bims-meract 2025-05-11 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–05–11
twenty papers selected by
Andrea Morandi, Università degli Studi di Firenze

Glycolytic enzyme PFKFB4 governs lipolysis by promoting de novo lipogenesis to drive the progression of hepatocellular carcinoma.
Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice.
MiR-22/GLUT1 Axis Induces Metabolic Reprogramming and Sorafenib Resistance in Hepatocellular Carcinoma.
Metabolic reprogramming of tumor-associated neutrophils in tumor treatment and therapeutic resistance.
The oncoprotein SET promotes serine-derived one-carbon metabolism by regulating SHMT2 enzymatic activity.
m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability.
Inhalable biomimetic polyunsaturated fatty acid-based nanoreactors for peroxynitrite-augmented ferroptosis potentiate radiotherapy in lung cancer.
GPX1 confers resistance to metabolic stress in BCR/ABL-T315I mutant chronic myeloid leukemia cells.
The anti-diabetic PPARγ agonist Pioglitazone inhibits cell proliferation and induces metabolic reprogramming in prostate cancer.
Deacetylation of ANXA2 by SIRT2 desensitizes hepatocellular carcinoma cells to donafenib via promoting protective autophagy.
Targeting PSMD14 combined with arachidonic acid induces synthetic lethality via FADS1 m6A modification in triple-negative breast cancer.
OTUD4 inhibits ferroptosis by stabilizing GPX4 and suppressing autophagic degradation to promote tumor progression.
Lipid-degrading small molecule kills cancer cells by ferroptosis.
(R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation.
Inhibition of ABCG2 by SCO-101 Enhances Chemotherapy Efficacy in Cancer.
NADK tetramer defective mutants affect lung cancer response to chemotherapy via controlling NADK activity.
SIRT2-mediated ACSS2 K271 deacetylation suppresses lipogenesis under nutrient stress.
Iron overload enhances the susceptibility to cysteine deprivation-induced ferroptosis in non-small cell lung cancer cells.
Palmitoylation prevents B7-H4 lysosomal degradation sustaining tumor immune evasion.
Defects in the necroptosis machinery are a cancer resistance mechanism to checkpoint inhibitor immunotherapy.

Cancer Lett. 2025 May 06. pii: S0304-3835(25)00340-4. [Epub ahead of print] 217774

Glycolytic enzyme PFKFB4 governs lipolysis by promoting de novo lipogenesis to drive the progression of hepatocellular carcinoma.

Shuo Zhou, Yao Liu, Ning Zhang, Linmao Sun, Changyong Ji, Tianming Cui, Qi Chu, Shugeng Zhang, Jiabei Wang, Lianxin Liu.

  Hepatocellular carcinoma (HCC) is among the most aggressive malignancies, marked by high recurrence rates and limited treatment efficacy, especially in HBV-associated HCC (HBV-HCC). This subtype exhibits pronounced metabolic reprogramming, with lipid synthesis playing a pivotal role in driving tumor aggressiveness and therapeutic resistance. However, the molecular mechanisms underlying this metabolic shift remain unclear. In our study, analysis of the LIHC-TCGA database and comparisons between HCC tissues and adjacent peri-tumoral tissues revealed that 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is significantly upregulated in HBV-HCC. Moreover, elevated PFKFB4 expression correlates with poorer prognosis and unfavorable overall survival among HBV-HCC patients. Functional assays demonstrated that PFKFB4 promotes HCC proliferation by enhancing glycolysis and de novo lipid synthesis. Notably, PFKFB4 not only increases glycolytic flux but also upregulates sterol regulatory element-binding protein 1 (SREBP1) expression via its enzymatic activity. Mechanistically, PFKFB4 suppresses phosphorylated AMP-activated protein kinase (p-AMPK) through enhanced aerobic glycolysis, which in turn stimulates the level of SREBP1. Collectively, these findings position PFKFB4 as a critical mediator of metabolic reprogramming in HBV-HCC and a promising therapeutic target.

Keywords:  Hepatocellular carcinoma; PFKFB4; glycolysis; lipid de novo synthesis

DOI:  https://doi.org/10.1016/j.canlet.2025.217774
Nat Commun. 2025 May 08. 16(1): 4292

Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice.

Omri Yosef, Leonor Cohen-Daniel, Oded Shamriz, Zahala Bar-On, Wajeeh Salaymeh, Amijai Saragovi, Ifat Abramovich, Bella Agranovich, Veronika Lutz, Joseph Tam, Anna Permyakova, Eyal Gottlieb, Magdalena Huber, Michael Berger.

T cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT in wild-type T cells recapitulates the Ant2-/- phenotype and improves adoptive T cell therapy of cancer in mouse models. Our findings thus suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T cell function and highlighting the therapeutic potential of targeting ANT for immune modulation.

