bims-meract 2026-02-22 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–02–22
twelve papers selected by
Andrea Morandi, Università degli Studi di Firenze

Modulating metabolic signatures to mitigate cabozantinib resistance in FLT3-ITD acute myeloid leukemia cell models.
Transcriptomic Analysis Reveals an NRF2-Mediated Redox and Metabolic Reprogramming in Sorafenib-Resistant Hepatocellular Carcinoma Cells.
ΔNp63α drives serine synthesis to promote carboplatin resistance in NSCLC.
AFP confers the resistance of lenvatinib in hepatocellular carcinoma by activating PI3K/AKT/LDHA signaling axis.
16-h fasting optimizes cancer immunotherapy in mice and humans.
ACSL4-associated lipid metabolism is a distinct therapeutic vulnerability in KMT2A-rearranged acute myeloid leukemia.
A Glutamine-Metabolism-Intervening Nanoplatform Activates Lipophagy to Potentiate Ferroptosis and Immune Activation in Breast Cancer.
Decoding cancer across scales with metabolomics.
Fatty acid and cysteine metabolic interplay regulate ferroptosis and highlight xCT as a selenium-chrysin target in breast carcinoma.
Cellular mechanisms of brain lipid metabolism in health and disease.
mTOR-driven autophagy suppression defines metabolic vulnerability in CDK4/6 inhibitor-resistant HR+/HER2- breast cancer.
SNHG18 deficiency reprograms arginine metabolism to foster an immunosuppressive microenvironment in prostate cancer bone metastasis.

Cell Death Discov. 2026 Feb 17. 12(1): 98

Modulating metabolic signatures to mitigate cabozantinib resistance in FLT3-ITD acute myeloid leukemia cell models.

Yu-Hsuan Fu, Kit Man Ng, Chi-Yang Tseng, Ang-Chu Huang, Chin-Hsien Tu, Wen-Chun Chen, Pei-Chi Lang, Hsiung-Fei Chien, Liang-In Lin.

Drug resistance remains a major challenge in treating acute myeloid leukemia (AML), despite advancements in targeted therapies. We established cabozantinib-resistant FLT3-ITD+ AML cell lines (MV4-11-XR, Molm13-XR) from parental MV4-11 and Molm13 cells. In addition to resistance to cabozantinib, they also exhibited resistance to FDA-approved sorafenib and quizartinib with substantial increases in IC50. The FLT3 D835Y mutation emerged in both cell lines, while an additional 1.3 kb deletion in FLT3 (FLT3¹.³) was present in MV4-11-XR cells. Both resistant cells displayed higher proliferation rates and increased colony formation, as well as increased phosphorylation of FLT3 and its downstream signaling molecules, including ERK, STAT5, and AKT. Transcriptomic analysis identified 1113 and 1057 differentially expressed genes (DEGs) in MV4-11-XR and Molm13-XR, respectively, compared with their parentals, of which 81 and 74 DEGs are metabolic-related. Further metabolic assays confirmed that cabozantinib resistance was associated with significant metabolic alterations, including enhanced glycolysis with increased glucose uptake, lactate production, GAPDH activity, and glycolytic gene expression, as well as impaired oxidative phosphorylation and reduced mitochondria mass. Further in silico drug screening and in vitro experiments demonstrated that PI3K/mTOR dual inhibitor omipalisib and HSP90 inhibitor radicicol effectively reversed the metabolic reprogramming in cabozantinib-resistant cells. Moreover, both omipalisib and radicicol exhibited synergistic effects with cabozantinib, highlighting their therapeutic potential. Overall, we identified metabolic dysregulation as a hallmark of cabozantinib resistance and suggested that targeting metabolic vulnerabilities with PI3K/mTOR or HSP90 inhibitors could be an option to mitigate drug resistance.

DOI: https://doi.org/10.1038/s41420-026-02957-8
BioTech (Basel). 2026 Feb 11. pii: 18. [Epub ahead of print]15(1):

Transcriptomic Analysis Reveals an NRF2-Mediated Redox and Metabolic Reprogramming in Sorafenib-Resistant Hepatocellular Carcinoma Cells.

Angelo Michilli, Cristian Bassi, Farzaneh Moshiri, Bruno De Siena, Rosaria Marinaro, Elisa Callegari, Massimo Negrini, Silvia Sabbioni.

