhances the chemosensitivity of nasopharyngeal carcinoma-derived CNE2 cells to paclitaxel and identify potential molecular mediators.MethodsCNE2 cells were treated with naringin alone or in combination with paclitaxel, cisplatin, or 5-fluorouracil. Cell viability, proliferation, and migration were assessed using cell counting kit-8 and Transwell assays. Transcriptomic profiling followed by bioinformatic analysis of Gene Expression Omnibus datasets (GSE53819, GSE12452, and GSE102349) was performed to identify nasopharyngeal carcinoma prognosis-related genes. AKR1C3 overexpression was established via lentiviral transduction, and pharmacological inhibition was performed using ASP9521. mRNA and protein expression were validated using reverse transcription quantitative polymerase chain reaction and Western blot analysis.ResultsNaringin (160 μM) demonstrated a trend toward reducing the half-maximal inhibitory concentration of paclitaxel from 10.52 to 8.04 nM; however, it did not significantly alter sensitivity to cisplatin or 5-fluorouracil. Combined treatment with 2 nM paclitaxel and 160 μM naringin synergistically suppressed CNE2 proliferation and migration compared with that using either agent alone (p < 0.05). Bioinformatic analysis revealed that high AKR1C3 expression was correlated with improved survival in patients with nasopharyngeal carcinoma (p < 0.05), whereas high PAIP1, PRKDC, PTPRR, and COL12A1 expressions were correlated with poorer outcomes. Reverse transcription quantitative polymerase chain reaction confirmed that both naringin and paclitaxel upregulated AKR1C3 mRNA, with the combination producing the strongest effect. Gain-of-function studies demonstrated that AKR1C3 overexpression significantly enhanced paclitaxel sensitivity, with half-maximal inhibitory concentration values decreasing from 13.63 to 6.994 nM in CNE2 cells and from 8.534 to 4.668 nM in CNE1 cells. Furthermore, the specific AKR1C3 inhibitor, ASP9521, significantly attenuated the synergistic anti-proliferative and anti-migratory effects of paclitaxel + naringin in CNE2 cells, confirming that naringin enhances chemosensitivity to paclitaxel by upregulating AKR1C3 expression.ConclusionsNaringin sensitizes CNE2 cells to paclitaxel, potentially via AKR1C3 upregulation. This flavonoid may represent a low-toxicity adjunct to enhance the efficacy of paclitaxel in nasopharyngeal carcinoma.

Keywords:  AKR1C3; Nasopharyngeal carcinoma; chemosensitization; naringin; paclitaxel

DOI:  https://doi.org/10.1177/03000605261470618
Oncogene. 2026 Jul 30.

TKTL1 mediates metabolic adaptation and stress resistance in pancreatic cancer cells under nutrient-deprived conditions.

Takefumi Onodera, Shuichi Sakamoto, Shunichi Ohba, Manabu Kawada, Isao Momose.

Pancreatic tumors frequently develop in nutrient-poor microenvironments due to impaired perfusion, forcing cancer cells to engage in metabolic adaptation for survival. This study identified the upregulation of transketolase-like 1 (TKTL1) as a nutrient-stress-responsive factor associated with metabolic adaptation of pancreatic cancer cells under amino-acid starvation, particularly glutamine scarcity. In particular, we found that TKTL1 induction was specifically observed in cancer cells and not in normal pancreatic ductal cells. Functional assays showed that TKTL1 overexpression increased proliferative capacity and tumor growth, whereas its knockdown attenuated these phenotypes and reduced cancer cell fitness under nutrient stress. Although TKTL1 exhibits weak intrinsic enzymatic activity, our data support a functional association with transketolase (TKT), accompanied by increased total transketolase activity. Protein-protein interaction assays further indicated that TKTL1 binds to TKT more prominently under nutrient deprivation than under nutrient-rich conditions. Furthermore, transcriptional analyses and NF-κB inhibition experiments suggest that TKTL1 upregulation is partially regulated by the NF-κB/p50 axis. Together, these findings are consistent with a model in which TKTL1 contributes to metabolic adaptation and stress tolerance in nutrient-deprived pancreatic cancer cells, in part through interaction with TKT, and suggest that the TKTL1 axis may represent a context-dependent therapeutic target in nutrient-limited tumors.