DOI: https://doi.org/10.1038/s41467-025-59310-3
Int J Mol Sci. 2025 Apr 17. pii: 3808. [Epub ahead of print]26(8):

MiR-22/GLUT1 Axis Induces Metabolic Reprogramming and Sorafenib Resistance in Hepatocellular Carcinoma.

Ilaria Leoni, Giuseppe Galvani, Elisa Monti, Clara Vianello, Francesca Valenti, Luca Pincigher, Ambra A Grolla, Marianna Moro, Camelia A Coada, Alessandro Perrone, Valeria Righi, Sara Marinelli, Gloria Ravegnini, Catia Giovannini, Maurizio Baldassarre, Milena Pariali, Matteo Ravaioli, Matteo Cescon, Francesco Vasuri, Marco Domenicali, Massimo Negrini, Fabio Piscaglia, Romana Fato, Claudio Stefanelli, Laura Gramantieri, Christian Bergamini, Francesca Fornari.

  The approval of immunotherapy has revolutionized the management of hepatocellular carcinoma (HCC) patients. However, sorafenib remains a first-line therapeutic option for advanced patients and, in particular, for patients not eligible for immune checkpoint inhibitors, but its efficacy is limited by the onset of acquired resistance, highlighting the urgent need for predictive biomarkers. This study investigates the role of miR-22 in metabolic reprogramming and its potential as a biomarker in HCC. The analysis of miR-22 expression was performed in HCC patients and preclinical models by qPCR. Functional analyses in HCC cells evaluated GLUT1 as a direct miR-22 target. Cellular and metabolic assays evaluated the miR-22/GLUT1 axis's role in metabolic changes, tumor aggressiveness, and sorafenib response. Circulating miR-22 was analyzed in sorafenib-treated HCC patients and rats. MiR-22 was downregulated in HCCs and associated with aggressive tumor features. Functionally, miR-22 modulated the HIF1A pathway, enhanced survival in stressful conditions, promoted a glycolytic shift, and enhanced cancer cell plasticity and sorafenib resistance via GLUT1 targeting. In addition, high serum miR-22 levels were associated with sorafenib resistance in HCC patients and rats. GLUT1 inhibition sensitized low miR-22-expressing HCC cells to sorafenib in preclinical models. These findings suggest that circulating miR-22 deserves attention as a predictive biomarker of sorafenib response. GLUT1 inhibition may represent a therapeutic strategy to combine with sorafenib, particularly in patients exhibiting high circulating miR-22 levels.

Keywords:  GLUT1; HCC; miR-22; sorafenib

DOI:  https://doi.org/10.3390/ijms26083808
Front Cell Dev Biol. 2025 ;13 1584987

Metabolic reprogramming of tumor-associated neutrophils in tumor treatment and therapeutic resistance.

Jun Lin, Xian-Lu He, Wei-Wei Zhang, Chun-Fen Mo.

  Tumor-associated neutrophils (TANs), pivotal immune cells within the tumor microenvironment (TME), exhibit dual potential in both pro- and anti-tumorigenic effects. These cells display remarkable heterogeneity and plasticity within the TME, adapting to hypoxic and nutrient-deprived conditions through metabolic reprogramming while critically influencing tumor progression, metastasis, and immune evasion. The metabolic reprogramming of TANs not only modulates their functional phenotypes but also reshapes tumor biological behaviors and therapeutic responses by regulating metabolic intermediates and cellular interactions within the TME. Therefore, elucidating the mechanisms underlying TANs metabolic reprogramming has significant implications for deciphering the molecular basis of tumorigenesis, identifying novel therapeutic targets, and optimizing immunotherapeutic strategies. This review systematically summarizes current knowledge regarding metabolic reprogramming mechanisms of TANs in the TME and their impact on tumor progression. We particularly focus on: 1) TAN-specific alterations in glucose, lipid, and amino acid metabolism within the TME; 2) Emerging immunotherapeutic strategies targeting TANs metabolic pathways; 3) Recent advances in understanding TAN-mediated immune evasion and therapy resistance. Furthermore, this review discusses potential challenges and corresponding solutions in targeting TANs metabolic reprogramming for therapeutic intervention, aiming to provide novel insights for advancing cancer immunotherapy.

Keywords:  immunotherapy; metabolic reprogramming; therapeutic resistance; tumor microenvironment; tumor-associated neutrophils

DOI:  https://doi.org/10.3389/fcell.2025.1584987
Proc Natl Acad Sci U S A. 2025 May 13. 122(19): e2412854122

The oncoprotein SET promotes serine-derived one-carbon metabolism by regulating SHMT2 enzymatic activity.

Zishan Jiao, Mi Zhang, Jingyuan Ning, Han Yao, Xiaojun Yan, Zhen Wu, Dexuan Wu, Yajing Liu, Meng Zhang, Lin Wang, Donglai Wang.

