bims-meract 2025-06-15 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–06–15
twenty papers selected by
Andrea Morandi, Università degli Studi di Firenze

Cholesterol metabolism regulated by CAMKK2-CREB signaling promotes castration-resistant prostate cancer.
The Splice Variant of the NCOR2 Gene BQ323636.1 Modulates ACSL4 Expression to Enhance Fatty Acid Metabolism and Support of Tumor Growth in Breast Cancer.
Metabolic reprogramming by PRDM16 drives cytarabine resistance in acute myeloid leukemia.
GCLM lactylation mediated by ACAT2 promotes ferroptosis resistance in KRASG12D-mutant cancer.
Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer.
Glutamate transporter SLC1A6 promotes resistance to immunotherapy in cancer.
Mapping the polar metabolome in Huh-7 liver cancer cells reveal the role of atorvastatin in enhancing chemotherapeutic efficacy of doxorubicin.
Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming.
Targeting tumor metabolism to augment CD8+ T cell anti-tumor immunity.
Pancreatic cancer cachexia is mediated by PTHrP-driven disruption of adipose de novo lipogenesis.
Targeting PPARα activation sensitizes glioblastoma cells to temozolomide and reverses acquired resistance by inhibiting H3K18 lactylation.
tsRNA-08614 inhibits glycolysis and histone lactylation by ALDH1A3 to confer oxaliplatin sensitivity in colorectal cancer.
Glucosylceramide Synthase, a Key Enzyme in Sphingolipid Metabolism, Regulates Expression of Genes Accounting for Cancer Drug Resistance.
Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia via a cytotoxic integrated stress response.
Impact of mtG3PDH inhibitors on proliferation and metabolism of androgen receptor-negative prostate cancer cells: Role of extracellular pyruvate.
Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis.
Loss of UFMylation supports prostate cancer metastasis and rewires cell metabolism towards hexosamine biosynthesis.
Selective Inhibition of the ABCG2 Transporter by Primaquine Derivatives Reverses the Multidrug Resistance of Tumor Cells.
Metabolic reprogramming in hepatocellular carcinoma: an integrated omics study of lipid pathways and their diagnostic potential.
Multimodal nanoparticles co-delivering bevacizumab and dichloroacetate for dual targeting of neoangiogenesis and hyperglycolysis in glioblastoma treatment.

Cell Rep. 2025 Jun 06. pii: S2211-1247(25)00563-7. [Epub ahead of print]44(6): 115792

Cholesterol metabolism regulated by CAMKK2-CREB signaling promotes castration-resistant prostate cancer.

Chenchu Lin, Thomas L Pulliam, Jenny J Han, Jiaqian Xu, Carlos Vera Recio, Sandi R Wilkenfeld, Yan Shi, Manoj Kushwaha, Sarah Bench, Eduardo Ruiz, Sanjanaa Senthilkumar, Jayasurya Dileep, Peter D A Shepherd, Nora M Navone, Albert R Klekers, Elizabeth M Whitley, Michael M Ittmann, Livia S Eberlin, Wenyi Wang, Daniel E Frigo.

  Castration-resistant prostate cancer (CRPC) remains an incurable disease in need of improved treatments. CAMKK2 is an emerging therapeutic target whose oncogenic effects in prostate cancer have, to date, been largely attributed to its activation of AMP-activated protein kinase (AMPK). Here, we demonstrate that CAMKK2 promotes prostate cancer growth through an alternative downstream pathway involving CAMKI and CREB. Unbiased transcriptomics identify CREB-mediated transcription as a CAMKK2-regulated process, findings that we validate using diverse molecular, genetic, and pharmacological approaches in vitro and in vivo. CAMKK2 promotes CREB phosphorylation/activation through CAMKIα independently of AMPK, CAMKIV, or other CAMKI isoforms. Functionally, the CREB family members CREB1 and ATF1 exhibit close redundancy, necessitating co-targeting for optimal anti-tumor efficacy. An inhibitor of CREB1/ATF1 blocks CRPC with minimal side effects. Mechanistically, CAMKK2 and CREB increase CRPC growth through augmenting cholesterol metabolism. Together, these findings identify an oncogenic pathway that could be exploited for the treatment of CRPC.

Keywords:  AMPK; CAMKI; CAMKK2; CP: Cancer; CP: Metabolism; CREB; androgen receptor; cholesterol; metabolism; prostate cancer

DOI:  https://doi.org/10.1016/j.celrep.2025.115792
Int J Mol Sci. 2025 May 22. pii: 4989. [Epub ahead of print]26(11):

The Splice Variant of the NCOR2 Gene BQ323636.1 Modulates ACSL4 Expression to Enhance Fatty Acid Metabolism and Support of Tumor Growth in Breast Cancer.

Ho Tsoi, Chan-Ping You, Koei Ho-Lam Cheung, Yin-Suen Tse, Ui-Soon Khoo.

  BQ323636.1 (BQ), a splice variant of NCOR2, is associated with endocrine therapy resistance and poorer prognosis in ER-positive breast cancer. This study investigates the role of BQ in modulating lipid metabolism to support tumor growth. RNA sequencing of BQ-overexpressing breast cancer cells revealed significant enrichment of fatty acid metabolism pathways (hsa01212 and hsa00061; p < 0.05), with ACSL4 identified as a key target. We show that BQ disrupts the NCOR2-PPARγ interaction, leading to ACSL4 upregulation, which enhances fatty acid oxidation (FAO), acetyl-CoA by 1.8-fold, and ATP production by 2.5-fold to fuel tumor proliferation. BQ also upregulates FASN and SCD, increasing lipids. A metabolites study with mass spectrometry indicated that BQ overexpression increases the fatty acid amount from 47.97 nmol/106 cells to 75.18 nmol/106 cells in MCF7 and from 56.19 nmol/106 cells to 95.37 nmol/106 cells in ZR-75. BQ activates NRF2, which mitigates ROS-induced stress, promoting cell survival. Targeting ACSL4 with the inhibitor PRGL493 reduced ATP production and suppressed tumor growth in vitro and in vivo, without inducing apoptosis, suggesting a cytostatic effect. PRGL493 treatment can reduce BQ overexpressing tumors by 40% in the xenograft model. These results highlight BQ can serve as a transcriptional hub driving lipid metabolism via ACSL4 in breast cancer. Our findings suggest that ACSL4 inhibition could be a novel therapeutic strategy to overcome treatment resistance in high-BQ expressing ER-positive breast cancer.