DOI: https://doi.org/10.1038/s41388-026-03913-7
Oncogene. 2026 Jul 27.

Enhancing the efficacy of B7-H3-targeting antibody-drug conjugate DS-7300a in TP53-deficient tumors by inducing ferroptosis.

Javier Leo, Feiyu Chen, Wei Shi, Xin Liang, Chenling Meng, Qianlin Gu, Yaman Albittar, Zhen Fan, Jie Zhang, Boyi Gan, Sangeeta Goswami, Kendra S Carmon, Daniel E Frigo, Ana Aparicio, Di Zhao.

Immune checkpoint B7-H3 is an emerging target for immunotherapy. DS-7300a is an advanced B7-H3-targeting antibody-drug conjugate (ADC) warheaded with the topoisomerase I inhibitor DXd. DS-7300a has demonstrated clinical activity, but molecular biomarkers to predict its therapeutic response remain elusive. TP53 is one of the most mutated tumor suppressor genes across cancers, and effective therapies are urgently needed for TP53-deficient cancers. Using prostate cancer (PCa) as a model system, we reported that DS-7300a's anti-tumor efficacy is highly dependent on functional p53 in cancer cells, and TP53 defects confer resistance to DS-7300a. Mechanistically, we found that DS-7300a and its payload, DXd, induce DNA damage and activate the ATM/ATR/CHK signaling cascade, thereby stabilizing p53 and inducing a pro-apoptotic and senescence-associated transcriptome. In contrast, TP53-deficient cells fail to sense DXd-induced DNA damage, maintain a high proliferation rate, and exhibit low levels of apoptosis and senescence, thereby conferring resistance to DS-7300a. Ferroptosis is an iron-dependent form of regulated cell death triggered by lipid peroxidation, which is mechanistically and morphologically distinct from apoptosis. Interestingly, DS-7300a treatment elevates lipid peroxidation in TP53-deficient cancer cells and upregulates glutathione peroxidase 4 (GPX4), an antioxidant enzyme that mitigates lipid peroxidation. Using isogeneic xenograft models and a newly developed humanized B7-H3 PCa model, we demonstrated that inducing ferroptosis by pharmacological inhibition of GPX4 enhances DS-7300a's efficacy in TP53-deficient tumors. Our studies demonstrate that TP53 status dictates anti-tumor responses to DS-7300a, and ferroptosis induction represents a promising therapeutic approach to overcome resistance to DS-7300a in malignancies harboring TP53 defects.

DOI: https://doi.org/10.1038/s41388-026-03921-7
Hemasphere. 2026 Jul;10(7): e70439

Combined inhibition of de novo pyrimidine synthesis and ATR promotes ATF4-mediated cell death in TP53-deficient ALL.

Kari J T Grünewald, Marjolein M G Kes, Gawin R Stoll, Willem P J Cox, Dorette S van Ingen Schenau, Enzo M Scutigliani, Emmely M Wagener, Ziqin Tang, Senna Visser, Jolanda Kooiman, Jessica Buijs-Gladdines, Maria Rodionova, Esther A Zaal, Jeroen W A Jansen, Jeroen F van Velzen, Jarno Drost, Laurens T van der Meer, Celia R Berkers, Frank N van Leeuwen.

Mutations or deletions affecting the TP53 gene predict a dismal outcome in relapsed acute lymphoblastic leukemia (ALL). Loss of p53 function compromises the response to many anti-leukemic therapies, underscoring the need for agents that are effective in TP53-deficient cells. Leukemic blasts depend on de novo pyrimidine synthesis to sustain proliferation, and the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) is essential for this pathway. While DHODH inhibitors (DHODHis) show preclinical anti-leukemic activity, the efficacy in TP53-deficient contexts has not been tested. Using both isogenic TP53-wildtype and knock-out cell line models and patient-derived xenografts (PDXs), we show that dual inhibition of DHODH and Ataxia Telangiectasia and Rad3-related (ATR) produces pronounced anti-leukemic effects, irrespective of the TP53 status. Through integrated transcriptomic and metabolomic analyses, we show that combined inhibition of DHODH and ATR leads to a reduced flux of glucose into the TCA cycle, accompanied by an increase in oxidative stress. This metabolic phenotype triggers cell death through a mechanism converging on Activating Transcription Factor 4 (ATF4), a key integrator of cellular responses to metabolic and oxidative stress, which operates largely independently of p53. Taken together, our findings identify ATF4-mediated cell death as a previously unrecognized vulnerability in TP53-deficient ALL.

