bims-meract 2025-03-09 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–03–09
seventeen papers selected by
Andrea Morandi, Università degli Studi di Firenze

-----Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma.
Large-scale CRISPRi screens link metabolic stress to glioblastoma chemoresistance.
ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion.
HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma.
Fucoxanthin suppresses pancreatic cancer progression by inducing bioenergetics metabolism crisis and promoting SLC31A1‑mediated sensitivity to DDP.
Cancer-associated fibroblasts promote doxorubicin resistance in triple-negative breast cancer through enhancing ZFP64 histone lactylation to regulate ferroptosis.
De Novo Serine Synthesis is a Metabolic Vulnerability that can be Exploited to Overcome Sunitinib Resistance in Advanced Renal Cell Carcinoma.
A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer.
Long non-coding RNA LINC01532 sustains redox homeostasis and accelerates lenvatinib resistance in hepatocellular carcinoma.
Macrophage-Derived Itaconate Suppresses Dendritic Cell Function to Promote Acquired Resistance to Anti-PD-1 Immunotherapy.
Intracellular accumulation of free cholesterol in macrophages triggers a PARP1 response to DNA damage and PARP1 impairs lipopolysaccharide-induced inflammatory response.
Suppression of the LKB1-AMPK-SLC7A11-GSH signaling pathway sensitizes NSCLC to albumin-bound paclitaxel via oxidative stress.
SOX11 exacerbates ferroptosis to reduce lenvatinib resistance in liver cancer cells by promoting ubiquitination degradation of SREBF1 through upregulating UBE3A.
IDO1 inhibition enhances CLDN18.2-CAR-T cell therapy in gastrointestinal cancers by overcoming kynurenine-mediated metabolic suppression in the tumor microenvironment.
PRMT5-mediated arginine methylation stabilizes GPX4 to suppress ferroptosis in cancer.
Methionine metabolite spermidine inhibits tumor pyroptosis by enhancing MYO6-mediated endocytosis.
iMetAct: An integrated systematic inference of metabolic activity for dissecting tumor metabolic preference and tumor-immune microenvironment.

Clin Cancer Res. 2025 Mar 07.

-----Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma.

Eugenio Morelli, Caroline Fidalgo Ribeiro, Silvia D Rodrigues, Claire Gao, Fabio Socciarelli, Domenico Maisano, Vanessa Favasuli, Na Liu, Katia Todoerti, Chandraditya Chakraborty, Yao Yao, Mariateresa Fulciniti, Mehmet Samur, Anil Aktas-Samur, Nicola Amodio, Marcello Turi, Francesca Barello, Johany Penailillo, Cesarina Giallongo, Alessandra Romano, Annamaria Gulla, Kenneth C Anderson, Giorgio Inghirami, Nikhil C Munshi, Massimo Loda.

PURPOSE: In multiple myeloma (MM), tumor cells reprogram metabolic pathways to sustain growth and monoclonal immunoglobulin production. This study examines acetyl-CoA carboxylase 1 (ACC1), the enzyme driving the rate-limiting step in de novo lipogenesis (DNL), in MM metabolic reprogramming, particularly in c-MYC (MYC)-driven subtypes.
EXPERIMENTAL DESIGN: ACC1 expression was evaluated across MM genetic subgroups, focusing on MYC translocations. Functional studies using ACC1 inhibitors and genetic knockdown assessed MM cell growth, lipid synthesis, and metabolic homeostasis in vitro and in vivo. The role of MYC overexpression in ACC1 sensitivity was examined, with palmitate rescue experiments. Lipidomic analysis and assessments of ER stress, protein translation, and oxidative damage elucidated underlying mechanisms.
RESULTS: ACC1 was overexpressed in MYC-translocated MM. Its inhibition or knockdown reduced MM cell growth in vitro and in vivo, particularly in MYC-overexpressing cells. ACC1 knockdown suppressed de novo lipid synthesis, partially rescued by palmitate. Lipidomic disruptions increased cholesterol ester desaturation and altered phospholipid ratios, inducing ER stress, impaired translation, protein carbonylation, oxidative damage, and apoptosis.
CONCLUSIONS: ACC1 is a metabolic vulnerability in MYC-driven MM. Inhibiting ACC1 disrupts lipid homeostasis, induces ER stress, and causes oxidative damage, impairing cell survival. Targeting lipid synthesis pathways, especially in MYC-dependent subtypes, offers a promising therapeutic strategy for MM.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-2000
J Transl Med. 2025 Mar 06. 23(1): 289

Large-scale CRISPRi screens link metabolic stress to glioblastoma chemoresistance.