Keywords:  ACSL4; BQ323636.1; breast cancer; lipid metabolism

DOI:  https://doi.org/10.3390/ijms26114989
Haematologica. 2025 Jun 12. 0

Metabolic reprogramming by PRDM16 drives cytarabine resistance in acute myeloid leukemia.

Junji Ikeda, Hiroyoshi Kunimoto, Yusuke Saito, Shin-Ichi Tsujimoto, Masanobu Takeuchi, Ayaka Miura, Takayuki Kurosawa, Koichi Murakami, Ikuma Kato, Megumi Funakoshi-Tago, Akihiko Yokoyama, Norio Shiba, Souichi Adachi, Daisuke Tomizawa, Tomohiko Tamura, Shuichi Ito, Hideaki Nakajima.

Acute myeloid leukemia (AML) patients with high PRDM16 expression frequently experience induction failure and have a poor prognosis. However, the molecular mechanisms underlying these clinical features remain elusive. We found that murine AML cells transformed by MLL::AF9 fusion and oncogenic short-isoform Prdm16 overexpression (hereafter, MF9/sPrdm16) exhibited resistance to cytarabine (AraC), but not to anthracycline, both in vitro and in vivo. Intriguingly, MF9/sPrdm16 cells displayed a gene expression signature of high oxidative phosphorylation (OxPHOS) and increased mitochondrial respiration. The inhibition of mitochondrial respiration with metformin or tigecycline abrogated AraC resistance in MF9/sPrdm16 cells via an energetic shift toward low OxPHOS status. Furthermore, sPrdm16 upregulated Myc and the glutamine transporter Slc1a5, activating TCA cycle and glutaminolysis. Of note, both OxPHOS and MYC-target gene signatures were significantly enriched in AML patient samples with high PRDM16 expression. Together, we showed that PRDM16 overexpression activates mitochondrial respiration through metabolic reprogramming via MYC-SLC1A5-Glutaminolysis axis, thereby conferring AraC resistance on AML cells. These results suggest that targeting mitochondrial respiration might be a novel treatment strategy to overcome chemoresistance in AML patients with high PRDM16 expression.

DOI: https://doi.org/10.3324/haematol.2024.287265
Cell Rep. 2025 Jun 09. pii: S2211-1247(25)00545-5. [Epub ahead of print]44(6): 115774

GCLM lactylation mediated by ACAT2 promotes ferroptosis resistance in KRASG12D-mutant cancer.

Yubin Chen, Qian Yan, Shiye Ruan, Jinwei Cui, Zhenchong Li, Zhongyan Zhang, Jiayu Yang, Jike Fang, SiYang Liu, Shanzhou Huang, Baohua Hou, Chuanzhao Zhang.

  KRAS mutations drive tumorigenesis, but their role in ferroptosis regulation remains unclear. Here, we construct wild-type KRAS (KRASWT) and KRASG12D-mutant cancer cells and demonstrate that G12D-mutant cells exhibit increased viability and reduced ferroptosis upon RSL3 or erastin treatment. These cells show diminished lipid peroxidation and mitochondrial damage, indicating ferroptosis resistance. KRASG12D activates MEK/ERK signaling to phosphorylate LDHA, enhancing glycolysis and lactate production. Exogenous lactate supplementation similarly protects WT cells from ferroptosis. Mechanistically, G12D-mutation-derived lactate induces glutamate-cysteine ligase (GCL) modifier (GCLM) lactylation, a process catalyzed by acetyl-coenzyme A (CoA) acetyltransferase 2 (ACAT2). Inhibition of GCLM lactylation either through the mutation of the lactylation site or by knockdown of ACAT2 diminished the enzymatic activity of GCL and suppressed glutathione synthesis. Importantly, ACAT2 depletion overcomes ferroptosis resistance in KRASG12D-mutant tumors in vivo. Our findings reveal a KRASG12D-driven metabolic adaptation linking GCLM lactylation to ferroptosis resistance, proposing ACAT2 inhibition as a therapeutic strategy for KRAS-mutant cancers.

Keywords:  CP: Cancer; CP: Metabolism; GCLM; KRAS mutation; ferroptosis; glutamate-cysteine ligase modifier; pancreatic cancer; protein lactylation

DOI:  https://doi.org/10.1016/j.celrep.2025.115774
bioRxiv. 2025 Jun 05. pii: 2025.05.29.656904. [Epub ahead of print]

Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer.

Suzanne Dufresne, Ramya S Kuna, Kristiana Wong, Anvita Komarla, Angelica Rock, Joel Rosada-Encarnación, Celina Shen, Payel Mondal, Louis R Parham, Fabiana Izidro Layng, Kristina L Peck, Alexandra Fowler, Andrew M Lowy, Dannielle Engle, Herve Tiriac, Reuben Shaw, Nicholas Cosford, Christian Metallo, Christina Towers.

