bims-meract 2025-02-02 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–02–02
25 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Glutamine and cancer: metabolism, immune microenvironment, and therapeutic targets.
BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer.
AGER-dependent macropinocytosis drives resistance to KRAS-G12D-targeted therapy in advanced pancreatic cancer.
SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation.
Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival.
Sorafenib enhanced the function of myeloid-derived suppressor cells in hepatocellular carcinoma by facilitating PPARα-mediated fatty acid oxidation.
Dual targeting PPARα and NPC1L1 metabolic vulnerabilities blocks tumorigenesis.
DLAT is involved in ovarian cancer progression by modulating lipid metabolism through the JAK2/STAT5A/SREBP1 signaling pathway.
VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis.
Repression of PFKFB3 sensitizes ovarian cancer to PARP inhibitors by impairing homologous recombination repair.
Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis.
CK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functions.
Enhancing Radiation Therapy Response in Prostate Cancer Through Metabolic Modulation by Mito-Lonidamine: A 1H and 31P Magnetic Resonance Spectroscopy Study.
Ferroptosis Inducers Erastin and RSL3 Enhance Adriamycin and Topotecan Sensitivity in ABCB1/ABCG2-Expressing Tumor Cells.
Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma.
Targeting aldehyde dehydrogenase ALDH3A1 increases ferroptosis vulnerability in squamous cancer.
Targeting pancreatic cancer glutamine dependency confers vulnerability to GPX4-dependent ferroptosis.
USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis.
Gboxin Induced Apoptosis and Ferroptosis of Cervical Cancer Cells by Promoting Autophagy-Mediated Inhibition of Nrf2 Signaling Under Low-Glucose Conditions.
HDAC2 promotes colorectal tumorigenesis by triggering dysregulation of lipid metabolism through YAP1.
SPHK1 enhances olaparib resistance in ovarian cancer through the NFκB/NRF2/ferroptosis pathway.
MK-8776 and Olaparib Combination Acts Synergistically in Hepatocellular Carcinoma Cells, Demonstrating Lack of Adverse Effects on Liver Tissues in Ovarian Cancer PDX Model.
PAX3-FOXO1 drives targetable cell state-dependent metabolic vulnerabilities in rhabdomyosarcoma.
CircTTC13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the miR-513a-5p/SLC7A11 axis.
Metal-Phenolic Nanomedicines Targeting Fatty Acid Metabolic Reprogramming to Overcome Immunosuppression in Radiometabolic Cancer Therapy.

Cell Commun Signal. 2025 Jan 24. 23(1): 45

Glutamine and cancer: metabolism, immune microenvironment, and therapeutic targets.

Ding Nan, Weiping Yao, Luanluan Huang, Ruiqi Liu, Xiaoyan Chen, Wenjie Xia, Hailong Sheng, Haibo Zhang, Xiaodong Liang, Yanwei Lu.

  Glutamine is the most abundant amino acid in human serum, and it can provide carbon and nitrogen for biosynthesis, which is crucial for proliferating cells. Moreover, it is widely known that glutamine metabolism is reprogrammed in cancer cells. Many cancer cells undergo metabolic reprogramming targeting glutamine, increasing its uptake to meet their rapid proliferation demands. An increasing amount of study is being done on the particular glutamine metabolic pathways in cancer cells.Further investigation into the function of glutamine in immune cells is warranted given the critical role these cells play in the fight against cancer. Immune cells use glutamine for a variety of biological purposes, including the growth, differentiation, and destruction of cancer cells. With the encouraging results of cancer immunotherapy in recent years, more investigation into the impact of glutamine metabolism on immune cell function in the cancer microenvironment could lead to the discovery of new targets and therapeutic approaches.Oral supplementation with glutamine also enhances the immune capabilities of cancer patients, improves the sensitivity to chemotherapy and radiotherapy, and improves prognosis. The unique metabolism of glutamine in cancer cells, its function in various immune cells, the impact of inhibitors of glutamine metabolism, and the therapeutic use of glutamine supplements are all covered in detail in this article.

Keywords:  Cancer; Glutaminase inhibitors; Glutamine antimetabolites; Glutamine metabolism; Immune cells

DOI:  https://doi.org/10.1186/s12964-024-02018-6
Life Metab. 2024 Aug;3(4): loae016

BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer.

Wen Mi, Jianwei You, Liucheng Li, Lingzhi Zhu, Xinyi Xia, Li Yang, Fei Li, Yi Xu, Junfeng Bi, Pingyu Liu, Li Chen, Fuming Li.

  Bromodomain and extra-terminal domain (BET) proteins, which function partly through MYC proto-oncogene (MYC), are critical epigenetic readers and emerging therapeutic targets in cancer. Whether and how BET inhibition simultaneously induces metabolic remodeling in cancer cells remains unclear. Here we find that even transient BET inhibition by JQ-1 and other pan-BET inhibitors (pan-BETis) blunts liver cancer cell proliferation and tumor growth. BET inhibition decreases glycolytic gene expression but enhances mitochondrial glucose and glutamine oxidative metabolism revealed by metabolomics and isotope labeling analysis. Specifically, BET inhibition downregulates miR-30a to upregulate glutamate dehydrogenase 1 (GDH1) independent of MYC, which produces α-ketoglutarate for mitochondrial oxidative phosphorylation (OXPHOS). Targeting GDH1 or OXPHOS is synthetic lethal to BET inhibition, and combined BET and OXPHOS inhibition therapeutically prevents liver tumor growth in vitro and in vivo. Together, we uncover an important epigenetic-metabolic crosstalk whereby BET inhibition induces MYC-independent and GDH1-dependent glutamine metabolic remodeling that can be exploited for innovative combination therapy of liver cancer.

Keywords:  BET; glutamate dehydrogenase 1; glutamine metabolism; oxidative phosphorylation; synthetic lethality

DOI:  https://doi.org/10.1093/lifemeta/loae016
Sci Transl Med. 2025 Jan 29. 17(783): eadp4986

AGER-dependent macropinocytosis drives resistance to KRAS-G12D-targeted therapy in advanced pancreatic cancer.

Changfeng Li, Yuanda Liu, Chang Liu, Fangquan Chen, Yangchun Xie, Herbert J Zeh, Chunhua Yu, Jiao Liu, Daolin Tang, Rui Kang.

