bims-meract 2026-03-01 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–03–01
nineteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Tumor metabolic adaptation induced by L-asparaginase reveals a vulnerability to PARP1/2 inhibitor in B-cell lymphomas.
Targeting UGCG sensitizes AML cells to venetoclax through RAB32-mediated endoplasmic reticulum-mitochondria communication.
A metabolism-specific drug-repurposing screen reveals itraconazole as a potent OXPHOS inhibitor in acute myeloid leukemia.
Deubiquitinase UCH-L1 confers paclitaxel resistance via stabilizing PKM2 to promote glycolysis in triple-negative breast cancer.
PDHA1 enhances resistance to ferroptosis in anoikis-resistant prostate cancer by upregulating AIFM2.
ARID1A Deficiency in Diffuse-Type Gastric Cancer Promotes a Pyrimidine Metabolic Vulnerability.
Vitamin B3 derivatives support pancreatic cancer cell survival and chemotherapy resistance.
Targeting ABCD1 inhibits peroxisomal fatty acid oxidation to selectively eliminate acute myeloid leukemia cells.
Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer.
Molecular mechanisms and therapies for tumor inhibition through the arginine metabolism pathway.
Marrow leptin-LEPR signaling rewires mitochondrial oxidative metabolism to confer chemoresistance in acute myeloid leukemia.
The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy.
Targeting PFKFB3 to enhance CDK4/6 inhibitor response in ER+ breast cancer.
NSD2 inhibits the expression of PD-L1 via oxidative phosphorylation to control immune surveillance in hepatocellular carcinoma.
Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC class I-deficient solid tumors.
Fatty acid-induced lipid accumulation promotes radiosensitization in Huh7 hepatocellular carcinoma cells.
Unraveling the role of 3-mercaptopyruvate sulfurtransferase-derived hydrogen sulfide in triple-negative breast cancer chemoresistance.
Apigenin 7-glucoside reprograms tumor metabolism and enhances immunotherapy efficacy in colorectal cancer via DLX5.
Targeting PCK1 to overcome CDK4/6 inhibitor resistance for breast cancer therapy.

Nat Commun. 2026 Feb 27.

Tumor metabolic adaptation induced by L-asparaginase reveals a vulnerability to PARP1/2 inhibitor in B-cell lymphomas.

Anaïs Aussel, Ivan Nemazanyy, Ashaina Vandenberghe, Pauline Meola, Noémie Dorat, Rachel Paul, Lama Habbouche, Laurie Exposito, Nicolas Nottet, Virginie Petrilli, Edmond Chiche, Nicolas Mounier, Sandrine Marchetti, Cédric Chaveroux, Jean-Ehrland Ricci, Johanna Chiche.

Secondary resistance to the amino-acid-depleting agent L-asparaginase (ASNase) remains poorly understood. Using ASNase-sensitive B-cell lymphoma (BCL) models, we investigate tumor relapse during treatment. Through in vitro and in vivo metabolic profiling, here we show that ASNase triggers a metabolic reprogramming characterized by increased de novo serine biosynthesis driven by phosphoglycerate dehydrogenase (PHGDH). This response mitigates treatment-induced oxidative stress and associated DNA damage, enabling malignant cells to survive. We evidence that ASNase-treated malignant cells exhibit features of replication stress and increase activity of poly(ADP-ribose) polymerase (PARP), revealing a dependence on DNA repair. Combining ASNase with the clinically approved PARP inhibitor Olaparib enhances the antineoplastic effect of each monotherapy in vitro and in vivo. Moreover, this combination shows effectiveness in homologous recombination-proficient colorectal cancer cells, suggesting broader therapeutic potential. Overall, our study identifies tumor metabolic and genomic vulnerabilities induced by ASNase and supports a rational combination strategy using clinically approved drugs.

DOI: https://doi.org/10.1038/s41467-026-70066-2
Cell Rep. 2026 Feb 23. pii: S2211-1247(26)00099-9. [Epub ahead of print]45(3): 117021

Targeting UGCG sensitizes AML cells to venetoclax through RAB32-mediated endoplasmic reticulum-mitochondria communication.

Xiaofan Sun, Yue Li, Danqi Pan, Caiping Wu, Weihao Xiao, Ganlu Feng, Nianhui Yang, Yizhen Li, Wei Xiong, Min Dai, Zhirou Zhang, Lei Hua, Liye Zhong, Guopan Yu, Suxia Geng, Chengxin Deng, Chengwei Luo, Ping Wu, Xin Du, Juan Du, Hui Zeng.