  Despite the advent of immune checkpoint inhibitor-based regimens, sorafenib remains an important therapeutic option for patients with advanced hepatocellular carcinoma (HCC) who are ineligible for immunotherapy. However, its clinical efficacy is limited by the emergence of drug resistance, whose underlying molecular mechanisms remain incompletely understood. To investigate these mechanisms, we established a murine model of acquired sorafenib resistance and performed comparative RNA sequencing of sorafenib-sensitive versus -resistant Hep55.1C hepatoma cells. Transcriptomic profiling revealed a distinct resistance-associated signature comprising 1264 significantly deregulated genes (adjusted p < 0.03, fold change > 3.0). Pathway analysis and Gene Set Enrichment Analyses (GSEA) indicated a coordinated downregulation of metabolic and intercellular signaling pathways, accompanied by marked upregulation of redox-regulatory, mitochondrial and cellular stress-response programs. Genes transcriptionally regulated by nuclear factor erythroid 2-related factor 2 (NRF2) including Gpx4, Txn1, Txnrd1, Hmox1, Fth1, Taldo1, Phgdh, and MafG, involved in antioxidant defense, ferroptosis suppression and metabolic rewiring, were all upregulated in resistant cells. Pharmacological inhibition of NRF2 activity using brusatol restored sensitivity to sorafenib, functionally implicating NRF2-dependent pathways in the maintenance of the resistant phenotype. These findings demonstrate that acquired sorafenib resistance in HCC is associated with a stable NRF2-driven transcriptional and metabolic reprogramming that enhances antioxidant capacity, suppresses ferroptosis and promotes tumor cell survival. Targeting NRF2-regulated redox metabolism may therefore represent a promising strategy to overcome therapeutic resistance in HCC.

Keywords:  NRF2; hepatocellular carcinoma; oxidative stress; redox metabolism; sorafenib resistance; transcriptomics

DOI:  https://doi.org/10.3390/biotech15010018
Cell Death Dis. 2026 Feb 17. 17(1): 227

ΔNp63α drives serine synthesis to promote carboplatin resistance in NSCLC.

Liyuan Deng, Xin Yang, Junli Zhang, Xuanyu Zhou, Ruidong Ma, Zhiqiang Wu, Hu Chen.

Serine metabolism is a critical vulnerability in cancer; however, its role in mediating therapeutic resistance in non-small cell lung cancer (NSCLC) remains incompletely understood. In this study, we identify key enzymes in the serine synthesis pathway (SSP), namely PHGDH, PSAT1 and PSPH, as well as the serine transporter SLC1A4, which are significantly overexpressed in lung cancer and correlate with poor patient prognosis. We show that serine contributes to carboplatin resistance in NSCLC, particularly in lung squamous cell carcinoma (LUSC). Notably, the LUSC lineage-specific oncogene ΔNp63α serves as a master transcriptional regulator of serine biosynthesis, directly transactivating the expression of PHGDH, PSAT1, PSPH, and SLC1A4. ΔNp63α-driven serine biosynthesis supports nucleotide synthesis and enhances antioxidant defense, enabling cancer cells to survive carboplatin-induced DNA damage and oxidative stress, thereby promoting therapeutic resistance. The combined inhibition of endogenous serine synthesis and restriction of exogenous serine/glycine significantly overcomes ΔNp63α-mediated carboplatin resistance. Our findings establish the ΔNp63α-SSP axis as a critical mechanism driving carboplatin resistance in LUSC. These results highlight dual-targeted disruption of serine availability as a promising therapeutic strategy to overcome chemotherapy resistance in ΔNp63α-driven LUSC. This study underscores the importance of lineage-specific metabolic dependencies as essential targets for precision oncology in NSCLC.

DOI: https://doi.org/10.1038/s41419-026-08497-4
Discov Oncol. 2026 Feb 16.

AFP confers the resistance of lenvatinib in hepatocellular carcinoma by activating PI3K/AKT/LDHA signaling axis.

Weimei Xing, Fang Wang, Siren Feng, Xiaowei Li, Yuli Zhou, Huayi Wu, Bo Lin, Xu Dong, Mengsen Li, Mingyue Zhu.