Pancreatic ductal adenocarcinoma (PDAC) driven by the KRAS-G12D mutation presents a formidable health challenge because of limited treatment options. MRTX1133 is a highly selective and first-in-class KRAS-G12D inhibitor under clinical development. Here, we report that the advanced glycosylation end product-specific receptor (AGER) plays a key role in mediating MRTX1133 resistance in PDAC cells. The up-regulation of AGER within cancer cells instigates macropinocytosis, facilitating the internalization of serum albumin and subsequent amino acid generation. These amino acids are then used to synthesize the antioxidant glutathione, leading to resistance to MRTX1133 treatment due to the inhibition of apoptosis. The underlying molecular mechanism involves AGER's interaction with diaphanous-related formin 1 (DIAPH1), a formin protein responsible for driving Rac family small GTPase 1 (RAC1)-dependent macropinosome formation. The effectiveness and safety of combining MRTX1133 with pharmacological inhibitors of the AGER-DIAPH1 complex (using RAGE299) or macropinocytosis (using EIPA) were confirmed in patient-derived xenografts, orthotopic models, and genetically engineered mouse PDAC models. This combination therapy also induces high-mobility group box 1 (HMGB1) release, resulting in a subsequent antitumor CD8+ T cell response in immunocompetent mice. Collectively, the study findings underscore the potential to enhance the efficacy of KRAS-G12D blockade therapy by targeting AGER-dependent macropinocytosis.

DOI: https://doi.org/10.1126/scitranslmed.adp4986
EMBO J. 2025 Jan 29.

SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ferroptosis susceptibility via FSP1 acetylation.

Wei Li, Jing Han, Bin Huang, Tengteng Xu, Yihong Wan, Dan Luo, Weiyao Kong, Ying Yu, Lei Zhang, Yong Nian, Bo Chu, Chengqian Yin.

  Ferroptosis, an iron-dependent form of programmed cell death characterized by excessive lipid hydroperoxides accumulation, emerges as a promising target in cancer therapy. Among the solute carrier (SLC) superfamily, the cystine/glutamate transporter system antiporter components SLC3A2 and SLC7A11 are known to regulate ferroptosis by facilitating cystine import for ferroptosis inhibition. However, the contribution of additional SLC superfamily members to ferroptosis remains poorly understood. Here, we use a targeted CRISPR-Cas9 screen of the SLC superfamily to identify SLC25A1 as a critical ferroptosis regulator in human cancer cells. SLC25A1 drives citrate export from the mitochondria to the cytosol, where it fuels acetyl-CoA synthesis by ATP citrate lyase (ACLY). This acetyl-CoA supply sustains FSP1 acetylation and prevents its degradation by the proteasome via K29-linked ubiquitin chains. K168 is the primary site of FSP1 acetylation and deacetylation by KAT2B and HDAC3, respectively. Pharmacological inhibition of SLC25A1 and ACLY significantly enhances cancer cell susceptibility to ferroptosis both in vitro and in vivo. Targeting the SLC25A1-ACLY axis is therefore a potential therapeutic strategy for ferroptosis-targeted cancer intervention.

Keywords:  ACLY; Acetylation; FSP1; Ferroptosis; SLC25A1

DOI:  https://doi.org/10.1038/s44318-025-00369-5
Cell Commun Signal. 2025 Jan 25. 23(1): 47

Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival.

Monika Komza, Jesminara Khatun, Jesse D Gelles, Andrew P Trotta, Ioana Abraham-Enachescu, Juan Henao, Ahmed Elsaadi, Andriana G Kotini, Cara Clementelli, JoAnn Arandela, Sebastian El Ghaity-Beckley, Agneesh Barua, Yiyang Chen, Mirela Berisa, Bridget K Marcellino, Eirini P Papapetrou, Masha V Poyurovsky, Jerry Edward Chipuk.

  One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.

Keywords:  Adaptations; Bioenergetics; Cancer; Chemotherapy; Glucose; Leukemia; Metabolism; Mitochondria; Oncogenes; Stem cells

DOI:  https://doi.org/10.1186/s12964-025-02044-y
Mol Cancer. 2025 Jan 28. 24(1): 34

Sorafenib enhanced the function of myeloid-derived suppressor cells in hepatocellular carcinoma by facilitating PPARα-mediated fatty acid oxidation.

Chunxiao Li, Liting Xiong, Yuhan Yang, Ping Jiang, Junjie Wang, Mengyuan Li, Shuhua Wei, Suqing Tian, Yuexuan Wang, Mi Zhang, Jie Tang.

   BACKGROUND: Sorafenib, an FDA-approved drug for advanced hepatocellular carcinoma (HCC), faces resistance issues, partly due to myeloid-derived suppressor cells (MDSCs) that enhance immunosuppression in the tumor microenvironment (TME).
METHODS: Various murine HCC cell lines and MDSCs were used in a series of in vitro and in vivo experiments. These included subcutaneous tumor models, cell viability assays, flow cytometry, immunohistochemistry, and RNA sequencing. MDSCs were analyzed for chemotaxis, immunosuppressive functions, fatty acid oxidation (FAO), and PPARα expression. The impact of sorafenib on tumor growth, MDSC infiltration, differentiation, and immunosuppressive function was assessed, alongside the modulation of these processes by PPARα.
RESULTS: Here, we revealed increased infiltration and enhanced function of MDSCs in TME after treatment with sorafenib. Moreover, our results indicated that sorafenib induced the accumulation of MDSCs mediated by CCR2, and pharmacological blockade of CCR2 markedly reduced MDSCs migration and tumor growth. Mechanistically, sorafenib promoted the effect and fatty acid uptake ability of MDSCs and modulated peroxisome proliferator-activated receptor α (PPARα)-mediated fatty acid oxidation (FAO). In addition, tumor-bearing mice fed a high-fat diet (HFD) at the beginning of sorafenib administration had worse outcomes than mice fed a regular diet. Genetic deficiency of PPARα weakens the effect of sorafenib on MDSCs in mice with HCC. Pharmacological inhibition of PPARα has a synergistic anti-tumor effect with sorafenib, which is attenuated by the inhibition of MDSCs. Mechanistically, sorafenib significantly inhibited the differentiation of macrophages by upregulating PPARα expression and suppressing the PU.1-CSF1R pathway.
CONCLUSION: Overall, our study demonstrated that sorafenib enhanced the function of MDSCs by facilitating PPARα-mediated FAO and further augmenting sorafenib resistance, which sheds light on dietary management and improves the therapeutic response in HCC.

Keywords:  Hepatocellular carcinoma; MDSCs; Macrophages; Myeloid-derived suppressor cells; Sorafenib

DOI:  https://doi.org/10.1186/s12943-025-02238-5
Cancer Lett. 2025 Jan 23. pii: S0304-3835(25)00057-6. [Epub ahead of print]612 217493

Dual targeting PPARα and NPC1L1 metabolic vulnerabilities blocks tumorigenesis.