  Uridine diphosphate (UDP)-glucose ceramide glucosyltransferase (UGCG) is an enzyme that glycosylates ceramide and blunts its pro-apoptotic activity in cancer cells. Targeting UGCG sensitizes solid cancer cells to chemotherapy. However, whether targeting UGCG can sensitize acute myeloid leukemia (AML) cells to venetoclax remains unclear. Here, we found that the inhibition of UGCG genetically or with its inhibitor eliglustat efficiently suppressed growth and promoted apoptosis in AML cells. Moreover, eliglustat in combination with venetoclax increased apoptosis, reduced AML cell viability, and inhibited AML effectively both for primary AML cells and xenograft models. Mechanistically, the combination induced ceramide accumulation, which activated the endoplasmic reticulum (ER) stress-GRP78/PERK/CHOP axis. Interestingly, combinatory treatment activated RAB32, which led to mitochondrial fission through ER-mitochondria communication and DRP1 activation. These findings demonstrate that targeting UGCG in combination with venetoclax is an alternative combinatory strategy to treat AML and provide insights into ceramide-mediated cell death in anti-cancer therapies.

Keywords:  CP: cancer; DRP1; RAB32; UGCG; acute myeloid leukemia; ceramide accumulation; endoplasmic reticulum stress; venetoclax

DOI:  https://doi.org/10.1016/j.celrep.2026.117021
Blood. 2026 Feb 24. pii: blood.2024027853. [Epub ahead of print]

A metabolism-specific drug-repurposing screen reveals itraconazole as a potent OXPHOS inhibitor in acute myeloid leukemia.

Ekaterini Himonas, Lucie de Beauchamp, Désirée Zerbst, Eudoxie Desmares-Romain, Daniele Sarnello, Eric R Kalkman, Kevin M Rattigan, Daniel James, Engy Shokry, Mhairi Copland, Emmanuel Griessinger, Christian Récher, Véronique Mansat-De Mas, Francois Vergez, David Sumpton, Aaron D Schimmer, Mark D Minden, Eyal Gottlieb, Emma Shanks, Jean-Emmanuel Sarry, Vignir Helgason.

Targeting mitochondrial oxidative phosphorylation (OXPHOS) enhances the effects of standard chemotherapy and overcomes treatment resistance in pre-clinical models of acute myeloid leukaemia (AML). So far, the few clinically available OXPHOS inhibitors have shown adverse effects or limited potency in clinical trials, therefore, identification of safe and effective drugs that can target mitochondrial metabolism in AML is critical. Here, we performed a high-throughput drug-repurposing screen, designed to identify clinically applicable OXPHOS-specific inhibitors through nutrient sensing. We uncover itraconazole, an FDA-approved antifungal compound, as a potent OXPHOS inhibitor in AML cells. Mechanistically, through stable isotope-assisted metabolomics and functional studies, we reveal that CYP51A1, which is part of the cytochrome P450 family and the prime target of azole antifungals, is involved in mitochondrial respiration and ETC complex I activity in AML cells. Critically, we demonstrate that itraconazole and related azole antifungals interfere with tricarboxylic acid cycle activity and inhibit OXPHOS through the inhibition of electron transport chain complex I activity. Over-expression of yeast NADH dehydrogenase-1 (NDI1) restored mitochondrial NADH oxidation and complex I activity upon itraconazole treatment. Using patient-derived cells and pre-clinical xenograft models, we demonstrate that itraconazole targets therapy-resistant leukaemic stem cells (LSCs) when used in combination with cytarabine, highlighting the repurposing potential for itraconazole as a clinically safe and effective therapeutic option for AML LSC eradication.

DOI: https://doi.org/10.1182/blood.2024027853
Cell Death Dis. 2026 Feb 25.

Deubiquitinase UCH-L1 confers paclitaxel resistance via stabilizing PKM2 to promote glycolysis in triple-negative breast cancer.

Xisha Chen, Xiaoming Zhou, Yingcai Meng, Ying Zhou, Wenjie Zhang, Liyang Yin, Yingying Shen, Jing Zhong, Taolan Zhang, Xuyu Zu.

Resistance to paclitaxel-based chemotherapy represents a major clinic challenge in triple-negative breast cancer (TNBC). Insights on the regulation genes of chemoresistance and underlying mechanisms in TNBC are waiting for in-depth investigation to address the current treatment bottlenecks. In this study, we identified that ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1) was preferentially overexpressed in TNBC and correlated with worse prognosis as well as poor response to chemotherapy. Upregulation of UCH-L1 attenuated the inhibitory effect of paclitaxel on tumor cells through modulating the aerobic glycolysis, while knockdown of UCH-L1 increased the responsiveness of TNBC cells to the drug both in vitro and in vivo. Coimmunoprecipitation results revealed that the N terminal of UCH-L1 interacts with the C-terminal domain of pyruvate kinase M2 (PKM2). UCH-L1 stabilized PKM2 via removing K48-linked polyubiquitination of PKM2 protein at K498, and thereby promoting glycolysis. Moreover, the expression levels of UCH-L1 and PKM2 were elevated in paclitaxel-resistant TNBC cells, and inhibition of UCH-L1/PKM2 axis-mediated glycolysis markedly sensitized the cells to paclitaxel treatment. Meanwhile, high expression of PKM2 was associated with shorter overall survival in TNBC patients who received chemotherapy. Clinically, PKM2 expression is positively correlated with the expression of UCH-L1 in TNBC tissues. In conclusion, our study reveals that high-expressed UCH-L1 was one of the biomarkers predicting and determining chemosensitivities of TNBC by advancing the cleavage of K48-linked polyubiquitin chains from PKM2 and enhancing glycolysis, and suggests that targeting UCH-L1/PKM2 axis holds great promise for reversing chemoresistance.