  Cancer cells frequently reprogram one-carbon metabolic pathways to fulfill their vigorous demands of biosynthesis and antioxidant defense for survival and proliferation. Dysfunction of oncogenes or tumor suppressor genes is critically involved in this process, but the precise mechanisms by which cancer cells actively trigger one-carbon metabolic alterations remain incompletely elucidated. Here, by using untargeted metabolomic analysis, we identify the oncoprotein SE translocation (SET) as a key regulator of one-carbon metabolism in cancer cells. SET physically interacts with mitochondrial SHMT2 and facilitates SHMT2 enzymatic activity. Loss of SET profoundly suppresses serine-derived one-carbon metabolic flux, whereas reexpression of ectopic SET leads to the opposite effect. Notably, although the presence of SHMT2 is critical for SET-mediated one-carbon metabolic alterations, the depletion of SHMT2 alone is insufficient to antagonize SET-induced tumor growth, probably due to functional compensation by its cytosolic isozyme SHMT1 upon SHMT2 knockdown. Instead, pharmacological targeting of cellular SHMT (including both SHMT1 and SHMT2) activity results in dramatic suppression of SET-induced tumor growth. Moreover, by using a Kras/Lkb1 mutation-driven lung tumor mouse model, we demonstrate that the loss of SET compromises both tumor formation and intratumoral SHMT2 enzymatic activity. Clinically, the overexpression of SET and SHMT2 is observed in lung tumors, both of which correlate with poor prognosis. Our study reveals a SET-SHMT2 axis in regulating serine-derived one-carbon metabolism and uncovers one-carbon metabolic reprogramming as a mechanism for SET-driven tumorigenesis.

Keywords:  SET; SHMT2; enzymatic activity; one-carbon metabolism; tumor

DOI:  https://doi.org/10.1073/pnas.2412854122
Nat Commun. 2025 May 06. 16(1): 4214

m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability.

Feng Huang, Yushuai Wang, Xiuxin Zhang, Weiwei Gao, Jingwen Li, Ying Yang, Hongjie Mo, Emily Prince, Yifei Long, Jiacheng Hu, Chuang Jiang, Yalin Kang, Zhenhua Chen, Yueh-Chiang Hu, Chengwu Zeng, Lu Yang, Chun-Wei Chen, Jianjun Chen, Huilin Huang, Hengyou Weng.

Metabolic reprogramming of amino acids represents a vulnerability in cancer cells, yet the mechanisms underlying serine metabolism in acute myeloid leukemia (AML) and leukemia stem/initiating cells (LSCs/LICs) remain unclear. Here, we identify RNA N6-methyladenosine (m6A) modification as a key regulator of serine biosynthesis in AML. Using a CRISPR/Cas9 screen, we find that depletion of m6A regulators IGF2BP3 or METTL14 sensitizes AML cells to serine and glycine (SG) deprivation. IGF2BP3 recognizies m6A on mRNAs of key serine synthesis pathway (SSP) genes (e.g., ATF4, PHGDH, PSAT1), stabilizing these transcripts and sustaining serine production to meet the high metabolic demand of AML cells and LSCs/LICs. IGF2BP3 silencing combined with dietary SG restriction potently inhibits AML in vitro and in vivo, while its deletion spares normal hematopoiesis. Our findings reveal the critical role of m6A modification in the serine metabolic vulnerability of AML and highlight the IGF2BP3/m6A/SSP axis as a promising therapeutic target.

DOI: https://doi.org/10.1038/s41467-025-58966-1
J Nanobiotechnology. 2025 May 08. 23(1): 338

Inhalable biomimetic polyunsaturated fatty acid-based nanoreactors for peroxynitrite-augmented ferroptosis potentiate radiotherapy in lung cancer.

Yiting Chen, Xueli Huang, Ruining Hu, Enhao Lu, Kuankuan Luo, Xin Yan, Zhiwen Zhang, Yan Ma, Minghe Zhang, Xianyi Sha.

  The limited efficacy and poor tumor accumulation remain crucial challenges for radiotherapy against lung cancer. To address these limitations, we rationally developed a polyunsaturated fatty acid (PUFA)-based nanoreactor (DHA-N@M) camouflaged with macrophage cell membrane to improve tumoral distribution and achieve peroxynitrite-augment ferroptosis for enhanced radiotherapy against lung cancer. After nebulization, the nanoreactors exhibited superior pulmonary accumulation in orthotopic lung cancer-bearing mice, with 70-fold higher than intravenously injected nanoreactors at 12 h post-administration, and distributed deeply in the tumors. DHA-N@M selectively released nitric oxide (NO) in glutathione (GSH)-enriched tumor cells, with consumption of GSH and subsequent inactivation of glutathione peroxidase 4 (GPX4). Under radiation, NO reacted with radiotherapy-induced reactive oxygen species (ROS) to generate peroxynitrite (ONOO-), resulting in redox homeostasis disruption. Combined with docosahexaenoic acid (DHA)-induced lipid metabolism disruption, overwhelming ferroptosis was induced both in vitro and in vivo. Notably, DHA-N@M mediated ferroptosis-radiotherapy significantly suppressed tumor growth with a 93.91% inhibition in orthotopic lung cancer models. Therefore, this design provides a nebulized ferroptosis-radiotherapy strategy for lung cancer.