DOI: https://doi.org/10.1002/hem3.70439
STAR Protoc. 2026 Jul 27. pii: S2666-1667(26)00389-8. [Epub ahead of print]7(3): 104736

Protocol to study the antitumor and metabolic effects of intermittent fasting plus cisplatin and metformin in ovarian cancer PDX models.

Ludovica Perotti, Elena Capellini, Federica Guffanti, Anna Maria Ronchi, Daniela Corna, Domenico Cerullo, Cristina Matteo, Laura Sala, Eugenio Scanziani, Federica Maggi, Melissa Tiddia, Flavia Funari, Giovanna Damia, Laura Brunelli, Francesca Ricci.

  Different dietary regimens are being explored as safe, low-cost approaches to enhance cancer therapy. This protocol describes the evaluation of antitumor and metabolic effects of intermittent fasting (IF) combined with cisplatin and metformin in an ovarian cancer patient-derived xenograft (PDX) model. Procedures include IF cycles, drug administration, antitumor activity assessment, drug quantification in plasma and tumors, toxicity evaluation, and immunohistochemical analyses. For complete information on the generation and use of this protocol, please refer to Capellini et al.1.

Keywords:  Cancer; Metabolism; Model Organisms

DOI:  https://doi.org/10.1016/j.xpro.2026.104736
Leukemia. 2026 Jul 31.

Targeting ACSF2 overcomes Ara-C resistance in acute myeloid leukemia via the cholesterol metabolism-ERK signaling axis.

Chenxi Liao, Jin Wen, Xiao Ma, Nan Wang, Ying Chen, Lei Li, Lingbo Liu, Danyue Peng.

Therapeutic resistance to cytarabine (Ara-C), a cornerstone of acute myeloid leukemia (AML) therapy, remains an unmet clinical need. Here, we identify ACSF2 as a key metabolic determinant of Ara-C resistance. ACSF2 inhibition suppresses Ara-C-resistant AML cell proliferation, restores Ara-C sensitivity in vitro and in vivo. Mechanistically, ACSF2 inhibition impairs cholesterol esterification. Therefore, the increased cholesterol accumulation on mitochondrial membranes results in mitochondrial dysfunction, elevated mitochondrial reactive oxygen species (ROS), and suppression of pro-survival ERK signaling. Furthermore, we first established SREBF1 as a direct transcriptional activator of ACSF2 in this context. Notably, the SREBF1 inhibitor fatostatin synergizes with Ara-C against resistant AML with downregulation of ACSF2. These findings define a crucial role of ACSF2 in Ara-C resistance and highlight the SREBF1-ACSF2 axis as a promising therapeutic target for relapsed/refractory AML.

DOI: https://doi.org/10.1038/s41375-026-03053-7
Oncogene. 2026 Jul 27.

USP15-mediated deubiquitination of FIS1 impairs mitochondrial function and sensitizes bladder cancer cells to radiotherapy.

Ruxin Xiong, Mingxu Wang, Jiaming Du, Bingqian Chai, Qianqian Zhou, Yating Yan, Jiang Han, Yang Yao, Chao Liu, Jiani Yang, Bojun Wang, Shuijie Li, Yuanfei Yao, Ruiqi Liu.

While radiation therapy plays a pivotal role in the treatment of advanced invasive bladder cancer, its efficacy is often limited when used as alone, underscoring the need to identify molecular targets that regulate radiosensitivity. In this study, we identify USP15 as a novel regulator of mitochondrial function and demonstrate that USP15 serves as a key target for enhancing radiosensitivity in bladder cancer cells. In orthotopic bladder cancer mouse models, USP15 overexpression combined with radiotherapy effectively suppressed tumor growth. Mechanistically, as a canonical deubiquitinase, mitochondria-localized USP15 directly interacts with FIS1 and stabilizes FIS1 protein by deubiquitinating it at the K25 site, leading to mitochondrial dysfunction and downregulation of oxidative phosphorylation (OXPHOS), which in turn increases radiosensitivity. Conversely, treatment with the mitochondrial inhibitor metformin reversed the radioresistance observed in bladder cancer tissues with low USP15 expression, effectively inhibiting the growth of patient-derived xenograft (PDX) tumors and significantly improving survival benefits. In summary, USP15 plays a critical role in regulating radiosensitivity, and targeting USP15-mediated mitochondrial OXPHOS may represent a promising therapeutic strategy to enhance the efficacy of radiotherapy in bladder cancer, providing a novel treatment approach for the treatment of bladder cancer patients.