DOI: https://doi.org/10.1038/s41419-026-08521-7
Cell Death Discov. 2026 Feb 23. pii: 105. [Epub ahead of print]12(1):

PDHA1 enhances resistance to ferroptosis in anoikis-resistant prostate cancer by upregulating AIFM2.

Yukun Cong, Kang Chen, Yunjie Ju, Qingliu He, Chunyu Liu, Jiawei Chen, Fang Lv, Jinyu Chen, Haoran Li, Liang Chen, Yarong Song.

Cells that detach from the extracellular matrix (ECM) undergo various forms of cell death, including ferroptosis. Previous studies have demonstrated that prostate cancer (PCa) cells undergo ferroptosis following ECM detachment, and resistance to ferroptosis may facilitate tumor metastasis. Pyruvate dehydrogenase E1 alpha 1 (PDHA1) has been identified as a key regulator in the progression of several malignancies; however, its role in ferroptosis and prostate cancer metastasis remains unclear. In this study, anoikis resistance (AnoR) prostate cancer cells exhibited a substantial increase in PDHA1 expression, which enhanced their survival and metastatic potential by increasing resistance to ferroptosis. Mechanistically, nuclear PDHA1 in AnoR cells facilitated histone H3 lysine 9 acetylation (H3K9Ac) that significantly accumulated at the promoter region of peroxisome proliferator-activated receptor alpha (PPARA), thereby upregulating its expression. PPARA, in turn, activated the transcription of apoptosis-inducing factor mitochondria-associated 2 (AIFM2), whose upregulation inhibited ferroptosis in AnoR prostate cancer cells. This study demonstrates that PDHA1 expression is found to be elevated in primary tumors from patients with metastatic prostate cancer. Additionally, the aberrant overexpression of PDHA1 in AnoR prostate cancer cells upregulates PPARA and AIFM2 expression through nuclear translocation, collectively suppressing ferroptosis and promoting metastasis. These findings reveal a novel role for PDHA1 in mediating ferroptosis resistance during ECM detachment and provide a potential therapeutic target for prostate cancer treatment.

DOI: https://doi.org/10.1038/s41420-026-02958-7
Mol Cancer Res. 2026 Feb 27.

ARID1A Deficiency in Diffuse-Type Gastric Cancer Promotes a Pyrimidine Metabolic Vulnerability.

Harumi Hirano, Hideki Makinoshima, Hideaki Ogiwara.

Loss-of-function mutations in ARID1A define an aggressive subtype of diffuse gastric cancer (DGC) that is often resistant to standard chemotherapy. Here, we uncover a precise metabolic vulnerability in ARID1A-deficient DGC driven by a specific transporter defect. Through integrated metabolomic and transcriptomic analyses, we demonstrate that ARID1A loss transcriptionally represses the high-affinity nucleoside transporter SLC28A3. Our profiling revealed a critical lack of redundancy in the concentrative transporter family (CNT) in DGC, establishing a strict reliance on SLC28A3 for maintaining intracellular deoxycytidine (dC) pools. Consequently, ARID1A deficiency creates a severe "low-dCTP" metabolic bottleneck. We show that the dC analog Gemcitabine exploits this state through a distinct functional dichotomy: it enters via intact equilibrative transporters (ENTs) to target cells that have lost their competitive dC barrier. Mechanistically, Gemcitabine exerts a "dual-hit" effect by outcompeting the scarce dC pool for DNA incorporation while simultaneously inhibiting ribonucleotide reductase, thereby blocking de novo nucleotide synthesis. This synergistic collapse of pyrimidine metabolism was validated in patient-derived ex vivo cultures and in vivo peritoneal dissemination models. Our findings provide a robust mechanistic basis for repurposing Gemcitabine as a precision therapy for ARID1A-deficient DGC, offering a potent strategy for this intractable malignancy. Implications: This work uncovers a metabolic vulnerability in ARID1A-deficient gastric cancer caused by SLC28A3 loss. It provides a compelling rationale for repurposing Gemcitabine as a targeted therapy for this intractable malignancy.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-1069
Cancer Lett. 2026 Feb 20. pii: S0304-3835(26)00097-2. [Epub ahead of print] 218334

Vitamin B3 derivatives support pancreatic cancer cell survival and chemotherapy resistance.

Faith Nakazzi, Mehrdad Zarei, Mariana Lopes, Hallie J Graor, William C Beegan, Eric Gu, Sakineh Rezaei, Peder J Lund, Jordan M Winter.