Keywords:  Ferroptosis; Inhalation; Lung cancer; Nanoreactor; Radiotherapy

DOI:  https://doi.org/10.1186/s12951-025-03409-8
Cell Death Discov. 2025 May 09. 11(1): 229

GPX1 confers resistance to metabolic stress in BCR/ABL-T315I mutant chronic myeloid leukemia cells.

Jun-Dan Wang, Jin-Xing Wang, Zhi-Li Lin, Na Xu, Ling Zhang, Jia-Jun Liu, Rui Gao, Zi-Jie Long.

Chronic myeloid leukemia (CML) harboring BCR/ABL-T315I mutation has been a challenging obstacle for targeted therapy due to the acquired resistance to tyrosine kinase inhibitor (TKI)-based therapy. Thus, it is especially urgent to investigate more effective therapeutic targets to overcome T315I-induced resistance. Here, we reported that BCR/ABL-T315I mutant CML cells possessed a long-term proliferative capacity and tolerance to metabolic stress. Importantly, we also found that selenoamino acid metabolism was increased in the bone marrows of BCR/ABL-T315I patients compared with non-T315I patients by GSEA from RNA-Seq data. Indeed, GPX1 was highly expressed in T315I mutant cells, while knockout of GPX1 significantly suppressed cell proliferation and triggered apoptosis under glucose-deprived condition. GPX1 knockout showed decreased cell metabolism signaling as well as mitochondrial gene expression by RNA-Seq. Mechanistically, GPX1 maintained mitochondrial activity and oxygen consumption rate (OCR), retaining mitochondrial redox homeostasis and oxidative phosphorylation (OXPHOS). Additionally, mercaptosuccinic acid (MSA), a GPX inhibitor, inhibited CML colony formation and induced cell apoptosis under glucose-free condition. Therefore, GPX1 is a promising therapeutic target to overcome drug resistance induced by the T315I mutation, which provides a novel approach for BCR/ABL-T315I CML treatment by disturbing mitochondrial OXPHOS.

DOI: https://doi.org/10.1038/s41420-025-02502-z
Mol Cancer. 2025 May 05. 24(1): 134

The anti-diabetic PPARγ agonist Pioglitazone inhibits cell proliferation and induces metabolic reprogramming in prostate cancer.

Emine Atas, Kerstin Berchtold, Michaela Schlederer, Sophie Prodinger, Felix Sternberg, Perla Pucci, Christopher Steel, Jamie D Matthews, Emily R James, Cécile Philippe, Karolína Trachtová, Ali A Moazzami, Nastasiia Artamonova, Felix Melchior, Torben Redmer, Gerald Timelthaler, Elena E Pohl, Suzanne D Turner, Isabel Heidegger, Marcus Krueger, Ulrike Resch, Lukas Kenner.

  Prostate cancer (PCa) and Type 2 diabetes (T2D) often co-occur, yet their relationship remains elusive. While some studies suggest that T2D lowers PCa risk, others report conflicting data. This study investigates the effects of peroxisome proliferator-activated receptor (PPAR) agonists Bezafibrate, Tesaglitazar, and Pioglitazone on PCa tumorigenesis. Analysis of patient datasets revealed that high PPARG expression correlates with advanced PCa and poor survival. The PPARγ agonists Pioglitazone and Tesaglitazar notably reduced cell proliferation and PPARγ protein levels in primary and metastatic PCa-derived cells. Proteomic analysis identified intrinsic differences in mTORC1 and mitochondrial fatty acid oxidation (FAO) pathways between primary and metastatic PCa cells, which were further disrupted by Tesaglitazar and Pioglitazone. Moreover, metabolomics, Seahorse Assay-based metabolic profiling, and radiotracer uptake assays revealed that Pioglitazone shifted primary PCa cells' metabolism towards glycolysis and increased FAO in metastatic cells, reducing mitochondrial ATP production. Furthermore, Pioglitazone suppressed cell migration in primary and metastatic PCa cells and induced the epithelial marker E-Cadherin in primary PCa cells. In vivo, Pioglitazone reduced tumor growth in a metastatic PC3 xenograft model, increased phosho AMPKα and decreased phospho mTOR levels. In addition, diabetic PCa patients treated with PPAR agonists post-radical prostatectomy implied no biochemical recurrence over five to ten years compared to non-diabetic PCa patients. Our findings suggest that Pioglitazone reduces PCa cell proliferation and induces metabolic and epithelial changes, highlighting the potential of repurposing metabolic drugs for PCa therapy.