Xiaona You, Xi Hu, Zenghui Sun, Wenwen Xu, Lanlan Liu, Tao Huang, Shenli Yuan, Jilong Yin, Hao Wang, Limei Wang, Juncheng Wang, Wei Xu, Zhiyue Zhang, Yingjie Zhang, Yuchen Fan, Fabao Liu.

  Dysregulated lipid metabolism is linked to tumor progression. In this study, we identified Niemann-Pick C1-like 1 (NPC1L1) as a downstream effector of PKM2. In breast cancer cells, PKM2 knockout (KO) enhanced NPC1L1 expression while downregulating peroxisome proliferator-activated receptor α (PPARα) signaling pathway. PPARα and nuclear factor-E2 p45-related factor 1/2(Nrf1/2) are transcription factors regulating NPC1L1. In vitro PKM2 KO enhanced recruitment of Nrf1/2 to the NPC1L1 promoter region. Fenofibrate, a PPARα activator, promoted NPC1L1 expression; ezetimibe, an NPC1L1 inhibitor and effective Nrf2 activator, also elevated NPC1L1 expression. Combined administration of fenofibrate and ezetimibe significantly induced cytoplasmic vacuolation, and cell apoptosis. Mechanistically, this combined administration activated inositol required enzyme 1α(IRE1α) and produced the spliced form of X-box binding protein (XBP1s), which in turn enhanced lysine demethylase 6B (KDM6B) transcription. XBP1s interacts with KDM6B to activate genes involved in the unfolded protein response by demethylating di- and tri-methylated lysine 27 of histone H3 (H3K27), consequently increasing H3K27 acetylation levels in breast cancer cell lines. Fenofibrate and ezetimibe synergistically inhibited tumor growth in vivo. Our findings reveal that dual targeting of PPARα and NPC1L1 may represent a novel therapeutic regimen for breast cancer therapy.

Keywords:  Lipid metabolism; NPC1L1; PKM2; PPARα; Synergistic effect

DOI:  https://doi.org/10.1016/j.canlet.2025.217493
Cancer Cell Int. 2025 Jan 27. 25(1): 25

DLAT is involved in ovarian cancer progression by modulating lipid metabolism through the JAK2/STAT5A/SREBP1 signaling pathway.

Hui Wang, Shen Luo, Yue Yin, Yang Liu, Xiaomei Sun, Ling Qiu, Xin Wu.

   BACKGROUND: Ovarian cancer (OC) remains a lethal gynecological malignancy with an alarming mortality rate, primarily attributed to delayed diagnosis and a lack of effective treatment modalities. Accumulated evidence highlights the pivotal role of reprogrammed lipid metabolism in fueling OC progression, however, the intricate underlying molecular mechanisms are not fully elucidated.
METHODS: DLAT expression was assessed in OC tissues and cell lines by immunohistochemistry, western blot and qRT-PCR analysis. The effects of DLAT silencing on changes in lipid metabolism, cell viability, migration, and invasion were examined in SKOV3 and OVCAR3 cells using CCK-8, colony formation, Transwell migration and invasion, and wound-healing assays. GSEA analysis was used to examine the relationship between DLAT and lipid metabolism-related enzymes. Rescue experiments in which SREBP1 was overexpressed in DLAT-silenced cells were carried out. Western blot analysis was performed to determine whether the JAK2/STAT5 signaling pathway was involved in DLAT-regulated SREBP1 expression. Commercially available triglyceride and cholesterol detection kits, as well as Nile Red and Oil red O staining were used to measure lipid metabolism. A subcutaneous tumor model was established in BALB/c mice to confirm the role of the DLAT/SREBP1 axis in OC growth and metastasis in vivo.
RESULTS: DLAT expression was significantly upregulated in OC patient tissue and associated with poor prognosis. Silencing DLAT reduced lipid content and impaired OC cell proliferation, migration, and invasion. DLAT upregulated SREBP1 expression via the JAK2/STAT5 signaling pathway, enhancing expression of fatty acid synthesis enzymes and altering lipid metabolism. SREBP1 was essential for DLAT-dependent OC cell growth and metastasis both in vitro and in vivo.
CONCLUSION: This study uncovers a novel DLAT/JAK2/STAT5/SREBP1 axis that reprograms lipid metabolism in OC, providing insights into metabolic vulnerabilities and potential therapeutic targets for OC treatment.

Keywords:  DLAT; JAK2/STAT5 signaling; Lipid metabolism; Ovarian cancer; SREBP1

DOI:  https://doi.org/10.1186/s12935-025-03656-7
Nat Commun. 2025 Jan 29. 16(1): 1160

VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis.

Juan Yang, Xiao Lu, Jing-Lan Hao, Lan Li, Yong-Tong Ruan, Xue-Ni An, Qi-Lai Huang, Xiao-Ming Dong, Ping Gao.

Ferroptosis is a form of iron-dependent programmed cell death, which is distinct from apoptosis, necrosis, and autophagy. Mitochondria play a critical role in initiating and amplifying ferroptosis in cancer cells. Voltage-Dependent Anion Channel 1 (VDAC1) embedded in the mitochondrial outer membrane, exerts roles in regulation of ferroptosis. However, the mechanisms of VDAC1 oligomerization in regulating ferroptosis are not well elucidated. Here, we identify that a VDAC1 binding protein V-Set and Transmembrane Domain Containing 2 Like (VSTM2L), mainly localized to mitochondria, is positively associated with prostate cancer (PCa) progression, and a key regulator of ferroptosis. Moreover, VSTM2L knockdown in PCa cells enhances the sensitivity of RSL3-induced ferroptosis. Mechanistically, VSTM2L forms complex with VDAC1 and hexokinase 2 (HK2), enhancing their binding affinity and preventing VDAC1 oligomerization, thereby inhibiting ferroptosis and maintaining mitochondria homeostasis in vitro and in vivo. Collectively, our findings reveal a pivotal role for mitochondria-localized VSTM2L in driving ferroptosis resistance and highlight its potential as a ferroptosis-inducing therapeutic target for the treatment of PCa.

DOI: https://doi.org/10.1038/s41467-025-56494-6
Cell Commun Signal. 2025 Jan 25. 23(1): 48

Repression of PFKFB3 sensitizes ovarian cancer to PARP inhibitors by impairing homologous recombination repair.

Yinan Xiao, Yu Wu, Qilong Wang, Mo Li, Chaolin Deng, Xiaoyang Gu.