Autophagy inhibitors are promising compounds to treat pancreatic ductal adenocarcinoma (PDA) but their efficacy in patients is unclear, highlighting a need to understand mechanisms of resistance. We used a novel approach to uncover metabolic adaptations that bypass autophagy inhibition. Utilizing PDA cells with acquired resistance to different autophagy inhibitors, we found that severe autophagy depletion induces metabolic rewiring to sustain TCA intermediates and nucleotides for biosynthesis. Long-term autophagy inhibition results in altered pyruvate metabolism likely regulated by lower pyrimidine pools. Cells adapting to loss of autophagy preferentially salvage pyrimidines to replenish these pools instead of synthesizing them de novo. Exploiting this metabolic vulnerability, we found that acquired resistance to autophagy inhibition promotes increased salvage and therefore sensitivity to pyrimidine analogues, including gemcitabine and trifluridine/tipiracil leading to combinatory effects with autophagy inhibitors and pyrimidine analogs. These studies provide mechanistic insight defining how autophagy inhibition can be leveraged to treat pancreatic cancer.

DOI: https://doi.org/10.1101/2025.05.29.656904
Cancer Immunol Immunother. 2025 Jun 07. 74(8): 240

Glutamate transporter SLC1A6 promotes resistance to immunotherapy in cancer.

Chenchen Li, Yi Lin, Haoran Zheng, Hengda Zeng, Longhao Xu, Daqin Wu, Jianwen Lao, Peicong Cai, Shuai Liang, Chunhui Wang, Tianxin Lin, Wenlong Zhong.

   BACKGROUND: Resistance to immune checkpoint inhibitors remains a significant challenge in the treatment of cancer. Emerging evidence suggests that metabolic reprogramming plays a crucial role in tumor metabolism and progression. Our study strived to investigate the role and underlying mechanisms of the glutamate transporter SLC1A6 in resistance to immunotherapy of cancer.
METHODS: Single-cell RNA sequencing was performed on bladder cancer patients receiving neoadjuvant immunotherapy to identify the expression of SLC1A6 in treatment-resistant cases. The clinical prognostic value of SLC1A6 in cancer was validated using publicly available lung cancer single-cell datasets, as well as transcriptomic data from both bladder and lung cancer cohorts. Flow cytometry was employed to assess the impact of SLC1A6 knockdown on the effector function of CD8⁺ T cell. In vivo tumor models were used to evaluate the role of SLC1A6 in immunotherapy resistance, with immunofluorescence staining performed to examine GZMB⁺ CD8⁺ T cell infiltration.
RESULTS: SLC1A6 was highly expressed in bladder cancer patients resistant to neoadjuvant immunotherapy, and its expression was associated with disease progression, poor prognosis, and low immune infiltration. Knockdown of SLC1A6 in tumor cells enhanced CD8⁺ T cell effector function. SLC1A6 knockdown also improved the efficacy of immunotherapy and increased the infiltration of GZMB⁺ CD8⁺ T cells within the tumor microenvironment.
CONCLUSIONS: SLC1A6 plays a critical role in resistance to immunotherapy in cancer. Targeting SLC1A6 may provide a promising therapeutic strategy for improving responses to neoadjuvant immunotherapy and advancing combination treatment approaches.

Keywords:  Cancer treatment; Immunotherapy; SLC1A6; T cells

DOI:  https://doi.org/10.1007/s00262-025-04074-4
J Pharm Biomed Anal. 2025 Jun 06. pii: S0731-7085(25)00353-X. [Epub ahead of print]265 117012

Mapping the polar metabolome in Huh-7 liver cancer cells reveal the role of atorvastatin in enhancing chemotherapeutic efficacy of doxorubicin.

Maria Kopsida, Lotta Regtop, Hans Lennernäs, Mikael Hedeland, Femke Heindryckx, Mikael K R Engskog.

  Hepatocellular carcinoma is an aggressive cancer characterized by metabolic reprogramming in lipid-, nucleotide and amino acid metabolism/catabolism and oxidative stress management. This in vitro study investigates the potential cytotoxic and metabolic effects of the novel combination of doxorubicin and atorvastatin, a cholesterol-lowering drug, in the well-characterized Huh-7 cell line. The cytotoxicity of statins and fibrates was assessed through dose-response curves and the half-maximal inhibitory concentration (IC50) for each treatment, both individually and in combination. Synergism was determined using the Chou-Talalay method. Among the tested agents, atorvastatin exhibited the most potent cytotoxicity, with an IC50 of 70.45 µM. When combined with doxorubicin, the IC50 of doxorubicin decreased significantly from 165.25 µM to 26.85 µM, indicating a synergistic effect. Metabolic profiling revealed distinct changes in lipid metabolism, fatty acid oxidation and the carnitine shuttle system, specifically within the combination treatment. The combination treatment also seems to affect oxidative stress management via the urea cycle, polyamine biosynthesis, and catabolism of nucleotides and amino acids. By limiting energy production, while simultaneously disrupting oxidative stress management, this therapy creates a plausible metabolic bottleneck, which may impair cancer cell adaptation to stress and growth. These findings suggest that combining atorvastatin with doxorubicin might enhance treatment efficacy and/or reduce resistance.

Keywords:  Atorvastatin; Doxorubicin; Fatty acid metabolism, Oxidative stress; Hepatocellular carcinoma; Metabolic profiling

DOI:  https://doi.org/10.1016/j.jpba.2025.117012
Cell Metab. 2025 Jun 09. pii: S1550-4131(25)00265-7. [Epub ahead of print]

Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming.

Ting Zhao, Lingli He, Lai Ping Wong, Shenglin Mei, Jun Xia, Yanxin Xu, Jonathan G Van Vranken, Michael Mazzola, Lei Chen, Catherine Rhee, Tiancheng Fang, Tsuyoshi Fukushima, Leanne C Sayles, Matthew Diaz, J Alex B Gibbons, Raul Mostoslavsky, Steven P Gygi, Zhixun Dou, David B Sykes, Ruslan I Sadreyev, E Alejandro Sweet-Cordero, David T Scadden.