Xing Li, Wansong Zhang, Yitong Fang, Tianhu Sun, Jian Chen, Ruilin Tian.

   BACKGROUND: Glioblastoma (GBM) patients frequently develop resistance to temozolomide (TMZ), the standard chemotherapy. While targeting cancer metabolism shows promise, the relationship between metabolic perturbation and drug resistance remains poorly understood.
METHODS: We performed high-throughput CRISPR interference screens in GBM cells to identify genes modulating TMZ sensitivity. Findings were validated using multiple GBM cell lines, patient-derived glioma stem cells, and clinical data. Molecular mechanisms were investigated through transcriptome analysis, metabolic profiling, and functional assays.
RESULTS: We identified phosphoglycerate kinase 1 (PGK1) as a key determinant of TMZ sensitivity. Paradoxically, while PGK1 inhibition suppressed tumor growth, it enhanced TMZ resistance by inducing metabolic stress. This activated AMPK and HIF-1α pathways, leading to enhanced DNA damage repair through 53BP1. PGK1 expression levels correlated with TMZ sensitivity across multiple GBM models and patient samples.
CONCLUSIONS: Our study reveals an unexpected link between metabolic stress and chemoresistance, demonstrating how metabolic adaptation can promote therapeutic resistance. These findings caution against single-agent metabolic targeting and suggest PGK1 as a potential biomarker for TMZ response in GBM.

Keywords:   PGK1 ; CRISPR screening; DNA damage repair; Glioblastoma; Metabolic stress; Temozolomide resistance

DOI:  https://doi.org/10.1186/s12967-025-06261-4
Nat Cell Biol. 2025 Mar 03.

ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion.

Yuran Duan, Zhiqiang Hu, Peng Han, Bo Lei, Shuo Wang, Zheng Wang, Yueru Hou, Yanni Lin, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Shenghan Lou, Laishou Yang, Xueli Bai, Shengzhong Duan, Peng Zhan, Tong Liu, Zhimin Lu, Daqian Xu.

Highly aggressive tumours have evolved to restrain the cGAS-STING pathway for immune evasion, and the mechanisms underlying this hijacking remain unknown. Here we demonstrate that hypoxia induces robust STING activation in normal mammary epithelial cells but not in breast cancer cells. Mechanistically, adenylosuccinate lyase (ADSL), a key metabolic enzyme in de novo purine synthesis, is highly expressed in breast cancer tissues and is phosphorylated at T350 by hypoxia-activated IKKβ. Phosphorylated ADSL interacts with STING at the endoplasmic reticulum, where ADSL-produced fumarate binds to STING, leading to the inhibition of cGAMP binding to STING, STING activation and subsequent IRF3-dependent cytokine gene expression. Disrupting the ADSL-STING association promotes STING activation and blunts tumour growth. Notably, a combination treatment with ADSL endoplasmic reticulum translocation-blocking peptide and anti-PD-1 antibody induces an additive inhibitory effect on tumour growth accompanying a substantially increased immune response. Notably, ADSL T350 phosphorylation levels are inversely correlated with levels of STING activation and predicate poor prognosis in patients with breast cancer. These findings highlight a pivotal role of the metabolite fumarate in inhibiting STING activation and uncover new strategies to improve immune-checkpoint therapy by targeting ADSL-moonlighting function-mediated STING inhibition.

DOI: https://doi.org/10.1038/s41556-025-01627-8
Cell Death Dis. 2025 Mar 06. 16(1): 160

HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma.

Peijun Zhou, Xingzhi Peng, Kun Zhang, Jin Cheng, Min Tang, Lin Shen, Qin Zhou, Dan Li, Lifang Yang.

Protein acetylation modification plays important roles in various aspects of tumor progression. Ferroptosis driven by lethal lipid peroxidation is closely related to tumor development. Targeting ferroptosis has become a promising strategy. However, the crosstalk between protein acetylation and ferroptosis remains unclear. In present study, we found that the acetylation of acyl-CoA synthase long-chain family member 4 (ACSL4) enhances its protein stability and a double-edged sword regulation in nasopharyngeal carcinoma (NPC). On the one hand, ACSL4 could promote the malignant progress of tumors; on the other hand, it enhanced radiosensitivity by endowing NPC cells with ferroptosis-sensitive properties in vitro and in vivo. Mechanistically, histone acetyltransferase 1 (HAT1) directly promotes the acetylation of ACSL4 at lysine 383, and deacetylase sirtuin 3 (SIRT3) mediates the deacetylation of ACSL4. Meanwhile, another deacetylase histone deacetylase 2 (HDAC2) enhances ACSL4 acetylation through inhibiting the transcription of SIRT3. Acetylation of ACSL4 inhibits F-box protein 10 (FBXO10)-mediated K48-linked ubiquitination, resulting in enhanced protein stability of ACSL4. This study reveals the novel regulatory mechanism of ferroptosis-related protein from the perspective of protein acetylation, and provides a novel method for the radiosensitivity of NPC.