   BACKGROUND: Ovarian cancer (OC), particularly high-grade serous ovarian carcinoma (HGSOC), is the leading cause of mortality from gynecological malignancies worldwide. Despite the initial effectiveness of treatment, acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPis) represents a major challenge for the clinical management of HGSOC, highlighting the necessity for the development of novel therapeutic strategies. This study investigated the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a pivotal regulator of glycolysis, in PARPi resistance and explored its potential as a therapeutic target to overcome PARPi resistance.
METHODS: We conducted in vitro and in vivo experiments to assess the role of PFKFB3 in OC and its impact on PARPi resistance. We analyzed PFKFB3 expression and activity in primary OC tissues and cell lines using western blotting and immunohistochemistry. CRISPR-Cas9 and pharmacological inhibitors were employed to inhibit PFKFB3, and the effects on PARPi resistance, homologous recombination (HR) repair efficiency, and DNA damage were evaluated. RNA sequencing and proximity labeling were employed to identify the molecular mechanisms underlying PFKFB3-mediated resistance. The in vivo efficacy of PARPi and PFK158 combination therapy was evaluated in OC xenograft models.
RESULTS: PFKFB3 activity was significantly elevated in OC tissues and associated with PARPi resistance. Inhibition of PFKFB3, both genetically and pharmacologically, sensitized OC cells to PARPis, impaired HR repair and increased DNA damage. Proximity labeling revealed replication protein A3 (RPA3) as a novel PFKFB3-binding protein involved in HR repair. In vivo, the combination of PFK158 and olaparib significantly inhibited tumor growth, increased DNA damage, and induced apoptosis in OC xenografts without exacerbating adverse effects.
CONCLUSIONS: Our findings demonstrate that PFKFB3 is crucial for PARPi resistance in OC. Inhibiting PFKFB3 sensitizes HR-proficient OC cells to PARPis by impairing HR repair, leading to increased DNA damage and apoptosis. PFKFB3 represents a promising therapeutic target for overcoming PARPi resistance and improving outcomes in OC patients.

Keywords:  Homologous recombination repair; Ovarian cancer; PARP inhibitors; PFKFB3

DOI:  https://doi.org/10.1186/s12964-025-02056-8
J Biomed Sci. 2025 Jan 20. 32(1): 9

Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis.

Xuejie Gao, Qilin Feng, Qikai Zhang, Yifei Zhang, Chaolu Hu, Li Zhang, Hui Zhang, Guanli Wang, Ke Hu, Mengmeng Ma, Zhuning Wang, Yujie Liu, Dong An, Hongfei Yi, Yu Peng, Xiaosong Wu, Gege Chen, Xinyan Jia, Haiyan Cai, Jumei Shi.

   BACKGROUND: Enolase 1 (ENO1) is a conserved glycolytic enzyme that regulates glycolysis metabolism. However, its role beyond glycolysis in the pathophysiology of multiple myeloma (MM) remains largely elusive. Herein, this study aimed to elucidate the function of ENO1 in MM, particularly its impact on mitophagy under bortezomib-induced apoptosis.
METHODS: The bone marrow of clinical MM patients and healthy normal donors was used to compare the expression level of ENO1. Using online databases, we conducted an analysis to examine the correlation between ENO1 expression and both clinicopathological characteristics and patient outcomes. To investigate the biological functions of ENO1 in MM and the underlying molecular mechanisms involved, we conducted the following experiment: construction of a subcutaneous graft tumor model, co-immunoprecipitation, western blot, quantitative real-time polymerase chain reaction, immunohistochemistry, flow cytometry, and cell functional assays.
RESULTS: ENO1 was identified as an unfavorable prognostic factor in MM. ENO1 knockdown suppresses tumorigenicity and causes cell cycle arrest. Inhibition of ENO1-regulated mitophagy sensitizes tumor cells to apoptosis. ENO1 enhanced the stability of the YWHAZ protein by increasing the acetylation of lysine in YWHAZ while antagonizing its ubiquitination, which in turn promoted mitophagy. HDAC6 mediates the deacetylation of YWHAZ by deacetylating the K138 site of YWHAZ. Inhibition of HDAC6 increased YWHAZ acetylation and decreased YWHAZ ubiquitination. Furthermore, combination treatment with bortezomib and pharmaceutical agents targeting ENO1 has synergistic anti-MM effects both in vivo and in vitro.
CONCLUSION: Our data suggest that ENO1 promotes MM tumorigenesis and progression. ENO1 activates mitophagy by promoting the stability of YWHAZ and inhibits apoptosis and thus, leads to the drug resistance. ENO1-dependent mitophagy promotes MM proliferation and suppresses the level of bortezomib-induced apoptosis. Inhibition of ENO1 may represent a potential strategy to reverse the resistance of MM to bortezomib.

Keywords:  Chemoresistance; ENO1; Mitophagy; Multiple myeloma; YWHAZ

DOI:  https://doi.org/10.1186/s12929-024-01101-x
Cell Death Dis. 2025 Jan 18. 16(1): 27

CK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functions.

Lei Huang, Yalei Wen, Qin Guo, Caishi Zhang, Xiao Yang, Mei Li, YiXia Liu, Xinying Li, Jiaxin Tang, Xiaofeng Zhou, Qi Qi, Haoxing Zhang, Tongzheng Liu.

The aberrant upregulation of Yes-associated protein 1 (YAP1) in a variety of solid cancers contributes to tumor progression and poor clinical outcomes, rendering it an appealing therapeutic target. However, effective therapies to directly target YAP1 remain challenging. In this study, we perform a high-throughput screening and identify Casein kinase II (CK2) as an uncharacterized upstream regulator of YAP1 turnover in cancer cells of ovarian cancer and several other cancer types. Pharmacological inhibition of Casein kinase II by Silmitasertib or genetic depletion of the catalytic subunit of Casein kinase II (CK2α) markedly destabilizes YAP1 and consequently suppresses its oncogenic functions in vitro and in vivo. Moreover, we reveal that DUB3 as a bona fide deubiquitinase of YAP1, which functionally links CK2 and YAP1 stability in a variety of human cancers. Mechanistically, CK2α directly phosphorylates DUB3 at Thr495, thereby facilitating DUB3-mediated deubiquitination process of YAP1. On the contrary, the loss of Thr495 phosphorylation by the phosphorylation-defective mutant DUB3 T495A, the cancer-related mutant DUB3 D496H and CK2 inhibition failed to deubiquitinate and stabilize YAP1 effectively. Notably, upregulated expressions of CK2α and DUB3 in ovarian cancer positively correlate with YAP1 overexpression. Collectively, our findings demonstrate the functional significance of the CK2α-DUB3 axis in YAP1 stabilization and YAP1-driven tumor progression, highlighting that strategies to target this axis might be of benefit in the clinical management of ovarian cancer and several other lethal cancers with aberrantly upregulated YAP1.