  Nicotinamide adenine dinucleotide (NAD+) is a central metabolic cofactor essential for cell survival and stress response in normal tissues. Its dietary precursors, commonly referred to as vitamin B3 derivatives, including nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), are marketed as nutraceuticals with potential energy-boosting, cardioprotective, and neuroprotective benefits. Consequently, many cancer patients utilize NAD+ precursors to alleviate chemotherapy-induced toxicity and promote health. However, the impact of NAD+ supplements on intrinsic tumor biology and progression remains controversial and incompletely characterized. In this study, we assessed the impact of common vitamin B3 derivatives, NAM, NR, and NMN, on chemotherapy efficacy in pancreatic ductal adenocarcinoma (PDAC) using both in vitro and in vivo models. Among the compounds tested, NMN exhibited the strongest protective effect on cancer cells, enhancing resistance to oxaliplatin, 5-fluorouracil, and gemcitabine in vitro. Mechanistically, NAD+ precursors promoted mitochondrial function, reduced oxidative stress, and suppressed DNA damage and apoptosis in treated cancer cells, all contributing to chemotherapy resistance. In murine models, both immunocompetent and immunodeficient, supplementation with NAM and NMN similarly conferred resistance to standard chemotherapy and supported cancer growth. Our findings highlight a potentially concerning role for NAD+-boosting supplements in the context of an active cancer, especially when used in conjunction with chemotherapy. These data underscore the need for careful evaluation of nutraceutical use in cancer patients, particularly those with PDAC, as vitamin B3 derivatives may inadvertently promote tumor cell survival and compromise treatment efficacy.

Keywords:  DNA repair; NAD(+); NAD(+) precursors; Pancreatic cancer; chemotherapy resistance; mitochondria; oxidative stress; vitamin B3 derivatives

DOI:  https://doi.org/10.1016/j.canlet.2026.218334
Blood. 2026 Feb 26. pii: blood.2025031202. [Epub ahead of print]

Targeting ABCD1 inhibits peroxisomal fatty acid oxidation to selectively eliminate acute myeloid leukemia cells.

Ekaterina N Parfenova, Nikolina Vrdoljak, Drake Mosca, Juan J Aristizabal-Henao, Michael A Kiebish, Mark D Minden, Paul A Spagnuolo.

Altered lipid metabolism enables growth of acute myeloid leukemia (AML) cells. While mitochondrial lipid oxidation is well characterized, the contribution of peroxisomal fatty acid oxidation (pFAO) is unclear. In this study, we demonstrate that AML cells upregulate the peroxisomal very-long-chain fatty acid (VLCFA) transporter ABCD1 and increase endogenous levels of pFAO relative to healthy hematopoietic cells. Genetic silencing or pharmacological inhibition of ABCD1, with eicosenol, impairs pFAO causing accumulation of VLCFAs and selective AML cell death in vitro and in vivo. Loss of ABCD1 disrupts peroxisomal fatty acid import and lipid homeostasis in AML, while normal progenitors remain viable by upregulating glycolysis. In murine models, ABCD1 inhibition with eicosenol reduces leukemia burden and prolongs survival without toxicity. These findings identify ABCD1 as a regulator of pFAO and a novel anti-AML therapeutic target.

DOI: https://doi.org/10.1182/blood.2025031202
Nat Commun. 2026 Feb 25.

Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer.

Yabing Nan, Kunyu Wang, Menghan Hu, Qingyu Luo, Xiaowei Wu, Xiao Yu, Xuantong Zhou, Li Chen, Bin Li, Zhumei Cui, Zhihua Liu.

Although poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) as monotherapy or in combination with other DNA-damaging agents exhibit promising clinical efficacy, the therapeutic responses are usually transient, with subsequent development of acquired resistance posing a significant challenge. Here, through a small-molecule compound screening, we identify elesclomol, a potent copper ionophore, which sensitizes BRCA-proficient ovarian cancer cells to PARPi by inhibiting activation of the ATR-CHK1 pathway. Mechanistically, we demonstrate that copper directly binds to ATRIP, a critical cofactor of ATR activation, disrupting the ATR-ATRIP interaction, further impairing ATR-mediated DNA damage repair signaling and potentiating PARPi sensitivity. Importantly, we reveal a secondary metabolic vulnerability in PARPi-resistant ovarian cancer associated with de novo pyrimidine synthesis, suggesting that targeting this pathway as an effective strategy to eradicate drug-adaptive residual tumors and resistant patient-derived xenograft models following ATR and PARP co-inhibition. These findings propose de novo pyrimidine synthesis as an adaptive metabolic vulnerability that can be therapeutically targeted to overcome PARPi resistance in BRCA-proficient ovarian cancer.

DOI: https://doi.org/10.1038/s41467-026-70001-5
Front Oncol. 2026 ;16 1774392

Molecular mechanisms and therapies for tumor inhibition through the arginine metabolism pathway.

Yuhang Xu, Mingxin Yu, Yi Zhang, Yiqing Jiang, Haiyan Zhu, Shujuan He, Guohua Yu, Niannian Li, Shuzhen Liu, Bin Liu.