Keywords:  Cancer therapy; Energy metabolism; Extracellular acidification; Metabolic rewiring; Oxygen consumption rate; PPAR agonists; Type 2 diabetes mellitus (T2DM)

DOI:  https://doi.org/10.1186/s12943-025-02320-y
Cell Death Differ. 2025 May 03.

Deacetylation of ANXA2 by SIRT2 desensitizes hepatocellular carcinoma cells to donafenib via promoting protective autophagy.

Liangbo Sun, Meng He, Dong Liu, Meihua Shan, Lingxi Chen, Mingzhen Yang, Xufang Dai, Jie Yao, Tao Li, Yan Zhang, Yang Zhang, Li Xiang, An Chen, Yingxue Hao, Fengtian He, Haojun Xiong, Jiqin Lian.

Hepatocellular carcinoma (HCC) is one of the most lethal forms of cancer globally. HCC cells frequently undergo macroautophagy, also known as autophagy, which can lead to tumor progression and chemotherapy resistance. Annexin A2 (ANXA2) has been identified as a potential therapeutic target in HCC and is involved in the regulation of autophagic process. Here, we for the first time showed that ANXA2 deacetylation plays a crucial role in donafenib-induced autophagy. Mechanistically, donafenib increased SIRT2 activity via triggering both SIRT2 dephosphorylation and deacetylation by respectively downregulating cyclin E/CDK and p300. Moreover, elevation of SIRT2 activity by donafenib caused ANXA2 deacetylation at K81/K206 sites, leading to a reduction of the binding between ANXA2 and mTOR, which resulted in a decrease of mTOR phosphorylation and activity, and ultimately promoted protective autophagy and donafenib insensitivity in HCC cells. Additionally, ANXA2 deacetylation at K81/K206 sites was positively correlated with poor prognosis in HCC patients. Meanwhile, we found that selective inhibition of SIRT2 increased the sensitivity of donafenib in HCC cells by strengthening ANXA2 acetylation. In summary, this study reveals that donafenib induces protective autophagy and decreases its sensitivity in HCC cells through enhancing SIRT2-mediated ANXA2 deacetylation, which suggest that targeting ANXA2 acetylation/deacetylation may be a promising strategy for improving the sensitivity of donafenib in HCC treatment.

DOI: https://doi.org/10.1038/s41418-025-01499-3
Sci Adv. 2025 May 09. 11(19): eadr3173

Targeting PSMD14 combined with arachidonic acid induces synthetic lethality via FADS1 m6A modification in triple-negative breast cancer.

Yuanhang Yu, Jin Hu, Wenwen Wang, Hao Lei, Zihan Xi, Peiyi Zhang, Ende Zhao, Chong Lu, Hengyu Chen, Chunping Liu, Lei Li.

Dysregulation of deubiquitination is essential for cancer growth. However, the role of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) in the progression of triple-negative breast cancer (TNBC) remains to be determined. Gain- and loss-of-function experiments showed that silencing PSMD14 notably attenuated the growth, invasion, and metastasis of TNBC cells in vitro and in vivo. Overexpression of PSMD14 produced the opposite results. Mechanistically, PSMD14 decreased K63-linked ubiquitination on SF3B4 protein to de-ubiquitin and stabilize SF3B4 protein. Then, SF3B4/HNRNPC complex bound to FADS1 mRNA and promoted exon inclusion in the target mRNA through m6A site on FADS1 mRNA recognized by HNRNPC, thereby up-regulating the expression of FADS1 and activating Akt/mTOR signaling. Exogenous arachidonic acid supplementation combined with PSMD14 knockdown induced synthetic lethality, which was further confirmed in TNBC organoid (PDO) and TNBC patient-derived xenograft (PDX) mouse models. Overall, our findings reveal an oncogenic role of PSMD14 in TNBC progression, which indicates a potential biomarker and ferroptosis-mediated therapeutic strategy for TNBC.

DOI: https://doi.org/10.1126/sciadv.adr3173
Cell Rep. 2025 May 06. pii: S2211-1247(25)00452-8. [Epub ahead of print]44(5): 115681

OTUD4 inhibits ferroptosis by stabilizing GPX4 and suppressing autophagic degradation to promote tumor progression.

Jinglian Chen, Chengqing Huang, Jiale Mei, Qiuhua Lin, Wenbo Chen, Jiali Tang, Xinjie Wei, Caixia Mo, Yueyan Zhang, Qi Zeng, Xianwei Mo, Weizhong Tang, Tao Luo.