  Metabolites are essential substrates for epigenetic modifications. Although nuclear acetyl-coenzyme A (CoA) constitutes a small fraction of the whole-cell pool, it regulates cell fate by locally providing histone acetylation substrate. Here, we report a nucleus-specific acetyl-CoA regulatory mechanism that can be modulated to achieve therapeutic cancer cell reprogramming. Combining phenotypic chemical screen, genome-wide CRISPR screen, and proteomics, we identified that the nucleus-localized pyruvate dehydrogenase complex (nPDC) is constitutively inhibited by the nuclear protein ELMSAN1 through direct interaction. Pharmacologic inhibition of the ELMSAN1-nPDC interaction derepressed nPDC activity, enhancing nuclear acetyl-CoA generation and reprogramming cancer cells to a postmitotic state with diminished cell-of-origin signatures. Reprogramming was synergistically enhanced by histone deacetylase 1/2 inhibition, resulting in inhibited tumor growth, durably suppressed tumor-initiating ability, and improved survival in multiple cancer types in vivo, including therapy-resistant sarcoma patient-derived xenografts and carcinoma cell line xenografts. Our findings highlight the potential of targeting ELMSAN1-nPDC as an epigenetic cancer therapy.

Keywords:  ELMSAN1; HDAC; ISX9; acetyl-CoA metabolism; cancer therapy; compartmentalized metabolism; epigenetic reprogramming; nuclear metabolism; pyruvate dehydrogenase complex; therapeutic reprogramming

DOI:  https://doi.org/10.1016/j.cmet.2025.05.009
J Pharm Anal. 2025 May;15(5): 101150

Targeting tumor metabolism to augment CD8+ T cell anti-tumor immunity.

Huan Liu, Wenyong Yang, Jingwen Jiang.

  CD8+ T cell-based immune-therapeutics, including immune checkpoint inhibitors and adoptive cell therapies (tumor-infiltrating lymphocytes (TILs), T cell receptor-engineered T cells (TCR-T), chimeric antigen receptor T cells (CAR-T)), have achieved significant successes and prolonged patient survival to varying extents and even achieved cure in some cases. However, immunotherapy resistance and tumor insusceptibility frequently occur, leading to treatment failure. Recent evidences have highlighted the ponderance of tumor cells metabolic reprogramming in establishing an immunosuppressive milieu through the secretion of harmful metabolites, immune-inhibitory cytokines, and alteration of gene expression, which suppress the activity of immune cells, particularly CD8+ T cells to evade immune surveillance. Therefore, targeting tumor cell metabolic adaptations to reshape the immune microenvironment holds promise as an immunomodulatory strategy to facilitate immunotherapy. Here, we summarize recent advances in the crosstalk between immunotherapy and tumor reprogramming, focusing on the regulatory mechanisms underlying tumor cell glucose metabolism, amino acid metabolism, and lipid metabolism in influencing CD8+ T cells to provide promising metabolic targets or combinational strategies for immunotherapy.

Keywords:  CD8+ T cell; Immunotherapy; Metabolism reprogramming; TME; Tumor

DOI:  https://doi.org/10.1016/j.jpha.2024.101150
bioRxiv. 2025 Jun 07. pii: 2025.06.03.657464. [Epub ahead of print]

Pancreatic cancer cachexia is mediated by PTHrP-driven disruption of adipose de novo lipogenesis.

Nikita Bhalerao, Yamini Ogoti, Jessica Peura, Calvin Johnson, Qingbo Chen, Ekaterina D Korobkina, Faith N Keller, Maximilian Wengyn, Robert J Norgard, Claire Shamber, Kelsey Klute, Dominick DiMaio, Karine Sellin, Paul M Grandgenett, Rui Li, Michael A Hollingsworth, Adilson Guilherme, Michael P Czech, Richard Kremer, Lihua Julie Zhu, Emma V Watson, Marcus Ruscetti, David A Guertin, Jason R Pitarresi.

Pancreatic cancer patients have the highest rates and most severe forms of cancer cachexia, yet cachexia etiologies remain largely elusive, leading to a lack of effective intervening therapies. PTHrP has been clinically implicated as a putative regulator of cachexia, with serum PTHrP levels correlating with increased weight loss in PDAC patients. Here we show that cachectic PDAC patients have high expression of tumor PTHrP and use a genetically engineered mouse model to functionally demonstrate that deletion of Pthlh (encoding the PTHrP protein) blocks cachectic wasting, dramatically extending overall survival. The re-expression of PTHrP in lowly cachectic models is sufficient to induce wasting and reduce survival in mice, which is reversed by the conditional deletion of the PTHrP receptor, Pth1r , in adipocytes. Mechanistically, tumor-derived PTHrP suppresses de novo lipogenesis in adipocytes, leading to a molecular rewiring of adipose depots to promote wasting in the cachectic state. Finally, the pharmacological disruption of the PTHrP-PTH1R signaling axis abrogates wasting, highlighting that a targeted disruption of tumor-adipose crosstalk is an effective means to limit cachexia.
STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is the prototypical cancer type associated with cancer cachexia, a debilitating wasting syndrome marked by adipose tissue loss and muscle atrophy. Herein, we establish that PTHrP is a tumor-derived factor that facilitates cachexia by downregulating de novo lipogenesis in adipocytes and that blocking PTHrP is an effective means to limit wasting in preclinical mouse models.

DOI: https://doi.org/10.1101/2025.06.03.657464
Acta Pharmacol Sin. 2025 Jun 11.

Targeting PPARα activation sensitizes glioblastoma cells to temozolomide and reverses acquired resistance by inhibiting H3K18 lactylation.