DOI: https://doi.org/10.1038/s41388-026-03918-2
FEBS J. 2026 Jul 29.

Inhibition of mitochondrial protein translation sensitizes tumor cells to death receptor 5 agonistic antibody.

Gabriele Casagrande Raffi, Jian Chen, Elsemieke Passchier, Cor Lieftink, Chrysa Papagianni, Jeanette H W Leusen, Roderick L Beijersbergen, Liqin Wang, Rene Bernards.

  While many antagonistic antibodies are in routine clinical use, only a single agonistic antibody has received regulatory approval to date. While antibodies that activate Death Receptor 5 (DR5) were thought to have utility in the treatment of cancer by enhancing extrinsic apoptosis signaling, to date all clinical studies with these DR5 agonists have failed to deliver significant clinical benefit. A notable example of this is the DR5 agonistic antibody conatumumab. Here, we provide two potential avenues to improve the activity of DR5 agonists. First, we show that a dimeric IgA version (dIgA2) of the conatumumab antibody has a higher toxicity to cancer cells and a shorter half-life in vivo compared to the original IgG version of the antibody. Moreover, we conducted a genome-wide CRISPR screen to identify genes for which inactivation enhances the sensitivity of cancer cells to the dIgA2 DR5 antibody. We found that inhibition of mitochondrial protein translation synergizes with DR5 agonists. Consequently, antibiotics that inhibit mitochondrial protein translation also synergize with DR5 agonists. Finally, we show that these antibiotics activate the Integrated Stress Response (ISR) and upregulate DR5 through the EIF2a-ATF4 axis, which sensitizes cancer cells to DR5 activation. These data suggest a potential combination strategy for the effective use of DR5 agonistic antibodies.

Keywords:  CRISPR screening; apoptosis; dimeric IgA; integrated stress response; mitochondria

DOI:  https://doi.org/10.1111/febs.70669
Immunology. 2026 Jul 29.

HMGB1-Induced Metabolic Rewiring of Macrophages via RAGE/MAPK Fosters Endocrine Resistance in Breast Cancer.

Donglin Liu, Shengnan Sun, Junning Peng, Shuling Shi, Yuwei Deng, Qingyuan Zhang.

  Endocrine resistance remains a critical challenge in hormone receptor-positive (HR+) breast cancer. The impact of the immune microenvironment on endocrine therapy efficacy is increasingly recognised, but its mechanisms are not fully understood. Here, we investigated that nuclear HMGB1 expression in tumour cells was closely associated with endocrine therapy resistance in HR+ breast cancer using tumour genomic databases. Specially, tumours with high HMGB1 expression induced M2-like macrophage polarisation, which was related to HMGB1 paracrine signalling. Mechanistically, HMGB1 bound to the RAGE receptor on macrophages, activating the downstream MAPK signalling pathway and was closely linked to the activation of fatty acid metabolism pathways. Macrophages co-cultured with high-HMGB1 tumour cells exhibited metabolic characteristics associated with carcinogenesis, a loss of glycolytic intermediates and a shift toward a pro-tumourigenic metabolic state compared to those co-cultured with low-HMGB1 cells. Co-culture with M2-like macrophages significantly activated growth signalling pathways like NF-κB in the high-HMGB1 tumour cells. Taken together, high expression of HMGB1 in tumour cells promotes fatty acid metabolic remodelling and functional polarisation in macrophages, contributing to endocrine therapy resistance in HR+ breast cancer. HMGB1 acts as a candidate for immune mediator and paved a way to develop potential target drug.