  This study aimed to explore whether alpha-fetoprotein (AFP) promotes resistance of hepatocellular carcinoma (HCC) cells to lenvatinib by regulating the activity of lactate dehydrogenase A (LDHA) and triggering the Warburg effect. Analysis of 30 clinical HCC samples revealed that the expression of AFP and LDHA in cancer tissues was significantly higher than that in adjacent tissues and that there was a positive correlation between their expression levels. Cell function experiments (such as MTT and colony formation assays) confirmed that AFP significantly enhances the resistance of HCC cells to lenvatinib. Mechanistic studies have found that AFP can promote glycolysis in HCC cells (manifested as an enhanced Warburg effect, increased glucose consumption, lactate production, and ATP production) and upregulate the expression of glycolysis-related proteins, which is dependent on LDHA. Further mechanistic studies indicated that AFP regulates LDHA activity by activating the PI3K/AKT signaling pathway. Therefore, this study revealed that AFP enhances glycolysis by stimulating the activation of the PI3K/AKT/LDHA signaling axis, thereby inducing resistance of HCC cells to lenvatinib. This study provided a new theoretical basis for overcoming lenvatinib resistance by targeting AFP and inhibiting LDHA expression.

Keywords:  Alpha-fetoprotein; Drug resistance; Hepatocellular carcinoma; Lactic acid dehydrogenase A; Lenvatinib

DOI:  https://doi.org/10.1007/s12672-026-04637-6
Cell Metab. 2026 Feb 19. pii: S1550-4131(26)00014-8. [Epub ahead of print]

16-h fasting optimizes cancer immunotherapy in mice and humans.

Sheng Chen, Tianyi Hu, Kaixiang Zhu, Yue Liu, Yidong Yang, Xiangyuan Li, Jinjie He, Wenyu Cui, Zhexu Chi, Weiwei Yu, Duojiao Chen, Zhen Wang, Jian Zhang, Ruya Sun, Dehang Yang, Siqi Dai, Qianzhou Yu, Quanquan Wang, Qian Xiao, Junbin Qian, Kefeng Ding, Di Wang.

  Dietary interventions hold promise for cancer therapy but often require prolonged, poorly tolerated regimens. Furthermore, how transient nutrient deprivation affects the metabolic interplay between tumor and immune cells within the tumor microenvironment (TME) remains unknown. Here, we introduce a brief, 16-h fasting regimen that enhances immunotherapy efficacy in both mice and humans. We found that this transient nutrient stress alters tumor-cell nutrient preferences, creating a metabolic window that can be leveraged to augment treatment. Mechanistically, short-term fasting induces intratumoral accumulation of isoleucine, which reconfigures CD8+ T cell epigenetic programs and phospholipid remodeling, thereby licensing enhanced anti-tumor capacity. In patients receiving neoadjuvant immunotherapy, short-term fasting was able to enhance CD8+ clonal expansion and cytotoxic programs. These findings establish a clinically feasible, well-tolerated dietary regimen that counters nutrient competition in the TME and that provides a tractable path to strengthen existing immunotherapy regimens.

Keywords:  diet intervention; immune checkpoint therapy; immunometabolism; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cmet.2026.01.015
Cell Rep. 2026 Feb 18. pii: S2211-1247(26)00088-4. [Epub ahead of print]45(3): 117010

ACSL4-associated lipid metabolism is a distinct therapeutic vulnerability in KMT2A-rearranged acute myeloid leukemia.

Silvia Schäfer, Elahe Rahimian, Lola Schmitz-Hübsch, Mehak Shaikh, Silke Brilloff, Vida Kufrin, Sandra Küchler, Maria Fedorova, Natalie Kusebauch, Zhixu Ni, Dominic Helm, Irmela Jeremias, Denis M Schewe, Claudia R Ball, Martin Bornhäuser, Hanno Glimm, Meritxell Alberich-Jorda, Marius Bill, Alexander A Wurm.