DOI: https://doi.org/10.1038/s41419-025-07477-4
Int J Oncol. 2025 Apr;pii: 31. [Epub ahead of print]66(4):

Fucoxanthin suppresses pancreatic cancer progression by inducing bioenergetics metabolism crisis and promoting SLC31A1‑mediated sensitivity to DDP.

Fugen Shangguan, Nengfang Ma, Yang Chen, Yuansi Zheng, Ting Ma, Jing An, Jianhu Lin, Hailong Yang.

  Pancreatic cancer (PC) is one of the most malignant tumors, with a 5‑year survival rate <10%. Chemosynthetic drugs are widely used in the treatment of PC; however, their toxicity and side effects often reduce the quality of life for patients. MTT and colony formation assay were performed to detect cell growth and viability in PC cells. Levels of ROS in whole cell and mitochondria were analyzed through flow cytometry. ATP production was evaluated using an ATP Assay Kit. Cellular bioenergetics were analyzed with a Seahorse XFe96 Analyzer, and changes in target molecules were monitored by western blotting. The present study reports that fucoxanthin (FX), a carotenoid derived from aquatic brown seaweed, significantly inhibits PC by inhibiting cell proliferation and inducing cell death via the non‑classical pathway. FX switches mitochondrial respiration to aerobic glycolysis in PC cells. Furthermore, FX decreases whole‑cell ATP levels, which indicates that promotion of glycolysis does not compensate for FX‑induced ATP depletion in mitochondria. Moreover, FX decreased the reduced glutathione/oxidized glutathione ratio observed under glucose‑limited conditions. These alterations caused by FX may decrease metabolic flexibility, indicating higher sensitivity to glucose‑limited (GL) conditions. FX increased the cytotoxicity of cisplatin (DDP) and the expression of solute carrier family 31 member 1 (SLC31A1) in PC cells. Furthermore, the knockdown of SLC31A1 can attenuate cytotoxicity caused by the combination of FX and DDP. It was inferred that FX increased the sensitivity of PC cells to DDP), potentially by upregulating SLC31A1 expression. In conclusion, FX exhibited potent antitumor effects by reprogramming energy metabolism and inducing a distinct form of regulated cell death. Therefore, combining FX with GL treatment or DDP presents a promising therapeutic strategy for PC.

Keywords:  GSH/GSSG; SLC31A1; energy metabolism; fucoxanthin; glucose-limited condition; pancreatic cancer

DOI:  https://doi.org/10.3892/ijo.2025.5737
J Transl Med. 2025 Feb 28. 23(1): 247

Cancer-associated fibroblasts promote doxorubicin resistance in triple-negative breast cancer through enhancing ZFP64 histone lactylation to regulate ferroptosis.

KeJing Zhang, Lei Guo, Xin Li, Yu Hu, Na Luo.

   BACKGROUND: Cancer-associated fibroblasts (CAFs) have been identified to drive chemotherapy resistance in triple-negative breast cancer (TNBC). This study evaluated the functions of CAFs-mediated suppressive ferroptosis in doxorubicin (DOX) resistance in TNBC and its detailed molecular mechanisms.
METHODS: TNBC cell lines were co-cultured with CAFs isolated from DOX-sensitive (CAF/S) or DOX-resistant (CAF/R) breast cancer tissues. Cell viability and death were assessed by cell counting Kit-8 (CCK-8) and propidium iodide (PI) staining. Ferroptosis was evaluated by detection of Fe2+, malondialdehyde (MDA), glutathione (GSH), and lipid reactive oxygen species (ROS) levels. Histone lactylation was determined by lactate production, pan-Kla and H3K18la expression. Molecular mechanism was determined by chromatin immunoprecipitation (ChIP) and dual luciferase reporter system. Molecule and protein expression was detected by quantitative Real-Time PCR (RT-qPCR), Western blotting, immunofluorescence and immunohistochemical staining. TNBC cells were injected into the mammary fat pad of nude mice to investigate DOX sensitivity in vivo.
RESULTS: CAFs-derived lactate repressed ferroptosis to confer resistance of TNBC cells to DOX. Moreover, zinc finger protein 64 (ZFP64) expression was elevated in DOX-resistant TNBC and was associated with high histone lactylation level. CAFs facilitated histone lactylation to enhance ZFP64 expression, which triggered ferroptosis inhibition and DOX resistance. In addition, ZFP64 bound to the promoters of GTP cyclohydrolase-1 (GCH1) and ferritin heavy chain 1 (FTH1), thereby promoting their expression. Rescue experiments indicated that ZFP64 silencing-induced ferroptosis and high sensitivity of TNBC cells to DOX could be counteracted by GCH1 or FTH1 overexpression.
CONCLUSION: CAFs acted as a ferroptosis inhibitor to cause DOX resistance of TNBC via histone lactylation-mediated ZFP64 up-regulation and subsequent promotion of GCH1-induced lipid peroxidation inhibition and FTH1-induced intracellular Fe2+ consumption.