DOI: https://doi.org/10.1038/s41419-024-07323-z
Int J Mol Sci. 2025 Jan 09. pii: 509. [Epub ahead of print]26(2):

Enhancing Radiation Therapy Response in Prostate Cancer Through Metabolic Modulation by Mito-Lonidamine: A 1H and 31P Magnetic Resonance Spectroscopy Study.

Stepan Orlovskiy, Pradeep Kumar Gupta, Fernando Arias-Mendoza, Dinesh Kumar Singh, Skyler Nova, David S Nelson, Vivek Narayan, Cameron J Koch, Micael Hardy, Ming You, Balaraman Kalyanaraman, Kavindra Nath.

  Radiation therapy (RT) is the cornerstone treatment for prostate cancer; however, it frequently induces gastrointestinal and genitourinary toxicities that substantially diminish the patients' quality of life. While many individuals experience transient side effects, a subset endures persistent, long-term complications. A promising strategy to mitigate these toxicities involves enhancing tumor radiosensitivity, potentially allowing for lower radiation doses. In this context, mito-lonidamine (Mito-LND), an antineoplastic agent targeting the mitochondrial electron transport chain's complexes I and II, emerges as a potential radiosensitizer. This study investigated Mito-LND's capacity to augment RT efficacy and reduce adverse effects through comprehensive in vitro and in vivo assessments using hormone-sensitive and hormone-refractory prostate cancer models. Employing a Seahorse analysis and 1H/31P magnetic resonance spectroscopy (MRS), we observed that Mito-LND selectively suppressed lactate production, decreased intracellular pH, and reduced bioenergetics and oxygen consumption levels within tumor cells. These findings suggest that Mito-LND remodels the tumor microenvironment by inducing acidification, metabolic de-energization, and enhanced oxygenation, thereby sensitizing tumors to RT. Our results underscore the potential of Mito-LND as a therapeutic adjunct in RT to improve patient outcomes and reduce radiation-associated toxicities in early-stage prostate cancer.

Keywords:  lonidamine; magnetic resonance imaging; magnetic resonance spectroscopy; metabolic modulation; mito-lonidamine; prostate cancer; radiation therapy

DOI:  https://doi.org/10.3390/ijms26020509
Int J Mol Sci. 2025 Jan 14. pii: 635. [Epub ahead of print]26(2):

Ferroptosis Inducers Erastin and RSL3 Enhance Adriamycin and Topotecan Sensitivity in ABCB1/ABCG2-Expressing Tumor Cells.

Lalith Perera, Shalyn M Brown, Brian B Silver, Erik J Tokar, Birandra K Sinha.

  Acquired resistance to chemotherapeutic drugs is the primary cause of treatment failure in the clinic. While multiple factors contribute to this resistance, increased expression of ABC transporters-such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance proteins-play significant roles in the development of resistance to various chemotherapeutics. We found that Erastin, a ferroptosis inducer, was significantly cytotoxic to NCI/ADR-RES, a P-gp-expressing human ovarian cancer cell line. Here, we examined the effects of both Erastin and RSL3 (Ras-Selected Ligand 3) on reversing Adriamycin resistance in these cell lines. Our results show that Erastin significantly enhanced Adriamycin uptake in NCI/ADR-RES cells without affecting sensitive cells. Furthermore, we observed that Erastin enhanced Adriamycin cytotoxicity in a time-dependent manner. The selective iNOS inhibitor, 1400W, reduced both uptake and cytotoxicity of Adriamycin in P-gp-expressing NCI/ADR-RES cells only. These findings were also confirmed in a BCRP-expressing human breast cancer cell line (MCF-7/MXR), which was selected for resistance to Mitoxantrone. Both Erastin and RSL3 were found to be cytotoxic to MCF-7/MXR cells. Erastin significantly enhanced the uptake of Hoechst dye, a well-characterized BCRP substrate, sensitizing MCF-7/MXR cells to Topotecan. The effect of Erastin was inhibited by 1400W, indicating that iNOS is involved in Erastin-mediated enhancement of Topotecan cytotoxicity. RSL3 also significantly increased Topotecan cytotoxicity. Our findings-demonstrating increased cytotoxicity of Adriamycin and Topotecan in P-gp- and BCRP-expressing cells-suggest that ferroptosis inducers may be highly valuable in combination with other chemotherapeutics to manage patients' cancer burden in the clinical setting.

Keywords:  Adriamycin; Erastin; P-gp protein; RSL3; Topotecan; breast cancer resistance protein; ferroptosis

DOI:  https://doi.org/10.3390/ijms26020635
J Clin Invest. 2025 Jan 30. pii: e187024. [Epub ahead of print]

Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma.

Kang Sun, Xiaozhen Zhang, Jiatao Shi, Jinyan Huang, Sicheng Wang, Xiang Li, Haixiang Lin, Danyang Zhao, Mao Ye, Sirui Zhang, Li Qiu, Minqi Yang, Chuyang Liao, Lihong He, Mengyi Lao, Jinyuan Song, Na Lu, Yongtao Ji, Hanshen Yang, Lingyue Liu, Xinyuan Liu, Yan Chen, Shicheng Yao, Qianhe Xu, Jieru Lin, Yan Mao, Jingxin Zhou, Xiao Zhi, Ke Sun, Xiongbin Lu, Xueli Bai, Tingbo Liang.

  Metabolic reprogramming shapes tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. "Immune cold" PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of pro-tumor macrophages, and reduced cytotoxic T cell in the TME. Analysis of 18F-FDG uptake in patients showed that increased global protein lactylation in PDAC correlates with worse clinical outcomes in immunotherapy. Inhibition of lactate production in pancreatic tumors via glycolysis or mutant-KRAS inhibition reshaped the TME, thereby increasing their sensitivity to immune checkpoint blockade (ICB) therapy. In pancreatic tumor cells, lactate induces K63 lactylation of Endosulfine alpha (ENSA-K63la), a crucial step that triggers STAT3-CCL2 signaling. Consequently, elevated CCL2 secreted by tumor cells facilitates tumor-associated macrophage (TAM) recruitment to the TME. High levels of lactate also drive transcriptional reprogramming in TAMs via ENSA-STAT3 signaling, promoting an immunosuppressive environment. Targeting ENSA-K63la or CCL2 enhances the efficacy of ICB therapy in murine and humanized pancreatic tumor models. In conclusion, elevated lactylation reshapes the TME and promotes immunotherapy resistance in PDAC. Therapeutic approach targeting ENSA-K63la or CCL2 has shown promise in sensitizing pancreatic cancer immunotherapy.