  Ferroptosis, a regulated cell demise predicated on iron metabolism and lipid peroxidation, has increasingly become a focal point in oncological therapies. Nonetheless, its governance, particularly the role of deubiquitination, is not fully delineated. This investigation concentrates on the deubiquitinase OTUD4, scrutinizing its functional and molecular implications in ferroptosis within tumor cells. By engineering OTUD4 knockout cell lines via CRISPR-Cas9, we observed that these cells exhibit heightened sensitivity to ferroptosis inducers, augmenting ferroptotic cell death and robustly diminishing tumor growth both in vitro and in vivo. Mechanistically, OTUD4 not only sustains protein stability by directly deubiquitinating GPX4 but also impedes its degradation via RHEB-mediated autophagy, collectively stalling the ferroptosis pathway. In vivo assays substantiate that OTUD4 deletion, when combined with regorafenib, drastically reduces tumor proliferation, showcasing potent synergistic antitumor activity. This study pioneers the revelation of OTUD4's bifunctional role in modulating ferroptosis through deubiquitination and autophagy, underscoring its potential as a therapeutic target in oncology.

Keywords:  CP: Cancer; CP: Molecular biology; GPX4; OTUD4; autophagy; ferroptosis; tumor

DOI:  https://doi.org/10.1016/j.celrep.2025.115681
Nature. 2025 May 07.

Lipid-degrading small molecule kills cancer cells by ferroptosis.

Mike Lange, James A Olzmann.



Keywords:  Cancer; Cell biology

DOI:  https://doi.org/10.1038/d41586-025-01337-z
Sci Rep. 2025 May 08. 15(1): 16018

(R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation.

Hiroshi Ureshino, Taichi Ueshima, Tomonori Yamaguchi, Miyuki Takashima, Yusuke Sanuki, Tatsuo Ichinohe.

  Hypomethylating agents combined with venetoclax (VEN), a BCL-2 inhibitor, represent a standard treatment strategy for patients with acute myeloid leukemia (AML). Although this combination is highly effective, acquired resistance commonly occurs. MCL-1, a BCL-2 family molecule, is frequently upregulated in VEN-resistant cells, playing a major role in VEN resistance. Previously, we demonstrated that (R)-WAC-224 is effective against AML with minimal cardiac toxicity. (R)-WAC-224 combined with VEN demonstrated strong antileukemia effects on VEN-resistant AML cells overexpressing MCL-1 in vitro. Gene expression profiles revealed that (R)-WAC-224 with VEN induced DNA damage pathways leading to cell apoptosis. (R)-WAC-224 elicited caspase 3 activation, which cleaved MCL-1; this effect was reversed by a caspase inhibitor, thus overcoming VEN resistance. A combination of azacitidine (AZA), a hypomethylating agent, VEN, and (R)-WAC-224 was highly effective against VEN-resistant AML in vivo without increasing toxicity. (R)-WAC-224 exhibited antileukemia effects on VEN-resistant AML via MCL-1 downregulation in vitro and in vivo. The combination of AZA, VEN, and (R)-WAC-224 may be a promising treatment strategy for patients with AML.

Keywords:  (R)-WAC-224; Acute myeloid leukemia; Anticancer quinolone; MCL-1; Venetoclax

DOI:  https://doi.org/10.1038/s41598-025-98534-7
Int J Mol Sci. 2025 Apr 17. pii: 3790. [Epub ahead of print]26(8):

Inhibition of ABCG2 by SCO-101 Enhances Chemotherapy Efficacy in Cancer.

Anamarija Pfeiffer, Luca Di Leo, Marc Baker Bechmann, Mubeen Nawabi, Sophie Ambjørner, Diba Ardeshir-Larijani, Louise Thybo Colstrup, Signe Vedel Borchert, Lasse Saaby, Birger Brodin, Michael Gajhede, Xamuel Loft Lund, Martina Čečková, Nils Brünner, Jan Stenvang.

  Chemotherapy resistance, particularly multidrug resistance (MDR), remains a significant barrier to effective cancer treatment, leading to high mortality rates. The development of novel therapeutic strategies targeting key molecular mechanisms to counteract drug resistance is thus an urgent clinical need. In this study, we evaluated the potential of the small molecule SCO-101 to restore chemotherapy sensitivity in drug-resistant cancer cells. Using in silico and in vitro models such as molecular docking, cell viability, colony formation, dye efflux, transporter assays and chemotherapy retention, we assessed the impact of SCO-101 on drug retention and response in several drug-resistant cancer cells. SCO-101 was found to inhibit the activity of breast cancer resistance protein (BCRP/ABCG2) and UDP Glucuronosyltransferase Family 1 Member A1 (UGT1A1), two key proteins involved in drug resistance by cellular drug excretion and drug metabolism. Our results demonstrate that inhibition of these proteins by SCO-101 leads to increased intracellular drug accumulation, enhancing the cytotoxic effects of chemotherapy agents. Additionally, we identified a strong correlation between high ABCG2 expression and MDR in non-drug-resistant models, where cells exhibiting elevated ABCG2 levels displayed chemotherapy resistance, which was effectively reversed by SCO-101 co-treatment. These findings highlight the therapeutic potential of SCO-101 in overcoming MDR by inhibiting drug efflux mechanisms and metabolism, thereby enhancing chemotherapy efficacy. SCO-101 is currently undergoing clinical trials as an orally administered drug and is considered a promising strategy for improving cancer treatment outcomes in patients with drug-resistant tumors.