Keywords:  CAFs; DOX resistance; Ferroptosis; Histone lactylation; TNBC; ZFP64

DOI:  https://doi.org/10.1186/s12967-025-06246-3
Cancer Res. 2025 Mar 03.

De Novo Serine Synthesis is a Metabolic Vulnerability that can be Exploited to Overcome Sunitinib Resistance in Advanced Renal Cell Carcinoma.

Manon Teisseire, Umakant Sahu, Julien Parola, Meng-Chen Tsai, Valérie Vial, Jérôme Durivault, Renaud Grépin, Yann Cormerais, Clément Molina, Arthur Gouraud, Gilles Pagès, Issam Ben-Sahra, Sandy Giuliano.

Sunitinib is an oral tyrosine kinase inhibitor used in treating advanced renal cell carcinoma (RCC) that exhibits significant efficacy but faces resistance in 30% of patients. Identifying the molecular mechanisms underlying resistance could enable the development of strategies to enhance sunitinib sensitivity. Here, we showed that sunitinib induces a metabolic shift leading to increased serine synthesis in RCC cells. Activation of the GCN2-ATF4 stress response pathway was identified as the mechanistic link between sunitinib treatment and elevated serine production. The increased serine biosynthesis supported nucleotide synthesis and sustained cell proliferation, migration, and invasion following sunitinib treatment. Inhibiting key enzymes in the serine synthesis pathway, such as PHGDH and PSAT1, enhanced the sensitivity of resistant cells to sunitinib. Beyond RCC, similar activation of serine synthesis following sunitinib treatment occurred in a variety of other cancer types, suggesting a shared adaptive response to sunitinib therapy. Together, this study identifies the de novo serine synthesis pathway as a potential target to overcome sunitinib resistance, offering insights into therapeutic strategies applicable across diverse cancer contexts.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1393
Nat Commun. 2025 Mar 04. 16(1): 2191

A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer.

Guillaume P Andrieu, Mathieu Simonin, Aurélie Cabannes-Hamy, Etienne Lengliné, Ambroise Marçais, Alexandre Théron, Grégoire Huré, Jérome Doss, Ivan Nemazanyy, Marie Émilie Dourthe, Nicolas Boissel, Hervé Dombret, Philippe Rousselot, Olivier Hermine, Vahid Asnafi.

The deregulated activation of the phosphoinositide 3-kinase (PI3K) pathway is a hallmark of aggressive tumors with metabolic plasticity, eliciting their adaptation to the microenvironment and resistance to chemotherapy. A significant gap lies between the biological features of PI3K-driven tumors and the specific targeting of their vulnerabilities. Here, we explore the metabolic liabilities of PI3K-altered T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer with dismal outcomes. We report a metabolic crosstalk linking glutaminolysis and glycolysis driven by PI3K signaling alterations. Pharmaceutical inhibition of mTOR reveals the singular plasticity of PI3K-altered cells toward the mobilization of glutamine as a salvage pathway to ensure their survival. Subsequently, the combination of glutamine degradation and mTOR inhibition demonstrates robust cytotoxicity in PI3K-driven solid and hematological tumors in pre-clinical and clinical settings. We propose a novel therapeutic strategy to circumvent metabolic adaptation and efficiently target PI3K-driven cancer.

DOI: https://doi.org/10.1038/s41467-025-57225-7
J Adv Res. 2025 Feb 27. pii: S2090-1232(25)00132-8. [Epub ahead of print]

Long non-coding RNA LINC01532 sustains redox homeostasis and accelerates lenvatinib resistance in hepatocellular carcinoma.

Yang Hu, Muhua Chen, Shiqi Sun, Chunfeng Zhang, Zechang Xin, Xiaoyan Sun, Kun Wang, Kemin Jin, Xiaojuan Du, Baocai Xing, Xiaofeng Liu.