Zhen-Chuan Wang, Chen Li, Zhao Zhang, Shan Lu, Ying-Min Liu, Peng Qi, Xi Chen, Yu-Bo Wang, Wen-Jie Feng, Cheng-Liang Pan, Qing-Xuan Wang, Zhi-Lin Ji, Ying Yu, Mei-Hua Piao, Guang-Fan Chi, Peng-Fei Ge.

  Temozolomide (TMZ) is an alkylating agent recommended as the first-line pharmaceutical for glioblastoma (GBM), but its efficacy is limited by the development of acquired resistance in GBM cells. TMZ resistance is regulated by multiple factors such as MGMT upregulation and metabolism reprogramming, its underlying mechanism still remains elusive. Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor regulating the metabolism of lipid and glucose, while histone 3 lactylation at lysine on position 18 (H3K18la) could promote cancer cells' resistance to therapeutic drugs. In this study we investigated the role of PPARα in regulating H3K18la and TMZ sensitivity in glioblastoma (GBM) cells. We established TMZ-resistant U87TR, U251TR, and U118TR cells by treating the parental U87, U251, and U118 cells with increased dosages of TMZ until the cells could resist TMZ (200 μM). We found that in TMZ-resistant cells, H3K18la level was apparently upregulated accompanied by increased ECAR (extracellular acidification rate) and intracellular lactate levels, whereas lactate (20 mM) time-dependently upregulated H3K18la in U87 and U251 cells. We found that PPARα was activated by TMZ in U87, U251, and U118 cells, but was inactivated when the cells became resistant to TMZ. In TMZ-sensitive glioma cells, TMZ triggered PPARα activation by causing DNA DSBs-dependent p38 MAPK activation. The activated PPARα upregulated its downstream signal ACOX1, which not only inhibited lactate-mediated H3K18 lactylation by promoting ROS-dependent PKM2 downregulation, but also reversely enhanced PPARα activation through ROS-activated ASK1/p38 MAPK pathway. In GBM cells resistant to TMZ, PPARα and p38 MAPK were both inactivated, but H3K18 lactylation was obviously upregulated. Targeting activation of PPARα with gemfibrozil or GW7647 not only sensitized GBM cells to TMZ but also effectively reversed the acquired resistance of GBM cells to TMZ by suppression of H3K18 lactylation through upregulation of ACOX1. Taken together, PPARα contributed to TMZ-induced growth arrest in GBM cells by inhibiting lactate-mediated H3K18 lactylation, targeting activation of PPARα may be a new strategy to improve the treatment effect of TMZ against GBM.

Keywords:  ACOX1; H3K18 lactylation; PKM2; PPARα; glioblastoma; temozolomide resistance

DOI:  https://doi.org/10.1038/s41401-025-01600-z
Transl Oncol. 2025 Jun 05. pii: S1936-5233(25)00158-5. [Epub ahead of print]58 102427

tsRNA-08614 inhibits glycolysis and histone lactylation by ALDH1A3 to confer oxaliplatin sensitivity in colorectal cancer.

Zhengbo Chen, Yiyang Zhang, Fang Yan, Gang Zhao, Yan Wang.

   BACKGROUND: Enhanced glycolysis contributes to the chemotherapy resistance of colorectal cancer (CRC). However, whether tRNA-derived small RNAs (tsRNAs) regulate CRC oxaliplatin sensitivity through glycolysis-mediated histone lactylation remains unclear.
METHODS: By analyzing RNA-seq data from CRC samples in the TCGA database, we identified a glucose metabolism-related tsRNA. Overexpression of tsRNA-08614 was investigated to explore its impact on CRC sensitivity to oxaliplatin. The targeting gene of tsRNA-08614 was validated through a dual-luciferase reporter assay. The specific molecular mechanism of tsRNA-08614 regulating CRC oxaliplatin sensitivity was further revealed by ChIP-seq and RNA-seq.
RESULTS: We found a down-regulated tsRNA-08614 targeted glycolysis-related gene, which was associated with chemotherapy resistance. Overexpression of tsRNA-08614 promoted oxaliplatin sensitivity of CRC cells. tsRNA-08614 inhibited the expression of the target gene ALDH1A3 and reduced glycolysis, whereas the glycolytic inducer reversed the enhanced sensitivity caused by tsRNA-08614. Interference of tsRNA-08614 increased H3K18la and pan-Kla levels, while the lactate inhibitor partially suppressed these effects. Furthermore, overexpression of tsRNA-08614 reprogrammed the transcription of genes mediated by histone lactylation modification, with EFHD2 showing the most significant differential expression. EFHD2 inhibited the sensitivity of CRC cells to oxaliplatin by upregulating CMPK2 and enhancing mitochondrial function. Finally, we demonstrated that tsRNA-08614 enhanced sensitivity to oxaliplatin in CRC by reducing histone lactylation levels in vivo.
CONCLUSION: tsRNA-08614 regulates ALDH1A3 to inhibit glycolysis and histone lactylation modification, thereby suppressing the transcriptional activity of EFHD2 and ultimately promoting the sensitivity of CRC to oxaliplatin. These findings suggest that tsRNA-08614 may represent a novel molecular target to combat oxaliplatin resistance in CRC chemotherapy.

Keywords:  Colorectal cancer; Glycolysis; Histone lactylation; tsRNA

DOI:  https://doi.org/10.1016/j.tranon.2025.102427
Int J Mol Sci. 2025 May 26. pii: 5112. [Epub ahead of print]26(11):

Glucosylceramide Synthase, a Key Enzyme in Sphingolipid Metabolism, Regulates Expression of Genes Accounting for Cancer Drug Resistance.

Md Saqline Mostaq, Lin Kang, Gauri A Patwardhan, Yunfeng Zhao, Runhua Shi, Yong-Yu Liu.