Keywords:  Cancer; Cancer immunotherapy; Immunology; Macrophages; Oncology

DOI:  https://doi.org/10.1172/JCI187024
Oncogene. 2025 Jan 25.

Targeting aldehyde dehydrogenase ALDH3A1 increases ferroptosis vulnerability in squamous cancer.

Shuai Kong, Huaguang Pan, Yuan-Wei Zhang, Fei Wang, Jian Chen, Jinxiu Dong, Chuntong Yin, Jiaqi Wu, Dan Zhou, Jingyi Peng, Junboya Ma, Jianian Zhou, Dianlong Ge, Yan Lu, Dan-Dan Wei, Jinman Fang, Wei Han, Chengyin Shen, H Phillip Koeffler, Boshi Wang, Yuan Jiang, Yan-Yi Jiang.

Ferroptosis is a unique modality of regulated cell death induced by excessive lipid peroxidation, playing a crucial role in tumor suppression and providing potential therapeutic strategy for cancer treatment. Here, we find that aldehyde dehydrogenase-ALDH3A1 tightly links to ferroptosis in squamous cell carcinomas (SCCs). Functional assays demonstrate the enzymatic activity-dependent regulation of ALDH3A1 in protecting SCC cells against ferroptosis through catalyzing aldehydes and mitigating lipid peroxidation. Furthermore, a specific covalent inhibitor of ALDH3A1-EN40 significantly enhances the ferroptosis sensitivity induced by the ferroptosis inducer. The combination of EN40 and a ferroptosis inducer exhibits a synergistic effect, effectively inhibiting the proliferation of SCC cells/organoids and suppressing tumor growth both in vitro and in vivo. On mechanism, high expression of ALDH3A1 is transcriptionally governed by TP63, which binds to super-enhancer of ALDH3A1. Collectively, our findings reveal a yet-unrecognized function of ALDH3A1 exploited by SCC cells to evade ferroptosis, and targeting ALDH3A1 may enhance the effect of ferroptosis-induced therapy in SCCs.

DOI: https://doi.org/10.1038/s41388-025-03277-4
Cell Rep Med. 2025 Jan 27. pii: S2666-3791(25)00001-1. [Epub ahead of print] 101928

Targeting pancreatic cancer glutamine dependency confers vulnerability to GPX4-dependent ferroptosis.

Xuqing Shen, Yueyue Chen, Yingying Tang, Ping Lu, Mingzhu Liu, Tiebo Mao, Yawen Weng, Feier Yu, Yimei Liu, Yujie Tang, Liwei Wang, Ningning Niu, Jing Xue.

  Pancreatic ductal adenocarcinoma (PDAC) relies heavily on glutamine (Gln) utilization to meet its metabolic and biosynthetic needs. How epigenetic regulators contribute to the metabolic flexibility and PDAC's response and adaptation to Gln scarcity in the tumor milieu remains largely unknown. Here, we elucidate that prolonged Gln restriction or treatment with the Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), leads to growth inhibition and ferroptosis program activation in PDAC. A CRISPR-Cas9 screen identifies an epigenetic regulator, Paxip1, which promotes H3K4me3 upregulation and Hmox1 transcription upon DON treatment. Additionally, ferroptosis-related repressors (e.g., Slc7a11 and Gpx4) are increased as an adaptive response, thereby predisposing PDAC cells to ferroptosis upon Gln deprivation. Moreover, DON sensitizes PDAC cells to GPX4 inhibitor-induced ferroptosis, both in vitro and in patient-derived xenografts (PDXs). Taken together, our findings reveal that targeting Gln dependency confers susceptibility to GPX4-dependent ferroptosis via epigenetic remodeling and provides a combination strategy for PDAC therapy.

Keywords:  PDAC; combination therapy; epigenetic remodeling; ferroptosis; pancreatic ductal adenocarcinoma; prolonged glutamine starvation

DOI:  https://doi.org/10.1016/j.xcrm.2025.101928
Commun Biol. 2025 Jan 16. 8(1): 64

USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis.

Jiawei Cao, Tao Wu, Tong Zhou, Zewei Jiang, Yinrui Ren, Jiawei Yu, Jiayi Wang, Changrui Qian, Guang Wu, Licai He, Hongzhi Li, Rixu Lin, Min Liu, Haihua Gu.

Anti-estrogen endocrine therapies greatly improve survival of estrogen receptor positive (ER + ) breast cancer. Unfortunately, about 30% of patients do not respond to endocrine therapies initially. We previously showed that deubiquitinase USP35 and ERα act in a positive feedback loop to promote the carcinogenesis of ER+ breast cancer although it is unclear whether USP35 regulates cell death in ER+ breast cancer. In this study, we uncovered that USP35 inhibited ferroptosis of ER+ breast cancer cells. Mechanistically, USP35 interacted with, deubiquitinated, and stabilized BRD4. Consequentially, BRD4 mediated USP35-induced SLC7A11 upregulation, inhibiting ferroptosis and promoting the growth of ER+ breast cancer cells. Furthermore, BRD4 inhibitor (+)-JQ-1 inhibited USP35-enhanced tumorigenesis in vivo. Our findings demonstrated that the USP35-BRD4-SLC7A11 axis contributes to the growth of ER+ breast cancer by inhibiting ferroptosis. Targeting USP35 together with ferroptosis inducer may represent a potential promising strategy for treating ER+ breast cancer that does not respond to endocrine therapies.

DOI: https://doi.org/10.1038/s42003-025-07513-1
Int J Mol Sci. 2025 Jan 09. pii: 502. [Epub ahead of print]26(2):

Gboxin Induced Apoptosis and Ferroptosis of Cervical Cancer Cells by Promoting Autophagy-Mediated Inhibition of Nrf2 Signaling Under Low-Glucose Conditions.

Wei Liu, Junlin Lu, Jiarui Li, Lu Wang, Yao Chen, Yulun Wu, Ziying Zhang, Jingying Zhang, Feng Gao, Chaoran Jia, Yongli Bao, Xiaoguang Yang, Zhenbo Song.