Keywords:  ABCG2; BCRP; SCO-101; UGT1A1; cancer multidrug resistance

DOI:  https://doi.org/10.3390/ijms26083790
Genes Dis. 2025 Jul;12(4): 101510

NADK tetramer defective mutants affect lung cancer response to chemotherapy via controlling NADK activity.

Mengxue Hu, Fuxing Wang, Yue Zhu, Yi Yao, Huadong Pei, Zheng Liu, Pingfeng Zhang.

  Nicotinamide adenine dinucleotide (NAD+) kinase (NADK) phosphorylates NAD+ to generate NADP+, which plays a crucial role in maintaining NAD+/NADP+ homeostasis, cellular redox balance, and metabolism. However, how human NADK activity is regulated, and how dysregulation or mutation of NADK is linked to human diseases, such as cancers, are still not fully understood. Here, we present a cryo-EM structure of human tetrameric NADK and elaborate on the necessity of the NADK tetramer for its activity. The N-terminal region of human NADK, which does not exist in bacterial NADKs, modulates tetramer conformation, thereby regulating its activity. A methylation-deficient mutant, R45H, within the N-terminal region results in increased NADK activity and confers cancer chemotherapy resistance. Conversely, mutations in NADK identified among cancer patients alter the tetramer conformation, resulting in NADK inactivation and increasing the sensitivity of lung cancer cells to chemotherapy. Our findings partially unveil the structural basis for NADK regulation, offering insights into the cancer etiology of patients carrying NADK mutations.

Keywords:  Chemotherapy resistance; Lung cancer; Methylation; NADK mutants; NADK tetramer

DOI:  https://doi.org/10.1016/j.gendis.2024.101510
Elife. 2025 May 07. pii: RP97019. [Epub ahead of print]13

SIRT2-mediated ACSS2 K271 deacetylation suppresses lipogenesis under nutrient stress.

Rezwana Karim, Wendi Teng, Cameron D Behram, Hening Lin.

  De novo lipogenesis is associated with the development of human diseases such as cancer, diabetes, and obesity. At the core of lipogenesis lies acetyl coenzyme A (CoA), a metabolite that plays a crucial role in fatty acid synthesis. One of the pathways contributing to the production of cytosolic acetyl-CoA is mediated by acetyl-CoA synthetase 2 (ACSS2). Here, we reveal that when cells encounter nutrient stress, particularly a deficiency in amino acids, Sirtuin 2 (SIRT2) catalyzes the deacetylation of ACSS2 at the lysine residue K271. This results in K271 ubiquitination and subsequently proteasomal degradation of ACSS2. Substitution of K271 leads to decreased ubiquitination of ACSS2, increased ACSS2 protein level, and thus increased lipogenesis. Our study uncovers a mechanism that cells employ to efficiently manage lipogenesis during periods of nutrient stress.

Keywords:  SIRT2; acetyl-CoA synthetase 2; acetylation; biochemistry; cell biology; chemical biology; human; lipogenesis; mouse; nutrient stress; ubiquitylation

DOI:  https://doi.org/10.7554/eLife.97019
Med Oncol. 2025 May 06. 42(6): 201

Iron overload enhances the susceptibility to cysteine deprivation-induced ferroptosis in non-small cell lung cancer cells.

Selim Kim, Hyeon-Ok Jin, Se-Kyeong Jang, Se Hee Ahn, Gyeongmi Kim, Hyunggee Kim, Tae-Gul Lee, Cheol Hyeon Kim, In-Chul Park.

  Ferroptosis is an iron-dependent regulated cell death characterized by lipid peroxidation accumulation. Due to the high iron demand of cancer cells, targeting ferroptosis is considered a promising approach for cancer therapy. This study aimed to elucidate the mechanisms underlying the differences in ferroptosis sensitivity in non-small cell lung cancer (NSCLC) cells and identify strategies to overcome ferroptosis resistance. H1299 cells were more sensitive to cysteine deprivation-induced ferroptosis and exhibited higher transferrin receptor (TfR) expression than H460 cells. Transferrin enhanced ferroptosis in cysteine-deprived H1299 cells, while TfR knockdown reduced ferroptosis, suggesting the involvement of TfR/transferrin system in this process. In H460 cells with low TfR expression, transferrin treatment did not induce ferroptosis under cysteine deprivation, indicating that the TfR/transferrin system was not involved. However, treatment with cell-permeable ferric ammonium citrate increased the sensitivity of ferroptosis to cysteine deprivation or RSL3 treatment. In conclusion, iron overload could be a potential strategy to overcome ferroptosis resistance in NSCLC.