   INTRODUCTION: Lenvatinib is the first-line therapy of hepatocellular carcinoma (HCC) and the high frequency of lenvatinib resistance hinders the improvement of HCC treatment. Since NADPH plays vital roles in antioxidant defense and reductive biosynthesis, cancer cells exert NADPH metabolic adaptation to support their malignant activities, including drug resistance. However, the underlying mechanisms need to be further studied.
OBJECTIVES: This study aims to delineate the latent mechanism by which HCC cells modulate NADPH metabolic adaptation and lenvatinib resistance.
METHODS: Using high-throughput screening, we screened LINC01532 as a critical regulator in NADPH metabolic adaptation. The function of LINC01532 in drug resistance of HCC cells was analyzed by in vitro and in vivo model. NADPH assay, malondialdehyde (MDA) assay, and glutathione (GSH) detection assay were carried out to explore the role of LINC01532 in NADPH metabolism. Furthermore, RNA-binding protein immunoprecipitation, RNA pull-down assay, co-immunoprecipitation, and chromatin immunoprecipitation experiments were utilized to uncover the underlying mechanisms.
RESULTS: High expression of LINC01532 predicted poorer prognosis in HCC patients. LINC01532 stimulated NADPH production and blunted lenvatinib-induced cell death, leading to drug resistance. Mechanistically, LINC01532 bound to hnRNPK and promoted CDK2-mediated phosphorylation of hnRNPK, which facilitated G6PD pre-mRNA splicing, resulting in high expression of G6PD and upregulated NADPH synthesis. The elevated NADPH cleared reactive oxygen species (ROS), supported biomass synthesis, and epigenetically modulated gene expression. Inhibition of LINC01532 significantly enhanced lenvatinib sensitivity of HCC cells. The m6A modification induced by mTORC1 promoted the expression of LINC01532 in HCC cells.
CONCLUSION: Collectively, our findings demonstrate that LINC01532 confers lenvatinib resistance of HCC cells by modulating NADPH metabolic adaptation. LINC01532 might be a prognostic or therapeutic target for HCC.

Keywords:  Drug resistance; G6PD; Hepatocellular carcinoma; Long non-coding RNAs; NADPH

DOI:  https://doi.org/10.1016/j.jare.2025.02.035
Cancer Res. 2025 Mar 04.

Macrophage-Derived Itaconate Suppresses Dendritic Cell Function to Promote Acquired Resistance to Anti-PD-1 Immunotherapy.

Xiao Yang, Yue Deng, Ying Ye, Jingshu Meng, Mengyao Su, Wenwen Wei, You Qin, Haibo Zhang, Yu Tian, Suke Deng, Zhiyun Liao, Zhiyuan Zhou, Jie Li, Yan Hu, Bin Zhang, Yajie Sun, Lu Wen, Zhanjie Zhang, Fang Huang, Chao Wan, Kunyu Yang.

Adaptive resistance to immunotherapy remains a significant challenge in cancer treatment. The reshaping of the tumor immune microenvironment in response to therapeutic pressures is a crucial factor contributing to this resistance. Here, by comprehensive metabolic profiling of tumor tissues, we identified elevated itaconate in response to anti-PD-1 therapy as an adaptive resistance mechanism that promoted immune escape and tumor progression. CD8+ T-cell-derived interferon (IFN)-γ induced a significant upregulation of cis-aconitate decarboxylase 1 (ACOD1) in macrophages via the JAK-STAT1 pathway, thereby rewiring the Krebs cycle toward itaconate production. In murine models, macrophage-specific deletion of Acod1 increased the anti-tumor efficacy of anti-PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate (4-OI), suppressed the tumor antigen presentation and cross-priming ability of dendritic cells (DCs), resulting in the impairment of antigen-specific T-cell anti-tumor responses. In summary, these findings identify an IFN-γ-dependent immunometabolic mechanism of anti-PD-1 resistance, providing a promising strategy for combination therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2982
PLoS One. 2025 ;20(3): e0318267

Intracellular accumulation of free cholesterol in macrophages triggers a PARP1 response to DNA damage and PARP1 impairs lipopolysaccharide-induced inflammatory response.

Kenneth K Y Ting, Hisham M Ibrahim, Nitya Gulati, Yufeng Wang, Jonathan V Rocheleau, Myron I Cybulsky.