  Cervical cancer poses a substantial threat to women's health, underscoring the necessity for effective therapeutic agents with low toxicity that specifically target cancer cells. As cancer progresses, increased glucose consumption causes glucose scarcity in the tumor microenvironment (TME). Consequently, it is imperative to identify pharmacological agents capable of effectively killing cancer cells under conditions of low glucose availability within the TME. Previous studies showed that Gboxin, a small molecule, inhibited glioblastoma (GBM) growth by targeting ATP synthase without harming normal cells. However, its effects and mechanisms in cervical cancer cells in low-glucose environments are not clear. This study indicates that Gboxin notably enhanced autophagy, apoptosis, and ferroptosis in cervical cells under low-glucose conditions without significantly affecting cell survival under normal conditions. Further analysis revealed that Gboxin inhibited the activity of complex V and the production of ATP, concurrently leading to a reduction in mitochondrial membrane potential and the mtDNA copy number under low-glucose culture conditions. Moreover, Gboxin inhibited tumor growth under nutrient deprivation conditions in vivo. A mechanistic analysis revealed that Gboxin activated the AMPK signaling pathway by targeting mitochondrial complex V. Furthermore, increased AMPK activation subsequently promoted autophagy and reduced p62 protein levels. The decreased levels of p62 protein facilitated the degradation of Nrf2 by regulating the p62-Keap1-Nrf2 axis, thereby diminishing the antioxidant capacity of cervical cancer cells, ultimately leading to the induction of apoptosis and ferroptosis. This study provides a better theoretical basis for exploring Gboxin as a potential drug for cervical cancer treatment.

Keywords:  Gboxin; Nrf2; apoptosis; cervical; ferroptosis

DOI:  https://doi.org/10.3390/ijms26020502
Cell Signal. 2025 Jan 26. pii: S0898-6568(25)00040-3. [Epub ahead of print] 111627

HDAC2 promotes colorectal tumorigenesis by triggering dysregulation of lipid metabolism through YAP1.

Zhanghan Chen, Weifeng Hong, Bing Li, Dongli He, Zhong Ren, Mingyan Cai, Yirong Cheng, Jingyi Liu, Enpan Xu, Yanyun Du, Yuelun Dong, Shilun Cai, Qiang Shi, Zhipeng Qi, Yunshi Zhong.

  Dysfunction of lipid metabolism is important for the development and progression of colorectal cancer, but the underlying mechanisms remain unclear. Here, HDAC2 was identified as highly expressed in both adenoma and colorectal cancer. We aimed to explore the roles and mechanisms of HDAC2 in lipid metabolism in colorectal cancer. HDAC2 expression in adenoma and colorectal cancer tissues was measured using tissue arrays. The function of HDAC2/YAP1 was identified using in vitro and in vivo experiments. Coimmunoprecipitation experiments, DNA pull-down assays, luciferase analyses, and ChIP-qPCR (Chromatin Immunoprecipitation-quantitative real-time polymerase chain reaction) assays were used to identify the potential mechanisms of HDAC2. We found that HDAC2 can disrupt lipid metabolism in colorectal cancer by mediating the deacetylation of YAP1. Mechanistically, HDAC2 can bind to YAP1 and mediate deacetylation of the K280 site of YAP1. Furthermore, the deacetylation of YAP1 reduces the efficiency of its binding to the ZMYND11 promoter region, exacerbating lipid metabolism disorders, which in turn reduce lipid accumulation and increase lipid catabolism in colorectal cancer cells. Our study identified a novel regulatory mechanism of lipid metabolism in colorectal cancer in which HDAC2 increases lipid catabolism by regulating the deacetylation of the K280 site of YAP1, revealing that HDAC2 promotes tumor progression through the regulation of lipid metabolism.

Keywords:  Colorectal cancer; HDAC2; Lipid metabolism; YAP1

DOI:  https://doi.org/10.1016/j.cellsig.2025.111627
Cell Death Discov. 2025 Jan 28. 11(1): 29

SPHK1 enhances olaparib resistance in ovarian cancer through the NFκB/NRF2/ferroptosis pathway.

Kai Teng, Hanlin Ma, Panpan Gai, Xuelian Zhao, Gonghua Qi.

PARPis resistance is a challenge in the treatment of ovarian cancer. To investigate the potential mechanism involved in olaparib resistance of ovarian cancer, high-throughput sequencing was performed on olaparib-resistant SKOV3 cell line named SK/Ola. SPHK1 was upregulated in SK/Ola cells and was related to the PFS and OS in ovarian cancer patients. However, the effect and mechanism of SPHK1 on olaparib sensitivity in ovarian cancer were obscure. In this study, we found that SPHK1 promoted olaparib resistance. While, SPHK1 knockdown and SPHK1 inhibitor (PF-543 hydrochloride, named PF-543 in this article) enhanced the effect of olaparib on ovarian cancer cells. In mechanism, SPHK1 activated the NF-κB pathway through promoting p-IκBα degradation. Moreover, SPHK1 inhibited, but PF-543 activated ferroptosis in OC cells. Further investigation revealed that SPHK1 activated NF-κB p65, which in turn transcriptionally regulated NRF2 to inhibit ferroptosis in OC cells. Functionally, NF-κB p65 attenuated the PF-543-induced ferroptosis, and this effect was rescued by ferroptosis inducer erastin and RSL3. We conclude that SPHK1 inhibition triggers ferroptosis by restricting NF-κB-activated NRF2 transcription, thereby enhancing olaparib sensitivity in ovarian cancer. In vivo experiments also confirmed that the SPHK1 inhibitor increased olaparib sensitivity. A combination of SPHK1 inhibitors and olaparib may provide a therapeutic strategy for ovarian cancer.

DOI: https://doi.org/10.1038/s41420-025-02309-y
Int J Mol Sci. 2025 Jan 20. pii: 834. [Epub ahead of print]26(2):

MK-8776 and Olaparib Combination Acts Synergistically in Hepatocellular Carcinoma Cells, Demonstrating Lack of Adverse Effects on Liver Tissues in Ovarian Cancer PDX Model.

Wiktoria Bębenek, Arkadiusz Gajek, Agnieszka Marczak, Jan Malý, Jiří Smejkal, Małgorzata Statkiewicz, Natalia Rusetska, Magdalena Bryś, Aneta Rogalska.

  Hepatocellular carcinoma (HCC) cells critically depend on PARP1 and CHK1 activation for survival. Combining the PARP inhibitor (PARPi) olaparib with a CHK1 inhibitor (MK-8776, CHK1i) produced a synergistic effect, reducing cell viability and inducing marked oxidative stress and DNA damage, particularly in the HepG2 cells. This dual treatment significantly increased apoptosis markers, including γH2AX and caspase-3/7 activity. Both HCC cell lines exhibited heightened sensitivity to the combined treatment. The effect of drugs on the expression of proliferation markers in an olaparib-resistant patient-derived xenograft (PDX) model of ovarian cancer was also investigated. Ovarian tumors displayed reduced tissue growth, as reflected by a drop in proliferation marker Ki-67 levels in response to PARPi combined with CHK1i. No changes were observed in corresponding liver tissues using Ki-67 and pCHK staining, which indicates the absence of metastases and a hepatotoxic effect. Thus, our results indicate that the dual inhibition of PARP and CHK1 may prove to be a promising therapeutic approach in the treatment of primary HCC as well as OC tumors without the risk of liver metastases, especially in patients with olaparib-resistant tumor profiles.