  Tumors are one of the major diseases leading to human death. Arginine metabolism plays an important role in tumor occurrence and metastasis. Based on the levels of arginine in tumor cells, methods such as recombinant arginine deiminase are used to reduce arginine in order to inhibit tumor growth. However, arginine deprivation therapy has limited efficacy in tumor cells due to increased arginine synthesis, resistance to chemotherapeutic agents, metabolic reprogramming, and the suppression of immune cells in the tumor microenvironment. Meanwhile, with the revelation of many new molecular mechanisms by which arginine controls tumor cell growth, numerous newly designed molecules targeting arginine metabolic pathways for cancer treatment have emerged. In this review, we integrate and analyze the responses of tumor cells and immune cells such as T cells to arginine and strategies for cancer therapy. At the molecular level, we review and discuss the mechanisms of specifically blocking arginine-regulated metabolic reprogramming in cancer cells, the effector factors from pathogenic microorganisms and metabolites from plants in inhibiting cancer cells via arginine metabolism, and arginine tRNA metabolic pathway. Finally, we discuss the mechanisms and case studies of using antineoplastic agents that target arginine metabolic pathways in combination. This review collects and integrates the mechanisms and experiences of treating various cancers through arginine and its metabolic derivatives, providing direct therapy guidance for cancer patients with disordered arginine metabolism in the tumor and immune cells.

Keywords:  arginine deprivation; arginine metabolism; inhibitor; tRNA modification; tumor treatment

DOI:  https://doi.org/10.3389/fonc.2026.1774392
Cell Death Dis. 2026 Feb 23.

Marrow leptin-LEPR signaling rewires mitochondrial oxidative metabolism to confer chemoresistance in acute myeloid leukemia.

Xinai Liao, Wei Dai, Xiaolin Xu, Danni Cai, Maoqing Tan, Zukai Wang, Yanrong Huang, Diyu Hou, Jingru Liu, Liuhuan Wang, Jin Wang, Xiaoting Wang, Shuxia Zhang, Xinjian Lin, Huifang Huang.

Leptin is abundant within marrow adipose tissue, yet its impact on acute myeloid leukemia (AML) therapy response is undefined. Here, we report that elevated bone-marrow leptin and blast-cell leptin-receptor (LEPR) levels strongly associate with poor cytarabine (Ara-C) clearance and reduced survival in newly diagnosed AML patients. Mechanistic and functional validation in human AML lines, primary blasts, and two syngeneic mouse models (MLL-AF9, AML1-ETO9a) shows that exogenous leptin markedly blunts Ara-C cytotoxicity, whereas the high-affinity LEPR antagonist Allo-aca restores chemosensitivity without altering baseline leukemia growth. Leptin up-regulates LEPR and triggers JAK2/STAT3 signaling that boosts mitochondrial complex Ⅰ activity, oxidative phosphorylation, and mitochondrial reactive oxygen species (mtROS); the resulting mtROS surge activates a compensatory antioxidant program that shields blasts from drug-induced oxidative damage. These data identify an adipokine-driven metabolic circuit governing AML chemoresistance and reveal LEPR blockade as a tractable strategy to improve outcomes, underscoring adipose-tumor crosstalk as a general therapeutic vulnerability.

DOI: https://doi.org/10.1038/s41419-026-08528-0
PLoS One. 2026 ;21(2): e0329048

The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy.

Hernán A Tirado, Nithya Balasundaram, Jean Jacobs, Fleur Leguay, Lotfi Laaouimir, Nick van Gastel.

Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic stem and progenitor cells characterized by profound metabolic dysregulation. Pyrimidine biosynthesis has emerged as a critical metabolic dependency in AML, but clinical translation has been hampered by unacceptable toxicity of current pyrimidine synthesis inhibitors. Since aspartate is an essential nutrient for pyrimidine biosynthesis, we investigated the role of aspartate import via the excitatory amino acid transporter 1 (EAAT1) in AML. We found that EAAT1 is broadly expressed across AML cell lines and patient samples, with enrichment in M4 and M5 subtypes and increasing levels following chemotherapy treatment. Pharmacological inhibition of EAAT1 impaired AML cell viability in vitro, but metabolomic profiling and nutrient rescue experiments showed that these effects were independent of intracellular aspartate levels. Moreover, AML cells cultured in aspartate-free medium maintained proliferation and did not become more sensitive to chemotherapy. EAAT1 inhibition in mice increased bone marrow plasma aspartate levels, confirming inhibition of cellular aspartate uptake, but did not affect growth or chemosensitivity of MLL-AF9-expressing AML cells in vivo. These findings suggest that AML cells possess several complementary mechanisms to support their aspartate requirements and that EAAT1 inhibition does not impair AML growth or response to chemotherapy.

DOI: https://doi.org/10.1371/journal.pone.0329048
Res Sq. 2026 Feb 10. pii: rs.3.rs-8412774. [Epub ahead of print]

Targeting PFKFB3 to enhance CDK4/6 inhibitor response in ER+ breast cancer.

Sucheta Telang, Brian F Clem, Ariamna A Herrera Miret, Leanne Price, Susan M Dougherty, Anna Schmitz, Xinmin Yin, Xipeng Ma, Xiang Zhang, Jason Chesney, Yoannis Imbert-Fernandez.