Keywords:  Cysteine deprivation; Ferroptosis; Iron; Transferrin; Transferrin receptor

DOI:  https://doi.org/10.1007/s12032-025-02757-7
Nat Commun. 2025 May 08. 16(1): 4254

Palmitoylation prevents B7-H4 lysosomal degradation sustaining tumor immune evasion.

Yijian Yan, Jiali Yu, Weichao Wang, Ying Xu, Kole Tison, Rongxin Xiao, Sara Grove, Shuang Wei, Linda Vatan, Max Wicha, Ilona Kryczek, Weiping Zou.

B7-H4 functions as an immune checkpoint in the tumor microenvironment (TME). However, the post-translational modification (PTM) of B7-H4 and its translational potential in cancer remains incompletely understood. We find that ZDHHC3, a zinc finger DHHC-type palmitoyltransferase, palmitoylates B7-H4 at Cys130 in breast cancer cells, preventing its lysosomal degradation and sustaining B7-H4-mediated immunosuppression. Knockdown of ZDHHC3 in tumors results in robust anti-tumor immunity and reduces tumor progression in murine models. Moreover, abemaciclib, a CDK4/6 inhibitor, primes lysosome activation and promotes lysosomal degradation of B7-H4 independently of the tumor cell cycle. Treatment with abemaciclib results in T cell activation and mitigates B7-H4-mediated immune suppression via inducing B7-H4 degradation in preclinical tumor models. Thus, B7-H4 palmitoylation is an important PTM controlling B7-H4 protein stability and abemaciclib may be repurposed to promote B7-H4 degradation, thereby treating patients with B7-H4 expressing tumors.

DOI: https://doi.org/10.1038/s41467-025-58552-5
J Immunother Cancer. 2025 May 08. pii: e010433. [Epub ahead of print]13(5):

Defects in the necroptosis machinery are a cancer resistance mechanism to checkpoint inhibitor immunotherapy.

Anna Sax, Peter May, Stefan Enssle, Nardine Soliman, Tatiana Nedelko, Giada Mandracci, Fabian Stögbauer, Laura Joachim, Christof Winter, Florian Bassermann, Katja Steiger, Nadia El Khawanky, Hendrik Poeck, Simon Heidegger.

   BACKGROUND: Immune checkpoint inhibitors (ICIs) of programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) reinvigorate strong polyclonal T-cell immune responses against tumor cells. For many patients, these therapies fail because the development of spontaneous immune responses is often compromised, as the tumor microenvironment (TME) lacks proinflammatory signals resulting in suboptimal activation of antigen-presenting cells (APCs). Necroptosis is a special form of programmed cell death associated with leakage of inflammatory factors that can lead to APC maturation. However, it is unclear to which extent functional necroptosis in tumor cells contributes to ICI immunotherapy.
METHODS: With genetically engineered tumor cell lines that lack specific components of the necroptosis machinery (mixed lineage kinase domain-like pseudokinase (MLKL), receptor interacting protein kinase 3 (RIPK3)), we addressed the importance of necroptotic tumor cell death for the efficacy of ICI immunotherapy in murine models. Preclinical data were aligned with genome-wide transcriptional programs in patient tumor samples at diagnosis and during ICI treatment for the activity of these pathways and association with treatment outcome.
RESULTS: Mice bearing MLKL-deficient or RIPK3-deficient tumors failed to control tumor growth in response to anti-PD-1/anti-CTLA-4 immunotherapy. Mechanistically, defects in the necroptosis pathway resulted in reduced tumor antigen cross-presentation by type 1 conventional dendritic cells (DCs) in tumor-draining lymph nodes, and subsequently impaired immunotherapy-induced expansion of circulating tumor antigen-specific CD8+ T cells and their accumulation and activation in the TME. In vitro, co-culture of tumor cells undergoing necroptotic but not apoptotic programmed cell death resulted in increased uptake by phagocytic cells, associated with maturation and activation of DCs. Treatment of tumors with the epigenetic modulator azacytidine enhanced intrinsic transcriptional activity of the necroptosis machinery, and hence their susceptibility to ICI immunotherapy. In humans, transcriptome analysis of melanoma samples revealed a strong association between high expression of MLKL and prolonged overall survival and durable clinical response to immunotherapy with anti-PD-1 and/or anti-CTLA-4 checkpoint inhibitors.
CONCLUSIONS: Defective necroptosis signaling in tumor cells is a cancer resistance mechanism to ICI immunotherapy. Reversion of epigenetic silencing of the necroptosis pathway can render tumors susceptible to checkpoint inhibition.

Keywords:  Immune Checkpoint Inhibitor; Immunotherapy; T cell; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2024-010433