  Emergent cancer drug resistance and further metastasis can mainly be attributed to altered expression levels and functional activities of multiple genes of cancer cells under chemotherapy. In response to challenge with anticancer drugs, enhanced ceramide glycosylation catalyzed by glucosylceramide synthase (GCS) confers drug resistance and enrichment with cancer stem cells. p53 mutations, which gain function in tumor progression, are prevalently extant in ovarian cancers. Via integrated gene expression assessments, we characterized GCS-responsive genes in ovarian cancer cells treated with dactinomycin. NCI/ADR-RES cells dominantly expressed a p53 mutant (7 aa deleted in exon-5) and displayed anti-apoptosis; however, silencing GCS expression rendered these cells sensitive to dactinomycin-induced apoptosis. Microarray analyses of NCI/ADR-RES and its GCS transfected sublines found that elevated GCS expression or ceramide glycosylation was associated with altered expression of 41 genes, notably coding for ABCB1, FGF2, ALDH1A3, apolipoprotein E, laminin 2, chemokine ligands, and IL6, with cellular resistance to induced apoptosis and enrichment with cancer stem cells, promoting cancer progression. These findings were further corroborated through integrated genomic analyses of ovarian cancer from The Cancer Genome Atlas (TCGA) and cancer resistance to platinum-based chemotherapy. Altogether, our present study indicates that altered ceramide glycosylation can modulate expression of these GCS-responsive genes and alter cancer cell attributes under chemotherapy.

Keywords:  apoptosis; dactinomycin; gene mutation; glucosylceramide synthase; microarray; ovarian cancer; p53 tumor suppressor

DOI:  https://doi.org/10.3390/ijms26115112
bioRxiv. 2025 Jun 07. pii: 2025.06.06.657881. [Epub ahead of print]

Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia via a cytotoxic integrated stress response.

Johnson Ung, Su-Fern Tan, Jeremy J P Shaw, Maansi Taori, Tess M Deddens, Giovana da Costa Venancio, McLane M Montgomery, James T Hagen, Raphael T Aruleba, Upendar R Golla, Arati Sharma, B Bishal Paudel, Irene Sung-Ah Lee, Bhavishya Ramamoorthy, Kevin A Janes, Francine Garrett-Bakelman, Myles C Cabot, Kelsey H Fisher-Wellman, Todd E Fox, David F Claxton, Charles E Chalfant, David J Feith, Thomas P Loughran.

Resistance to combination regimens containing the BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) is a growing clinical challenge for this extensively utilized agent. We previously established the anti-leukemic properties of ceramide, a tumor-suppressive sphingolipid, in AML and demonstrated that upregulated expression of acid ceramidase (AC), a ceramide-neutralizing enzyme, supported leukemic survival and resistance to BH3 mimetics. Here, we report the anti-leukemic efficacy and mechanisms of co-targeting AC and BCL-2 in venetoclax-resistant AML. Analysis of the BeatAML dataset revealed a positive relationship between increased AC gene expression and venetoclax resistance. Targeting AC enhanced single-agent venetoclax cytotoxicity and the venetoclax + cytarabine combination in AML cell lines with primary or acquired venetoclax resistance. SACLAC + venetoclax was equipotent to the combination of venetoclax + cytarabine at reducing cell viability when evaluated ex vivo across a cohort of 71 primary AML patient samples. Mechanistically, SACLAC + venetoclax increased ceramide to levels that trigger a cytotoxic integrated stress response (ISR), ISR-mediated NOXA protein upregulation, mitochondrial dysregulation, and caspase-dependent cell death. Collectively, these data demonstrate the efficacy of co-targeting AC and BCL-2 in AML and rationalize targeting AC as a therapeutic approach to overcome venetoclax resistance.

DOI: https://doi.org/10.1101/2025.06.06.657881
PLoS One. 2025 ;20(6): e0325509

Impact of mtG3PDH inhibitors on proliferation and metabolism of androgen receptor-negative prostate cancer cells: Role of extracellular pyruvate.

Floriana Jessica Di Paola, Luiza Hd Cardoso, Efterpi Nikitopoulou, Bianca Kulik, Sandra Rühl, Alexander Eva, Natascha Sommer, Thomas Linn, Erich Gnaiger, Klaus Failing, Kathrin Büttner, Christian Frezza, Sybille Mazurek.

Mitochondrial glycerol 3-P dehydrogenase (mtG3PDH) plays a significant role in cellular bioenergetics by serving as a rate-limiting element in the glycerophosphate shuttle, which connects cytosolic glycolysis to mitochondrial oxidative metabolism. mtG3PDH was identified as an important site of electron leakage leading to ROS production to the mitochondrial matrix and intermembrane space. Our research focused on the role of two published mtG3PDH inhibitors (RH02211 and iGP-1) on the proliferation and metabolism of PC-3 and DU145 prostate cancer cells characterized by different mtG3PDH activities. Since pyruvate as a substrate of lactate dehydrogenase (LDH) may represent an escape mechanism for the recycling of cytosolic NAD+ via the glycerophosphate shuttle, we investigated the effect of pyruvate on the mode of action of the mtG3PDH inhibitors. Extracellular pyruvate weakened the growth-inhibitory effects of RH02211 and iGP-1 in PC-3 cells but not in DU145 cells, which correlated with higher H-type LDH and lower mitochondrial glutamate-oxaloacetate transaminase in DU145 cells. In the pyruvate-low medium, the strength of inhibition was more pronounced in PC-3 cells, characterized by higher mtG3PDH activities compared to DU145 cells. Pyruvate conversion rates (production in pyruvate-low and consumption in pyruvate-high PC-3 cells) were not impaired by RH02211 and iGP-1, suggesting that the conversion of extracellular pyruvate to lactate was not the primary factor responsible for the weakening effect of extracellular pyruvate on the RH02211-induced inhibition of PC-3 proliferation. In pyruvate-high PC-3 cells, the intracellular glycerol-3-P and dihydroxyacetone-P concentrations were consistent with an inhibition of mtG3PDH. In contrast, in pyruvate-low cells, the concentrations of these metabolites suggested an activation of mtG3PDH in parallel with an impairment of cytosolic G3PDH by RH02211. Of all metabolic characterizations recorded in this study (fluxes, intracellular intermediates, O2 consumption and H2O2 production), the decrease in glutaminolysis correlated best with the RH02211-induced inhibition of proliferation in pyruvate-low and pyruvate-high PC-3 cells.