Background Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used in the treatment of estrogen receptor-positive (ER⁺) breast cancer; however, the metabolic adaptations induced by CDK4/6 inhibition remain incompletely defined. In ER⁺ breast cancer, estrogen signaling plays a central role in coordinating cell cycle progression and metabolic programs that support tumor growth. Glycolytic flux is regulated at the level of phosphofructokinase-1 (PFK1) through the inducible enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which is transcriptionally regulated by estrogen receptor signaling and has been shown to promote glycolysis and proliferation in ER⁺ breast cancer cells. Yet, how CDK4/6 inhibition intersects with estrogen-regulated glycolytic control to rewire glucose utilization in ER⁺ breast cancer has not been explored. Methods Glucose metabolism was assessed using extracellular flux analysis, untargeted metabolomics, and stable isotope tracing with uniformly labeled 13 C-glucose in ER + breast cancer cell lines. In vivo metabolic tracing was performed following bolus administration of [U- 13 C]-glucose. The effects of pharmacologic PFKFB3 inhibition, alone and in combination with CDK4/6 inhibitors, were evaluated in vitro and in patient-derived xenograft (PDX) models. Statistical analyses were performed using appropriate tests with correction for multiple comparisons where applicable. Results CDK4/6 inhibition increased glycolytic flux, as evidenced by elevated basal and compensatory glycolysis, accumulation of early glycolytic intermediates, and increased 13 C labeling of fructose 1,6-bisphosphate. PFKFB3 silencing abrogated the CDK4/6 inhibitor-induced increase in glycolytic flux. Despite increased glycolysis, stable isotope tracing revealed markedly reduced incorporation of glucose-derived carbon into nucleotide biosynthesis and lipid-associated metabolites, consistent with reduced anabolic demand during G1 cell cycle arrest. In vivo glucose tracing demonstrated a dissociation between increased glycolytic flux and downstream biosynthetic utilization. Pharmacologic inhibition of PFKFB3 imposed additional constrains on glucose utilization and significantly enhanced the antitumor efficacy of CDK4/6 inhibition in PDX models. Conclusions CDK4/6 inhibition rewires glucose metabolism in ER + breast cancer by increasing glycolytic flux while limiting downstream glucose utilization, resulting in heightened reliance on regulated glycolytic control to maintain metabolic homeostasis during cell cycle arrest. Disruption of this adaptive metabolic state through PFKFB3 inhibition enhances the antitumor effects of CDK4/6 inhibition and supports the therapeutic potential of targeting glycolytic regulation in combination with CDK4/6 inhibitor-directed therapies.

DOI: https://doi.org/10.21203/rs.3.rs-8412774/v1
Cell Death Dis. 2026 Feb 27.

NSD2 inhibits the expression of PD-L1 via oxidative phosphorylation to control immune surveillance in hepatocellular carcinoma.

Wei Zhang, Wenxin Feng, Chunxiao Ma, Hanyu Rao, Changwei Liu, Yue Xu, Ningyuan Liu, Ziyi Wang, Rebiguli Aji, Ting Han, Wei-Qiang Gao, Xiuying Xiao, Li Li.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death, and patients usually exhibit impaired immune function within the tumor environment. NSD2 is an H3K36 methyltransferase and has been considered a cancer-promoting factor. However, the role of NSD2 in the occurrence and development of HCC is still unclear. In this study, the effects of NSD2 on HCC were assessed by both mouse and cell models. RNA-seq, ChIP-seq, and orthotopic tumor models were employed to decipher the downstream mechanisms of NSD2 responsible for HCC development. NSD2 alterations were characterized in patients with HCC. Hepatocyte-specific NSD2 overexpression suppresses the proliferation of tumor cells in DEN-treated mice. Mechanistically, NSD2 inhibits OXPHOS by activating target genes (Camk2d and Prkce) transcription. Downregulation of OXPHOS, caused by overexpression of NSD2, inhibits the expression of PD-L1 and enhances immune recognition of tumors. What's more, inhibition of OXPHOS suppresses the formation of HCC. Finally, patients with low expression of NSD2 have a better response to PD-L1 inhibitor treatment. These findings showed that NSD2 inhibits the progression of HCC by inhibiting the expression of PD-L1 through OXPHOS. Our results identify NSD2 as a tumor suppressor in the development of HCC.

DOI: https://doi.org/10.1038/s41419-026-08490-x
Cell Rep. 2026 Feb 25. pii: S2211-1247(26)00113-0. [Epub ahead of print]45(3): 117035

Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC class I-deficient solid tumors.

Yi Wang, Chao Huang, Guoxin Cai, Massimo Andreatta, Armand Kurum, Yang Zhao, Bing Feng, Min Gao, Santiago J Carmona, Zhan Zhou, Cheng Sun, Yugang Guo, Li Tang.