The formation of macrophage (Mφ) foam cells is a hallmark of atherosclerosis, yet how the process of lipid loading can modulate Mφ inflammatory responses by rewiring their intracellular metabolic circuits is not well understood. Our previous studies have shown that the accumulation of oxidized LDL (oxLDL) or free cholesterol in Mφs impaired their inflammatory response by suppressing HIF-1α-mediated glycolysis and upregulating NRF2 antioxidative response. However, it remains unclear if other metabolic processes are also contributory. In this study, we found that the accumulation of free cholesterol, but not oxLDL, in primary murine thioglycolate-elicited peritoneal Mφs (PMφs) enhanced a PARP1-dependent response associated with repair of DNA damage, which was characterized by poly ADP-ribosylation of proteins, phosphorylation of histone 2A.X and consumption of NAD + . Both oxLDL and cholesterol enhanced the PARP1 response after LPS stimulation. Treatment of PMφs with mitoTEMPO, a specific mitochondrial reactive oxygen species (mtROS) scavenger, alleviated mtROS during cholesterol loading, blocked the PARP1 response and partially restored LPS- induced inflammatory gene expression. In contrast to inhibition of PARP1 enzymatic activity, knockdown of PARP1 expression in RAW264.7 Mφs with siRNA elevated LPS-induced inflammatory gene expression. Overall, our study suggests that cholesterol accumulation triggers a PARP1 response to DNA damage in Mφs and that PARP1 inhibits LPS-mediated inflammation through a non-enzymatic function.

DOI: https://doi.org/10.1371/journal.pone.0318267
Redox Biol. 2025 Feb 25. pii: S2213-2317(25)00080-1. [Epub ahead of print]81 103567

Suppression of the LKB1-AMPK-SLC7A11-GSH signaling pathway sensitizes NSCLC to albumin-bound paclitaxel via oxidative stress.

Dade Rong, Liangliang Gao, Yiguan Chen, Xiang-Zheng Gao, Mingzhu Tang, Haimei Tang, Yuan Gao, Guang Lu, Zhi-Qiang Ling, Han-Ming Shen.

  Albumin-bound paclitaxel (nab-PTX) is an important chemotherapeutic drug used for the treatment of advanced and metastatic non-small cell lung cancer (NSCLC). One critical issue in its clinical application is the development of resistance; thus, a deeper understanding of the mechanisms underlying the primary resistance to nab-PTX is expected to help to develop effective therapeutic strategies to overcome resistance. In this study, we made an unexpected discovery that NSCLC with wild-type (WT) Liver kinase B1 (LKB1), an important tumor suppressor and upstream kinase of AMP-activated protein kinase (AMPK), is more resistant to nab-PTX than NSCLC with mutant LKB1. Mechanistically, LKB1 status does not alter the intracellular concentration of nab-PTX or affect its canonical pharmacological action in promoting microtubule polymerization. Instead, we found that LKB1 mediates AMPK activation, leading to increased expression of SLC7A11, a key amino acid transporter and intracellular level of glutathione (GSH), which then attenuates the production of reactive oxygen species (ROS) and apoptotic cell death induced by nab-PTX. On the other hand, genetic or pharmacological inhibition of AMPK in LKB1-WT NSCLC reduces the expression of SLC7A11 and intracellular GSH, increases ROS level, and eventually promotes the apoptotic cell death induced by nab-PTX in vitro. Consistently, the combination of nab-PTX with an AMPK inhibitor exhibits a greater therapeutic efficacy in LKB1-WT NSCLC using xenograft models in vivo. Taken together, our data reveal a novel role of LKB1-AMPK-SLC7A11-GSH signaling pathway in the primary resistance to nab-PTX, and provide a therapeutic strategy for the treatment of LKB1-WT NSCLC by targeting the LKB1-AMPK-SLC7A11-GSH pathway.

Keywords:  AMPK; Albumin-bound paclitaxel; LKB1; Non-small lung cancer; ROS; SLC7A11

DOI:  https://doi.org/10.1016/j.redox.2025.103567
Mol Cell Biochem. 2025 Mar 01.

SOX11 exacerbates ferroptosis to reduce lenvatinib resistance in liver cancer cells by promoting ubiquitination degradation of SREBF1 through upregulating UBE3A.

Zushun Chen, Lisong Ou, Liang Ma.