DOI: https://doi.org/10.1371/journal.pone.0325509
Nature. 2025 Jun 11.

Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis.

Dylan Calhoon, Lingjie Sang, Fubo Ji, Divya Bezwada, Sheng-Chieh Hsu, Feng Cai, Nathaniel Kim, Amrita Basu, Renfei Wu, Anastasia Pimentel, Bailey Brooks, Konnor La, Ana Paulina Serrano, Daniel L Cassidy, Ling Cai, Vanina Toffessi-Tcheuyap, Maryam E Moussa, Winnie Uritboonthai, Linh Truc Hoang, Meghana Kolli, Brooklyn Jackson, Vitaly Margulis, Gary Siuzdak, James Brugarolas, Ian Corbin, Derek A Pratt, Ryan J Weiss, Ralph J DeBerardinis, Kıvanç Birsoy, Javier Garcia-Bermudez.

Lipids are essential components of cancer cells due to their structural and signalling roles1. To meet metabolic demands, many cancers take up extracellular lipids2-5; however, how these lipids contribute to cancer growth and progression remains poorly understood. Here, using functional genetic screens, we identify uptake of lipoproteins-the primary mechanism for lipid transport in circulation-as a key determinant of ferroptosis sensitivity in cancer. Lipoprotein supplementation robustly inhibits ferroptosis across diverse cancer types, primarily through the delivery of α-tocopherol (α-toc), the most abundant form of vitamin E in human lipoproteins. Mechanistically, cancer cells take up lipoproteins through a pathway dependent on sulfated glycosaminoglycans (GAGs) linked to cell-surface proteoglycans. Disrupting GAG biosynthesis or acutely degrading surface GAGs reduces lipoprotein uptake, sensitizes cancer cells to ferroptosis and impairs tumour growth in mice. Notably, human clear cell renal cell carcinomas-a lipid-rich malignancy-exhibit elevated levels of chondroitin sulfate and increased lipoprotein-derived α-toc compared with normal kidney tissue. Together, our study establishes lipoprotein uptake as a critical anti-ferroptotic mechanism in cancer and implicates GAG biosynthesis as a therapeutic target.

DOI: https://doi.org/10.1038/s41586-025-09162-0
bioRxiv. 2025 Jun 04. pii: 2025.06.02.657324. [Epub ahead of print]

Loss of UFMylation supports prostate cancer metastasis and rewires cell metabolism towards hexosamine biosynthesis.

Laura Bozal-Basterra, María-Camila Salazar, Ana Margarida Ferreira Campos, Margherita Demicco, Daniel R Schmidt, Klaudia Sobczak, June Ereño-Orbea, Patricia Altea-Manzano, Ainara Miranda Villanueva, Belén Martínez La Osa, Saioa Garcia-Longarte, María Ponce-Rodriguez, Isabel Mendizabal, Onintza Carlevaris, Ianire Astobiza, Natalia Martin-Martin, Amaia Zabala-Letona, Ana Talamillo, Juan Fernández-García, Mikel Azkargorta, Ibon Iloro, Rosa Barrio, Félix Elortza, Sarah-Maria Fendt, Matthew G Vander Heiden, Jesús-Jiménez Barbero, James D Sutherland, Arkaitz Carracedo.

The acquisition of metastatic features in tumor cells encompasses genetic and non-genetic adaptation, including reprogramming of cellular metabolism. Here we show that loss of UFMylation reroutes glucose metabolism, promotes invasive capacity and supports prostate cancer metastasis. Through transcriptome-based bioinformatics analysis, we identified a reduction in the ubiquitin-like modifier UFM1 and its ligase UFL1 in metastatic prostate cancer. We demonstrate that loss of UFMylation results in enhanced cancer cell dissemination and a switch from cellular proliferation to invasion. Using biotin-based proteomics, we identified phosphofructokinase (PFKAP) as an unprecedented UFMylation substrate. Consistent with UFMylation playing a role in the regulation of phosphofructokinase activity, loss of UFMylation reduced glucose metabolism in favour of hexosamine biosynthesis, which resulted in elevated glycosylation of proteins relevant for cell invasion. These results reveal a role for UFMylation in the regulation of phosphofructokinase and glucose metabolism to support prostate cancer metastasis.

DOI: https://doi.org/10.1101/2025.06.02.657324
Int J Mol Sci. 2025 Jun 03. pii: 5367. [Epub ahead of print]26(11):

Selective Inhibition of the ABCG2 Transporter by Primaquine Derivatives Reverses the Multidrug Resistance of Tumor Cells.

Marija Mioč, Maja Beus, Karla Carević, Zrinka Rajić, Balázs Sarkadi, Ágnes Telbisz, Marijeta Kralj.