  Natural killer (NK) cells, a type of potent cytotoxic lymphocyte, are particularly promising for the treatment of cancers that lose or downregulate major histocompatibility complex class I (MHC class I) expression to evade T cell-mediated immunotherapy. However, the hostile and immunosuppressive tumor microenvironment (TME) greatly hinders the function of tumor-infiltrating NK cells, thus limiting the therapeutic efficacy. Here, we show a fusion protein of interleukin 21 (IL-21-Fc) that safely and effectively reprograms NK cell metabolism and restores their effector function in vivo. IL-21-Fc synergizes with IL-15 superagonist (IL-15SA) or adoptive NK cell transfer to eradicate MHC class I-deficient tumors and confer durable protection across multiple murine models. Mechanistically, we uncover that IL-21-Fc enhances NK cell effector function by upregulating glycolysis in a lactate dehydrogenase A (LDHA)-dependent manner. This study reveals LDHA-dependent metabolic reprogramming as a key axis for NK cell rejuvenation and positions IL-21-Fc as a promising, clinically translatable strategy to overcome TME-mediated suppression in solid tumors.

Keywords:  CP: cancer; CP: metabolism; LDHA; MHC class I-deficient tumor; NK cell exhaustion; NK cell therapy; cancer immunotherapy; glycolysis; immunometabolism; interleukin 21

DOI:  https://doi.org/10.1016/j.celrep.2026.117035
Oncol Lett. 2026 Apr;31(4): 134

Fatty acid-induced lipid accumulation promotes radiosensitization in Huh7 hepatocellular carcinoma cells.

Haruto Tanaka, Yasushi Mariya, Satoru Monzen.

  Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, represents a substantial global health burden, and the therapeutic efficacy of radiotherapy remains highly variable among patients with the condition. Metabolic alterations, particularly in lipid metabolism, may modulate radiosensitivity, although the underlying mechanisms are not fully understood. The present study investigated the impact of fatty acid uptake on radiosensitivity in HCC using the Huh7 cell line. Oleic acid (OA), a monounsaturated fatty acid, was used to induce intracellular lipid accumulation. Flow cytometry analyses revealed that OA treatment (1 mM; 18 h) considerably increased lipid content without inducing cytotoxicity. When combined with X-ray irradiation (10 Gy), OA pretreatment considerably enhanced cell death, as indicated by an increased proportion of propidium iodide-positive cells. This effect was associated with elevated levels of lipid hydroperoxides and reactive oxygen species, suggesting oxidative stress-mediated mechanisms. Furthermore, mRNA expression analyses revealed marked upregulation of ChaC glutathione specific γ-glutamylcyclotransferase 1, a gene involved in glutathione degradation and ferroptosis, in OA-treated cells. The expression levels of glutathione peroxidase 4 and glutamate-cysteine ligase catalytic subunit, key antioxidant defense genes, were also upregulated by OA and irradiation. These findings indicate that OA-induced lipid accumulation sensitized HCC cells to radiation through enhanced oxidative stress and lipid peroxidation. However, as the present study was based on an in vitro model using a single cell line, the potential clinical relevance of these findings remains speculative and requires further validation in in vivo models and clinical studies.

Keywords:  ferroptosis; hepatocellular carcinoma; lipid accumulation; oleic acid; oxidative stress; radiosensitization

DOI:  https://doi.org/10.3892/ol.2026.15487
Front Pharmacol. 2026 ;17 1748950

Unraveling the role of 3-mercaptopyruvate sulfurtransferase-derived hydrogen sulfide in triple-negative breast cancer chemoresistance.

Sousanna Hakim, Danira A Habashy, Kelly Ascenção, Rana A Youness, Carole Bourquin, Csaba Szabo, Mohamed Z Gad, Reham M Abdelkader.

   Background: Triple-negative breast cancer (TNBC) frequently develops resistance to chemotherapy. Cancer-supporting roles of the endogenous gaseous mediator hydrogen sulfide (H2S) have been identified. We investigated whether endogenous H2S, produced by 3-mercaptopyruvate sulfurtransferase (3-MST), mediates chemoresistance in TNBC and elucidated the underlying mechanisms involved.
Methods: A 3-MST inhibitor (HMPSNE) was used along with different chemotherapeutic drugs to determine whether 3-MST affects TNBC cell (MDA-MB-231) chemoresistance. H2S production was measured via AzMC fluorescence. H2S-synthesizing and H2S-degrading enzymes were quantified via Western blotting together with downstream signaling molecules involved in the PI3K/Akt/mTOR pathway. Cell viability, colony formation and migration assays were performed. qRT‒PCR and flow cytometry were conducted to assess the expression of the cancer stem cell marker CD44.
Results: HMPSNE enhanced the cytotoxic, anticlonogenic and antimigratory effects of doxorubicin on MDA-MB-231 cells. Doxorubicin increased H2S-synthesizing enzymes, whereas HMPSNE resulted in their downregulation, especially cystathionine beta-synthase (CBS) and 3-MST. A similar trend was observed for H2S-metabolizing enzymes, particularly thiosulfate sulfurtransferase (TST). A significant increase in CD44 was revealed upon doxorubicin treatment; 3-MST slightly affected this response. With respect to the PI3K/AKT/mTOR pathway, HMPSNE did not significantly modulate the effect of doxorubicin.
Conclusion: These findings suggest that TNBC chemoresistance is linked to the 3-MST/H2S pathway. Pharmacological inhibition of 3-MST by HMPSNE enhances the chemotherapeutic effect of doxorubicin on TNBC. Some of these effects may be related to the regulation of CD44 but are unlikely to be mediated via the PI3K/AKT/mTOR pathway. Therefore, pharmacological inhibition of 3-MST may serve as a promising target for further investigations to increase the sensitivity of TNBC cells to doxorubicin-based therapies.