  Lenvatinib is one of the most commonly used first-line drugs for liver cancer. However, lenvatinib resistance occurs in a large proportion of patients, posing a significant challenge. Ferroptosis, an iron-dependent form of cell death, plays a pivotal role in overcoming drug resistance. This study investigates the role of SRY-related HMG-box transcription factor 11 (SOX11) in regulating lenvatinib resistance in liver cancer through its impact on ferroptosis. qRT-PCR, western blot, and immunohistochemistry were performed to examine the expression of key molecules in patient samples and cell lines. Functional studies, including cell viability and proliferation assays, colony formation assays, flow cytometry, and measurements of iron metabolism markers, were conducted to explore the biological effects of these molecules. Additionally, Co-IP, ChIP, dual-luciferase reporter assays, and in vivo tumorigenesis experiments were performed to uncover the underlying regulatory mechanisms. Our results showed that UBE3A was markedly downregulated in lenvatinib-resistant liver cancer tissues and cells, and its overexpression markedly reduced lenvatinib resistance in liver cancer cells by promoting ferroptosis. Mechanically, UBE3A reduced lenvatinib resistance in lenvatinib-resistant liver cancer cells by mediating ubiquitination-independent degradation of SREBF1. In addition, SOX11 upregulation reduced lenvatinib resistance in liver cancer cells by promoting ferroptosis through transcriptionally activated UBE3A expression. In summary, SOX11 upregulation promoted ferroptosis in liver cancer cells by promoting SREBF1 ubiquitination degradation through transcriptionally elevating UBE3A expression, thereby sensitizing lenvatinib-resistant liver cancer cells to lenvatinib.

Keywords:  Ferroptosis; Lenvatinib resistance; Liver cancer; SOX11; SREBF1; UBE3A

DOI:  https://doi.org/10.1007/s11010-025-05218-x
J Transl Med. 2025 Mar 05. 23(1): 275

IDO1 inhibition enhances CLDN18.2-CAR-T cell therapy in gastrointestinal cancers by overcoming kynurenine-mediated metabolic suppression in the tumor microenvironment.

Zhaorong Wu, Hongye Wang, Zhigang Zheng, Yan Lin, Linke Bian, Haigang Geng, Xiaorong Huang, Jiufei Zhu, Hongshu Jing, Yi Zhang, Chen Ji, Bo Zhai.

   BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies but faces significant limitations in gastrointestinal tumors due to the immunosuppressive tumor microenvironment (TME). Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the TME, suppresses T cell efficacy by catalyzing tryptophan degradation to kynurenine (Kyn), leading to T cell exhaustion and reduced cytotoxicity. This study investigates the role of IDO1 inhibition in overcoming metabolic suppression by kynurenine and enhancing Claudin18.2 (CLDN18.2) CAR-T cell therapy in gastric and pancreatic adenocarcinoma models.
METHODS: We evaluated the impact of genetic knockdown and pharmacological inhibition of IDO1 (using epacadostat) on CAR-T cell functionality, including cytokine production and exhaustion marker expression. The effects of fludarabine and cyclophosphamide preconditioning on IDO1 expression, CAR-T cell infiltration, and antitumor activity was also examined. In vivo tumor models of gastric and pancreatic adenocarcinomas were used to assess the efficacy of combining IDO1 inhibition with CLDN18.2-CAR-T therapy.
RESULTS: IDO1 inhibition significantly enhanced CAR-T cell function by increasing cytokine production, reducing exhaustion markers by decreasing TOX expression and improving tumor cell lysis. Preconditioning with fludarabine and cyclophosphamide further suppressed IDO1 expression in the TME, facilitating enhanced CAR-T cell infiltration. In vivo studies demonstrated that combining IDO1 inhibition with CAR-T therapy led to robust tumor growth suppression and prolonged survival in gastric and pancreatic tumor models.
CONCLUSIONS: Targeting IDO1 represents a promising strategy to overcome immunosuppressive barriers in gastrointestinal cancers, improving the efficacy of CLDN18.2-CAR-T therapy. These findings highlight the potential for integrating IDO1 inhibition into CAR-T treatment regimens to address resistance in treatment-refractory cancers.

Keywords:  Chimeric antigen receptor T cell therapy (CAR-T); Gastrointestinal cancer; Indoleamine 2,3-dioxygenase 1; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s12967-025-06276-x
Nat Cell Biol. 2025 Mar 03.

PRMT5-mediated arginine methylation stabilizes GPX4 to suppress ferroptosis in cancer.

Yizeng Fan, Yuzhao Wang, Weichao Dan, Yilei Zhang, Li Nie, Zhiqiang Ma, Yanxin Zhuang, Bo Liu, Mengxing Li, Tianjie Liu, Zixi Wang, Leihong Ye, Yi Wei, Yuzeshi Lei, Chendong Guo, Jiale An, Chi Wang, Yulin Zhang, Jin Zeng, Wenyi Wei, Boyi Gan, Lei Li.