  Deregulated lipid metabolism contributes to leukemogenesis and the progression of acute myeloid leukemia (AML). By analyzing large-scale CRISPR-Cas9 screening data, we identified acyl-CoA synthetase long-chain family member 4 (ACSL4) as a selective vulnerability in lysine methyltransferase 2A-rearranged (KMT2Ar) AML. Functional validation using CRISPR interference and short hairpin RNA knockdown confirmed that ACSL4 loss impairs the growth of KMT2Ar but not non-KMT2Ar AML cells. ACSL4 knockdown reduced colony formation in cells derived from patients with KMT2Ar AML and murine MLL-AF9 cells and delayed leukemia onset in vivo in MLL-AF9 mice. A multi-omics approach, including transcriptomics, proteomics, and lipidomics, revealed depletion of polyunsaturated lipid species and compensatory activation of lipid metabolic pathways upon ACSL4 loss. Supplementation with exogenous polyunsaturated fatty acids (PUFAs) rescued the growth defect, linking ACSL4 dependency to defective PUFA utilization. Finally, we generated a KMT2Ar-ACSL4 dependency signature (KRADS12) that correlates with KMT2Ar status and predicts poor survival in patients with AML.

Keywords:  CP: cancer; CP: metabolism; acute myeloid leukemia; chromosomal rearrangements; lipid metabolism

DOI:  https://doi.org/10.1016/j.celrep.2026.117010
Adv Healthc Mater. 2026 Feb 20. e70969

A Glutamine-Metabolism-Intervening Nanoplatform Activates Lipophagy to Potentiate Ferroptosis and Immune Activation in Breast Cancer.

Jiayue Ding, Jingchao Liu, Liheng Liang, Weilin Wang, Yingchao Li, Chuanxiu Zhu, Jiayao Wen, Zhijing He, Jin Li, Yu Zhang, Guangxi Zhai, Xiaoye Yang.

  Aberrant glutamine (Gln) metabolism in tumor cells contributes to ferroptosis resistance and immunosuppression, challenging ferroptotic therapy. Our preliminary bioinformatic data uncovered that elevated expression of SLC1A5, a critical Gln transporter, confers poor prognosis in breast cancer, underscoring its potential as a therapeutic target for metabolic regulation. Encouraged by this, this work proposes to enhance ferroptosis of breast cancer by inhibiting SLC1A5. As a proof-of-concept, we develop a nanoplatform for ferroptosis named MICLM, which is obtained by encapsulating chlorin e6 (Ce6, a photosensitizer) and IMD-0354 (an SLC1A5 inhibitor) into metal-organic framework (NH2-MIL-101(Fe)), followed by surface coating for tumor-targeting. Experimental data reveal that Ce6-based photodynamic therapy synergizes with iron-mediated Fenton reaction, potently driving lipid peroxides (LPOs) accumulation and triggering ferroptosis of 4T1 cells. Meanwhile, IMD-0354-mediated Gln metabolic intervention is proven to inhibit glutathione (GSH) synthesis and activate lipophagy, thereby increasing free fatty acids (FFA) levels as an essential "fuel" for lipid peroxidation and overcoming a key limitation in ferroptosis efficacy. Additionally, Gln metabolism inhibition attenuates immunosuppressive M2 macrophage polarization, ultimately boosting antitumor immunity. Thus, MICLM effectively induces ferroptosis and remodels the tumor immune microenvironment via amino acid metabolic intervention, offering a promising strategy for ferroptosis-based therapy.

Keywords:  antitumor immune; ferroptosis; glutamine metabolism intervention; lipophagy; metal‐organic framework

DOI:  https://doi.org/10.1002/adhm.70969
Nat Rev Cancer. 2026 Feb 20.

Decoding cancer across scales with metabolomics.

Joe L Rowles, Gary J Patti.

It is well established that malignant cells alter their metabolism to support proliferation, but the nutrients required to meet the anabolic demands of different cancers located at various anatomical sites throughout the body remain largely unknown. Moreover, the extent to which nutrients are supplied by neighbouring stromal cells or distant tissues, possibly due to metabolic reprogramming, is poorly understood. Metabolomics provides a unique biochemical approach to address these gaps in our knowledge, but cancer studies require careful consideration because it is challenging to identify appropriately matched control samples for comparison. Here, we detail a collection of metabolomics workflows designed to interrogate cancer across three discrete scales. First, we describe experiments to define the nutrient demands of cancer cells themselves. Second, we focus on identifying metabolic relationships between neighbouring cells in the tumour microenvironment. Finally, we highlight strategies to explore the metabolic crosstalk between cancer cells and distant tissues in the tumour macroenvironment. The approaches outlined span cells in culture, animal models and human specimens from patients with cancer. Special emphasis is dedicated to the application of emerging technologies and computational pipelines in the field of mass spectrometry that enable global profiling of metabolites and lipids.