Keywords:  3-MST; H2S; TNBC; chemoresistance; doxorubicin

DOI:  https://doi.org/10.3389/fphar.2026.1748950
Clin Transl Oncol. 2026 Feb 25.

Apigenin 7-glucoside reprograms tumor metabolism and enhances immunotherapy efficacy in colorectal cancer via DLX5.

Guijun Zou, Yiwei Jiang, Rui Ma, Songyan Li, Chaojun Zhang.

   BACKGROUND: The progression of colorectal cancer (CRC) is closely associated with glycolysis, angiogenesis and immune response. While the natural flavonoid Apigenin 7-glucoside (A7G) exhibits anti-tumor potential, its effects on these three processes remain unclear. This study aims to investigate the impact of A7G on the CRC landscape and to assess its synergistic effect when combined with PD-1 inhibitors.
METHODS: Western blotting was used to detect the effect of A7G on glycolysis and angiogenesis-related factors. Immunohistochemistry and flow cytometry were employed to analyze changes in the tumor immune microenvironment. The CT26 mouse xenograft model with overexpressed DLX5 was established to evaluate the role of A7G in modulating metabolic and immune responses. Finally, the therapeutic effect of A7G in combination with PD-1 inhibitors was explored.
RESULTS: A7G significantly decreased the expression of glycolysis and angiogenesis-related factors, a process partially reversed by DLX5 overexpression. Flow cytometry analysis showed that A7G treatment increased the ratio of CD4⁺ T cells/CD8⁺ T cells and reduced the infiltration of M2 macrophages and Treg cells, which was also modulated by DLX5. When combined with PD-1 inhibitors, A7G markedly suppressed tumor growth and enhanced the efficacy of immune therapy.
CONCLUSION: A7G treatment demonstrated potential anti-tumor activity in CRC, which is characterized by the simultaneous attenuation of glycolysis and immune evasion via the DLX5 axis. When used in combination with PD-1 inhibitors, A7G significantly enhances the effects of immunotherapy, providing a novel strategy for cancer treatment.

Keywords:  Colorectal cancer; Glycolysis; Tumor immune microenvironment

DOI:  https://doi.org/10.1007/s12094-026-04286-9
Cancer Lett. 2026 Feb 24. pii: S0304-3835(26)00112-6. [Epub ahead of print] 218349

Targeting PCK1 to overcome CDK4/6 inhibitor resistance for breast cancer therapy.

Chen-Shiou Wu, Hsiao-Fan Chen, Kieu-Thanh Huynh, Wei-Chien Huang, Yi-Chuan Li, Wei-Chao Chang, Ling-Chu Chang, Ciao-Ling Jiang, Kevin Chih-Yang Huang, Liang-Chih Liu, K S Clifford Chao, Mien-Chie Hung.

  Phosphoenolpyruvate carboxykinase 1 (PCK1) is known for its role in gluconeogenesis and the regulation of PCK1 expression was shown to associate with oncogenic activity in pancreatic and colorectal cancers. However, in different cancer types such as liver cancer, PCK1 could function as a tumor suppressor, rendering complication for targeted therapy. In this study, we used breast cancer model to delineate its involvement in malignancy, we found PCK1 associated with oncogenic function to promotes cell proliferation, enhances colony formation, and stimulates DNA synthesis in breast cancer. Mechanistically, we found that PCK1 interacts with Cyclin D3, establishing a positive correlation between PCK1 and Cyclin D3 in clinical breast cancer tissues. Cyclin D3 forms a complex with CDK4/6, implicated in the development of resistance to CDK4/6 inhibitors. We identified PCK1 as a key factor in this resistance. Through an extensive screening process, we identified everolimus and auranofin as inhibitors of PCK1. We found that these drugs, in combination with CDK4/6 inhibitors, exhibit a synergistic effect in suppressing breast cancer. These findings reveal the connection between PCK1 and CDK4/6 inhibitor resistance, offering the possibility for improved treatment options for breast cancer. Interestingly, we also found PCK1 and Cyclin D3 interaction in pancreatic cancer, similar to that in breast cancer, but not in liver cancer. Thus, the results may resolve the puzzle for the role of PCK1 in tumor-promoting or -suppressive role in different cancer types.

Keywords:  CDK4/6 inhibitor; Cyclin D3; PCK1; breast cancer; drug resistance

DOI:  https://doi.org/10.1016/j.canlet.2026.218349