Keywords:  HMGB1; RAGE/MAPK signalling; endocrine resistance; hormone receptor‐positive breast cancer; macrophage polarisation; metabolic remodelling

DOI:  https://doi.org/10.1111/imm.70182
Cancer Med. 2026 Aug;15(8): e72131

The Zuo Jin Wan Formula Reverses Cisplatin Resistance in Gastric Cancer by Inhibiting the Mitochondrial Translocation of Dynamin-Related Protein 1 and Its Mediated Mitochondrial Fission and Mitophagy.

Zhuo Zhao, Meijie Yuan, Xiao Yang, Qing Ji, Guobin Liu, Qingfeng Tang, Jian Sun.

   BACKGROUND: Gastric cancer is a major global health concern characterized by high incidence and mortality rates. One of the key challenges in treating gastric cancer is the development of resistance to chemotherapy drugs like cisplatin (DDP). This study aimed to investigate the efficacy of Zuo Jin Wan (ZJW), a traditional Chinese medicine, in overcoming DDP resistance in gastric cancer cells.
METHODS: The research employed gastric cancer cells with DDP resistance, namely SGC7901/DDP and AGS/DDP, to explore the molecular mechanisms underlying ZJW's effects.
RESULTS: ZJW significantly reduced DDP resistance by inhibiting the phosphorylation and preventing mitochondrial translocation of Dynamin-related protein 1 (DRP1). ZJW treatment suppressed DRP1-mediated mitochondrial fission and mitophagy, thereby enhancing the sensitivity of resistant cells to DDP. Additionally, ZJW was observed to downregulate the AMPK signaling pathway, which plays a crucial role in DRP1 activation.
CONCLUSIONS: By modulating mitochondrial dynamics, ZJW disrupts protective mechanisms in resistant cancer cells, highlighting its potential as an adjunct therapy. This study underscores the therapeutic potential of integrating traditional Chinese medicine with conventional chemotherapy to combat drug resistance in gastric cancer.

Keywords:  DRP1; Zuo Jin Wan; cisplatin; drug resistance; gastric cancer

DOI:  https://doi.org/10.1002/cam4.72131
Nat Aging. 2026 Jul 30.

The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.

Aidan R Cole, Raquel Buj, Apoorva Uboveja, Evan Levasseur, Alexander Tom, Hui Wang, Katarzyna M Kedziora, Adam Chatoff, Andrea Andress Huacachino, Mariola M Marcinkiewicz, Amandine Amalric, Baixue Yang, Naveen Kumar Tangudu, Emily Noonan, Jeff Danielson, Miho Naruse, Amal Taher Elhaw, Sierra White, Danyang Li, Callen T Wallace, Frederick Keeney, Felicia Lazure, Esther Elishaev, Lauren Borho, Hope A Townsend, Robin D Dowell, Aaron Clauset, Dorota E Jazwinska, Matthew S Laird, Huda Atiya, Denarda Dangaj, Lan G Coffman, George Tseng, Steffi Oesterreich, Andrew Kossenkov, Qin Liu, Ana P Gomes, Aditi U Gurkar, Francisco J Schopfer, Francesmary Modugno, Simon C Watkins, Ioannis K Zervantonakis, Benjamin G Bitler, Wayne Stallaert, Nadine Hempel, Nathaniel W Snyder, Katherine M Aird.

Cellular senescence is a consequence of many chemotherapeutics that plays context-dependent roles in cancer. Senescent cells secrete an array of factors collectively known as the senescence-associated secretory phenotype (SASP). Here we show that the cisplatin-induced SASP enhances the detachment of high-grade serous ovarian cancer (HGSOC) cells in vitro and dissemination in vivo. We identify fructose as a metabolic component of the SASP that facilitates cell detachment and show that a high-fructose diet increases HGSOC dissemination in vivo. We identified complex I as the driver of SASP-mediated cell detachment and HGSOC dissemination. Mechanistically, this effect was driven by SASP-mediated inhibition of an NAD+-SIRT-SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. These findings reveal that the SASP reprograms the metabolic microenvironment, promoting metastatic dissemination in a paracrine fashion, and highlight a pro-tumorigenic metabolic effect of fructose in the SASP that may contribute to the high recurrence rate of HGSOC.

DOI: https://doi.org/10.1038/s43587-026-01172-5