Keywords:  CHK1 inhibitor; liver cancer; metastasis; olaparib; ovarian cancer; replication stress; targeted therapy

DOI:  https://doi.org/10.3390/ijms26020834
bioRxiv. 2025 Jan 19. pii: 2025.01.15.633227. [Epub ahead of print]

PAX3-FOXO1 drives targetable cell state-dependent metabolic vulnerabilities in rhabdomyosarcoma.

Katrina I Paras, Julia S Brunner, Jacob A Boyer, Angela M Montero, Benjamin T Jackson, Sangita Chakraborty, Abigail Xie, Kristina Guillan, Armaan Siddiquee, Lourdes Pajuelo Torres, Joshua D Rabinowitz, Andrew Kung, Daoqi You, Filemon Dela Cruz, Lydia W S Finley.

PAX3-FOXO1, an oncogenic transcription factor, drives a particularly aggressive subtype of rhabdomyosarcoma (RMS) by enforcing gene expression programs that support malignant cell states. Here we show that PAX3-FOXO1 + RMS cells exhibit altered pyrimidine metabolism and increased dependence on enzymes involved in de novo pyrimidine synthesis, including dihydrofolate reductase (DHFR). Consequently, PAX3-FOXO1 + cells display increased sensitivity to inhibition of DHFR by the chemotherapeutic drug methotrexate, and this dependence is rescued by provision of pyrimidine nucleotides. Methotrexate treatment mimics the metabolic and transcriptional impact of PAX3-FOXO1 silencing, reducing expression of genes related to PAX3-FOXO1-driven malignant cell states. Accordingly, methotrexate treatment slows growth of multiple PAX3-FOXO1 + tumor xenograft models, but not fusion-negative counterparts. Taken together, these data demonstrate that PAX3-FOXO1 induces cell states characterized by altered pyrimidine dependence and nominate methotrexate as an addition to the current therapeutic arsenal for treatment of these malignant pediatric tumors.

DOI: https://doi.org/10.1101/2025.01.15.633227
Mol Cancer. 2025 Jan 27. 24(1): 32

CircTTC13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the miR-513a-5p/SLC7A11 axis.

Ying Zhang, Ruiwei Yao, Mingyi Li, Chongkai Fang, Kunliang Feng, Xiuru Chen, Jinan Wang, Rui Luo, Hanqian Shi, Xinqiu Chen, Xilin Zhao, Hanlin Huang, Shuwei Liu, Bing Yin, Chong Zhong.

  The high mortality rate from hepatocellular carcinoma (HCC) is due primarily to challenges in early diagnosis and the development of drug resistance in advanced stages. Many first-line chemotherapeutic drugs induce ferroptosis, a form of programmed cell death dependent on ferrous iron-mediated oxidative stress, suggesting that drug resistance and ensuing tumor progression may in part stem from reduced ferroptosis. Since circular RNAs (circRNAs) have been shown to influence tumor development, we examined whether specific circRNAs may regulate drug-induced ferroptosis in HCC. Through circRNA sequencing, we identified a novel hsa_circ_0000195 (circTTC13) that is overexpressed in HCC tissues. This overexpression is linked to higher tumor grade, more advanced tumor stage, decreased ferroptosis, and poorer overall survival. Overexpression of CircTTC13 in HCC cell lines and explant tumors was associated with increased proliferation rates, enhanced metastatic capacity, and resistance to sorafenib, while also inhibiting ferroptosis. Conversely, circTTC13 silencing reduced malignant characteristics and promoted ferroptosis. In silico analysis, luciferase assays, and fluorescence in situ hybridization collectively demonstrated that circTTC13 directly targets and reduces miR-513a-5p expression, which in turn leads to the upregulation of the negative ferroptosis regulator SLC7A11. Moreover, the inhibition of SLC7A11 mirrored the effect of circTTC13 knockdown, whereas ferroptosis inhibition mimicked the effect of circTTC13 overexpression. Both circTTC13 and SLC7A11 were highly expressed in drug-resistant HCC cells, and circTTC13 silencing induced ferroptosis and reversed sorafenib resistance in explant tumors. These findings identify circTTC13 as a critical driver of HCC progression and resistance to drug-induced ferroptosis via upregulation of SLC7A11. The cicTTC13/miR-513a-5p/SLC7A11 axis represents a potential therapeutic target for HCC.

Keywords:  Ferroptosis; Hepatocellular carcinoma; SLC7A11; Sorafenib; circRNA; circTTC13; microRNA

DOI:  https://doi.org/10.1186/s12943-024-02224-3
ACS Appl Mater Interfaces. 2025 Jan 27.

Metal-Phenolic Nanomedicines Targeting Fatty Acid Metabolic Reprogramming to Overcome Immunosuppression in Radiometabolic Cancer Therapy.

Guohao Wang, Dongmei Wang, Lu Xia, Jiabian Lian, Qing Zhang, Dongyan Shen, Zhanxiang Wang, Yunlu Dai.

  Radiation therapy (RT) is a prevalent cancer treatment; however, its therapeutic outcomes are frequently impeded by tumor radioresistance, largely attributed to metabolic reprogramming characterized by increased fatty acid uptake and oxidation. To overcome this limitation, we developed polyphenol-metal coordination polymer (PPWQ), a novel nanoradiotherapy sensitizer specifically designed to regulate fatty acid metabolism and improve RT efficacy. These nanoparticles (NPs) utilize a metal-phenolic network (MPN) to integrate tungsten ions (W6+), quercetin (QR), and a PD-L1-blocking peptide within a PEG-polyphenol scaffold. When exposed to X-rays, PPWQ induces reactive oxygen species (ROS) to cause DNA damage, while QR inhibits CD36 expression, effectively curbing fatty acid uptake and mitigating immune evasion. In a 4T1 tumor-bearing mouse model, PPWQ demonstrated significant enhancement of RT by facilitating dendritic cell activation, boosting memory cytotoxic T lymphocytes, and skewing macrophages toward a pro-immune phenotype. These results underscore the potential of PPWQ to target metabolic vulnerabilities and advance the integration of immunotherapy with radiotherapy.

Keywords:  cancer radiotherapy; fatty acid; immunotherapy; metal−phenolic networks; radiosensitizer

DOI:  https://doi.org/10.1021/acsami.4c21028