  Multidrug resistance (MDR) poses a significant challenge in cancer therapy, often leading to treatment failure and relapse. ATP-binding cassette (ABC) transporters, particularly ABCG2, play a pivotal role in MDR development by actively expelling chemotherapeutic agents from cancer cells. This study investigates the effects of two groups of primaquine derivatives-fumardiamides (1a-d) and bis-ureas (2a, b), both bearing halogenated benzene rings-on the activity of P-glycoprotein (P-gp) and ABCG2. Their potential to reverse MDR was evaluated through a series of functional assays aimed at comparing transporter-compound interactions. The results indicated that fumardiamide derivatives, specifically 1a, 1b, and 1d, exhibited potent inhibition of ABCG2 while having no effect on P-gp, demonstrating a selective mode of action. The tested derivatives displayed low to moderate cytotoxicity and did not affect ABCG2 expression or localization. Moreover, these compounds enhanced the sensitivity of drug-resistant cancer cell lines to mitoxantrone, underscoring their potential to overcome ABCG2-mediated MDR. These findings suggest that chemical modifications of primaquine, particularly the incorporation of fumardiamide moieties, confer novel biological properties, providing promising leads for the development of selective ABCG2 inhibitors.

Keywords:  ABCG2; ATP-binding cassette (ABC) transporters; P-glycoprotein; in vitro functional studies; multidrug resistance; primaquine derivatives

DOI:  https://doi.org/10.3390/ijms26115367
J Transl Med. 2025 Jun 11. 23(1): 644

Metabolic reprogramming in hepatocellular carcinoma: an integrated omics study of lipid pathways and their diagnostic potential.

Peng Dai, Jing Feng, Yanyan Dong, Shujing Zhang, Jianghong Cao, Xiaopeng Cui, Xueliang Qin, Shiming Yang, Daguang Fan.

  Metabolic reprogramming is an important cancer hallmark. Recent studies have indicated that lipid metabolic reprogramming play a potential role in the development of hepatocellular carcinoma (HCC). However, the underlying mechanisms remain incompletely understood. In this study, we employed an integrated multi-omics approach, combining transcriptomic, proteomic, and metabolomic analyses, to explore the lipid metabolism pathways in HCC and evaluate their diagnostic potential.We collected ten pairs of HCC tissues (HCT) and adjacent non-tumor tissues (ANT) from patients undergoing surgical resection. Transcriptomic analysis identified 4,023 differentially expressed genes (DEGs) between HCT and ANT, with significant enrichment in lipid metabolism-related pathways, including fatty acid degradation and steroid hormone biosynthesis. Proteomic analysis revealed 2,531 differentially expressed proteins (DEPs), further highlighting lipid metabolism as a critical driver of HCC development. Metabolomic profiling identified 88 differentially expressed metabolites (DEMs), with notable alterations in lipid-related metabolites. Integrated analysis of transcriptomic, proteomic, and metabolomic data identified six key genes (LCAT, PEMT, ACSL1, GPD1, ACSL4, and LPCAT1) involved in lipid metabolism, which exhibited significant changes at both mRNA and protein levels and correlated strongly with lipid-related metabolites in HCT. Additionally, nine lipid-related metabolites were identified as potential diagnostic biomarkers for HCC, with six metabolites demonstrating high discriminative ability (AUC > 0.8) between HCT and ANT.Our findings provide new insights into the molecular mechanisms of lipid metabolism reprogramming in HCC, emphasize the critical role of lipid metabolism in its pathogenesis. The identification of lipid-related metabolites as potential diagnostic biomarkers holds significant promise for early detection and improved clinical management of HCC. The integrated multi-omics approach as a powerful tool for identifying novel biomarkers and therapeutic targets.

Keywords:  Diagnostic biomarkers; Hepatocellular carcinoma (HCC); Lipid metabolism; Metabolic reprogramming; Multi-omics analysis

DOI:  https://doi.org/10.1186/s12967-025-06698-7
J Control Release. 2025 Jun 06. pii: S0168-3659(25)00551-6. [Epub ahead of print]384 113931

Multimodal nanoparticles co-delivering bevacizumab and dichloroacetate for dual targeting of neoangiogenesis and hyperglycolysis in glioblastoma treatment.

Catarina Pacheco, Olaya de Dios, Maria Angeles Ramiréz-González, Cláudia Martins, Sílvia L Fialho, Fátima Baltazar, Bruno M Costa, Pilar Sánchez-Gómez, Bruno Sarmento.

  Glioblastoma (GBM) is a virtually incurable primary brain tumor, characterized by aggressive proliferation and sustained angiogenesis. The current anti-angiogenic treatment with systemically administered bevacizumab fails to increase patient survival. Encapsulation of bevacizumab into polymeric nanoparticles has shown promise in improving drug brain bioavailability after intranasal administration. Nevertheless, therapeutic efficacy remains limited by tumor cells adopting a hyperglycolytic metabolism. Here, we optimized BDNP, a multidrug formulation for GBM treatment, by co-entrapment of the anti-angiogenic bevacizumab and the glycolysis inhibitor dichloroacetate into poly(lactic-co-glycolic) acid nanoparticles. We then confirmed BDNP therapeutic potential through a series of in vitro and in vivo assays. BDNP preserved bevacizumab functionality, effectively inhibiting chorioallantoic membrane vascularization and endothelial cell angiogenesis fueled by GBM cell lines or patient-derived neurospheres. Moreover, BDNP successfully prevented the ∼3-fold increase in lactate production triggered by bevacizumab. Surface decoration with a CD147-targeting peptide increased BDNP retention in tumor cells in vitro by ∼10-fold, though it did not significantly improve brain accumulation in a U-251MG GBM mouse model. Regardless of decoration, nanoparticles reached and accumulated in animals' brains after intranasal administration. Intranasal administration of BDNP significantly improved a GBM mouse model survival, with no evidence of toxicity. A similar trend was observed in mice bearing patient-derived neurospheres. These findings highlight BDNP as a promising strategy for GBM therapy and establish valuable protocols for developing and validating novel multidrug nanoparticles, especially for antibodies and small molecule cocktails.

Keywords:  Glioblastoma; Hyperglycolysis; Intranasal delivery; Multidrug nanoparticles; Neoangiogenesis; Tumor-targeting

DOI:  https://doi.org/10.1016/j.jconrel.2025.113931