DOI: https://doi.org/10.1038/s41568-026-00908-0
J Pathol. 2026 Feb 18.

Fatty acid and cysteine metabolic interplay regulate ferroptosis and highlight xCT as a selenium-chrysin target in breast carcinoma.

Ana Hipólito, Bruna Abreu, Joana Gonçalves, Fernanda Silva, Carmo Martins, Laura Gouveia, Sofia A Pereira, Vasco D B Bonifácio, Saudade André, Cindy Mendes, Jacinta Serpa.

  Cancer metabolic remodeling impacts the entire network of metabolic pathways, and strategies that target various points within this system could contribute to successfully abrogating cancer cell survival. Fatty acids (FAs) are essential to cancer cells because they support membrane biosynthesis during proliferation and provide energy during metabolic stress. Fatty acid transport protein 1 (FATP1)has been shown to mediate FA uptake in breast carcinoma (BC). The light chain of cysteine/glutamate amino acid exchange transporter system Xc (xCT)is crucial for the uptake of cysteine serving as a carbon and sulfur source that contributes to redox control, bioenergetics, and biosynthesis. In this study, targeting of FA and cysteine metabolic pathways was shown to be a potential strategy for managing BC by inhibiting FATP1 and xCT with arylpiperazine 5k and selenium-chrysin (SeChry), respectively. In BC cell lines, FATP1 expression is controlled by estrogen receptor β (ER-β) and promotes the accumulation of lipid droplets (LDs), which is associated with triple-negative breast carcinoma (TNBC) cells showing increased rates of cell proliferation, two-dimensional directional cell migration, and higher chemoresistance. Expression of xCT was also associated with the TNBC molecular BC subtype. In BC specimens, an association between FATP1 and xCT expression was observed. In vitro, SeChry induced ferroptosis in BC cells by targeting xCT and cysteine reliance and ultimately inducing cell death. In xenograft BC tumors, arylpiperazine 5k abrogated the effects of SeChry encapsulated in polyurea dendrimers functionalized with folate (SeChry@PUREG4-FA2) by reducing intracellular FA and rescuing ferroptosis. In vitro, SeChry sensitized BC cells to cisplatin and may therefore serve as an alternative in combination therapy. Overall, our study confirmed FATP1 as a marker and xCT as both a marker and a target in BC, particularly in TNBC. Induction of ferroptosis by interfering with xCT function may provide an opportunity to improve BC treatment, and a therapeutic approach using SeChry@PUREG4-FA2 is a promising strategy. © 2026 The Pathological Society of Great Britain and Ireland.

Keywords:  SeChry nanoformulation (SeChry@PUREG4‐FA2); cysteine; fatty acid transport protein 1 (FATP1); fatty acids; ferroptosis; light chain of cysteine/glutamate amino acid exchange transporter system Xc (xCT)

DOI:  https://doi.org/10.1002/path.70027
Nat Cell Biol. 2026 Feb 20.

Cellular mechanisms of brain lipid metabolism in health and disease.

Francesco Petrelli, Carlotta Gilardi, Carla Marie Igelbüscher, Diana Panfilova, Alicia Rey, Rosa Chiara Paolicelli, Marlen Knobloch.

Lipid metabolism has recently regained considerable attention in neuroscience, as disturbances in lipid metabolic pathways have been linked to neurodevelopmental and neurodegenerative diseases. Here we examine brain lipid metabolism from a cellular perspective, focusing on lipid uptake, de novo synthesis, storage, breakdown and intercellular transfer. We cover the recent literature showing how these processes are important during brain development and how they occur in diverse brain cell types, including astrocytes, oligodendrocytes, neural stem and progenitor cells, microglia and neurons in the adult brain. We further discuss the consequences of disrupted lipid metabolism and highlight emerging insights into neuron-glia lipid exchange, as well as the importance of lipid droplets for brain health and disease.

DOI: https://doi.org/10.1038/s41556-026-01880-5
Cell Death Dis. 2026 Feb 19.

mTOR-driven autophagy suppression defines metabolic vulnerability in CDK4/6 inhibitor-resistant HR+/HER2- breast cancer.