The activation of ferroptosis has shown great potential for cancer therapy from an unconventional perspective, but revealing the mechanisms underlying the suppression of tumour-intrinsic ferroptosis to promote tumorigenesis remains a challenging task. Here we report that methionine is metabolized into S-adenosylmethionine, which functions as a methyl-group donor to trigger symmetric dimethylation of glutathione peroxidase 4 (GPX4) at the conserved arginine 152 (R152) residue, along with a prolonged GPX4 half-life. Inhibition of protein arginine methyltransferase 5 (PRMT5), which catalyses GPX4 methylation, decreases GPX4 protein levels by impeding GPX4 methylation and increasing ferroptosis inducer sensitivity in vitro and in vivo. This methylation prevents Cullin1-FBW7 E3 ligase binding to GPX4, thereby abrogating the ubiquitination-mediated GPX4 degradation. Notably, combining PRMT5 inhibitor treatment with ferroptotic therapies markedly suppresses tumour progression in mouse tumour models. In addition, the levels of GPX4 are negatively correlated with the levels of FBW7 and a poor prognosis in patients with human carcinoma. In summary, we found that PRMT5 functions as a target for improving cancer therapy efficacy, by acting to reduce the counteraction of ferroptosis by tumour cells by means of PRMT5-enhanced GPX4 stability.

DOI: https://doi.org/10.1038/s41556-025-01610-3
Nat Commun. 2025 Mar 04. 16(1): 2184

Methionine metabolite spermidine inhibits tumor pyroptosis by enhancing MYO6-mediated endocytosis.

Jiawei Wu, Cong Ding, Chuqing Zhang, Zhimin Xu, Zhenji Deng, Hanmiao Wei, Tingxiang He, Liufen Long, Linglong Tang, Jun Ma, Xiaoyu Liang.

The connection between amino acid metabolism and pyroptosis remains elusive. Herein, we screen the effect of individual amino acid on pyroptosis and identify that methionine inhibits GSDME-mediated pyroptosis. Mechanistic analyses unveil that MYO6, a unique actin-based motor protein, bridges the GSDME N-terminus (GSDME-NT) and the endocytic adaptor AP2, mediating endolysosomal degradation of GSDME-NT. This degradation is increased by the methionine-derived metabolite spermidine noncanonically by direct binding to MYO6, which enhances MYO6 selectivity for GSDME-NT. Moreover, combination targeted therapies using dietary or pharmacological inhibition in methionine-to-spermidine metabolism in the tumor promotes pyroptosis and anti-tumor immunity, leading to a stronger tumor-suppressive effect in in vivo models. Clinically, higher levels of tumor spermidine and expression of methionine-to-spermidine metabolism-related gene signature predict poorer survival. Conclusively, our research identifies an unrecognized mechanism of pyroptotic resistance mediated by methionine-spermidine metabolic axis, providing a fresh angle for cancer treatment.

DOI: https://doi.org/10.1038/s41467-025-57511-4
Cell Rep. 2025 Mar 06. pii: S2211-1247(25)00146-9. [Epub ahead of print]44(3): 115375

iMetAct: An integrated systematic inference of metabolic activity for dissecting tumor metabolic preference and tumor-immune microenvironment.

Binxian Wang, Chao Huang, Xuan Liu, Zhenni Liu, Yilei Zhang, Wei Zhao, Qiuran Xu, Ping-Chih Ho, Zhengtao Xiao.

  Metabolic enzymes play a central role in cancer metabolic reprogramming, and their dysregulation creates vulnerabilities that can be exploited for therapy. However, accurately measuring metabolic enzyme activity in a high-throughput manner remains challenging due to the complex, multi-layered regulatory mechanisms involved. Here, we present iMetAct, a framework that integrates metabolic-transcription networks with an information propagation strategy to infer enzyme activity from gene expression data. iMetAct outperforms expression-based methods in predicting metabolite conversion rates by accounting for the effects of post-translational modifications. With iMetAct, we identify clinically significant subtypes of hepatocellular carcinoma with distinct metabolic preferences driven by dysregulated enzymes and metabolic regulators acting at both the transcriptional and non-transcriptional levels. Moreover, applying iMetAct to single-cell RNA sequencing data allows for the exploration of cancer cell metabolism and its interplay with immune regulation in the tumor microenvironment. An accompanying online platform further facilitates tumor metabolic analysis, patient stratification, and immune microenvironment characterization.

Keywords:  CP: Cancer; CP: Metabolism; hepatocellular carcinoma; information propagation; metabolic enzyme activity; tumor stratification; tumor-immune microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2025.115375