Luise von Wichert, Alina Stroh, Marie Witt, Michael Wanzel, Marco Mernberger, Sebastian Griewing, Thomas Wündisch, Berit M Pfitzner, Julia Teply-Szymanski, Anne-Sophie Litmeyer, Carsten Denkert, Uwe Wagner, Thorsten Stiewe, Niklas Gremke.

Breast cancer (BC) is the most prevalent malignancy in women, with hormone receptor-positive, HER2-negative (HR+/HER2-) tumors representing ~70% of cases. While CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have transformed treatment for metastatic HR+/HER2- BC, acquired resistance remains a major obstacle. Using HR+/HER2- BC models with acquired resistance to the CDK4/6 inhibitors Palbociclib or Ribociclib, we uncovered a metabolic vulnerability in highly resistant clones, mediated by mTORC1 hyperactivation and autophagy suppression. Gene expression profiling revealed enrichment of glycolysis and mTORC1 pathways in CDK4/6i-resistant cells, which manifested as heightened sensitivity to the metabolic inhibitors Metformin and Dichloroacetate (DCA). Mechanistically, mTORC1 overactivation impaired autophagy via ULK1-Ser757 phosphorylation, as confirmed by LC3 flux assays, leaving resistant cells unable to adapt to energy stress. Treatment with metabolic drugs triggered AMPK activation, ACC inhibition, and PARP cleavage, culminating in apoptosis. Clinically, immunohistochemical analysis of a BC cohort revealed a significant correlation between mTORC1 activity (p4E-BP1T37/46) and autophagy suppression (p62 accumulation), supporting the translational relevance of this axis. Our findings propose mTORC1-mediated autophagy defects as a biomarker for metabolic vulnerability in CDK4/6i-resistant BC, offering a rationale for targeting these tumors with metabolic therapies to overcome resistance.

DOI: https://doi.org/10.1038/s41419-026-08496-5
Cancer Lett. 2026 Feb 15. pii: S0304-3835(26)00089-3. [Epub ahead of print]644 218326

SNHG18 deficiency reprograms arginine metabolism to foster an immunosuppressive microenvironment in prostate cancer bone metastasis.

Zhong Xie, Shaojie Li, Jie Yang, Zhengpeng Zhang, Shuren Li, Chuandong Lang, Mingxing Yang, Bin Wang, Xiaowei Yu, Zhihong Li, Yijun Kang, Chi Yin, Qing Yang.

Advanced prostate cancer (PCa) frequently metastasizes to bone, where the immunosuppressive tumor microenvironment (TME) limits immune checkpoint blockade (ICB) efficacy. Nevertheless, the molecular mechanisms underlying this immunosuppressive bone TME and bone metastasis (BM) are not yet fully understood. Analysis of clinical PCa samples, employing in situ hybridization, RT-qPCR, and bioinformatics, demonstrated a progressive downregulation of lncRNA SNHG18 throughout PCa progression, with the lowest expression levels observed in BM associated with poor prognosis. We demonstrate that the downregulation of SNHG18 contributes to castration-resistant prostate cancer (CRPC) and BM development by utilizing an androgen-independent Myc-CaP subline, derived from Androgen receptor positive (AR+) Myc-CaP cells through chronic steroid deprivation, alongside in vitro and in vivo models. SNHG18 alters the bone microenvironment through the reprogramming of arginine metabolism. Deficiency of SNHG18 resulted in the upregulation of ARG2 and NOS2, which caused arginine depletion, enhanced infiltration of immunosuppressive cells, and compromised effector T-cell function. Mechanistically, SNHG18 bound to YBX1 and recruited TRIM21 to induce YBX1 degradation, thereby inhibiting YBX1-mediated transcriptional activation of NOS2 and ARG2. Therapeutically, SNHG18 overexpression enhanced anti-PD-1 therapy efficacy in murine BM models. Consequently, SNHG18 deficiency fosters an immunosuppressive TME and promotes PCa BM. SNHG18 expression may serve as a predictive biomarker for ICB response, offering a novel strategy to overcome immunotherapy resistance in PCa BM.

DOI: https://doi.org/10.1016/j.canlet.2026.218326