bims-meract 2025-06-01 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–06–01
nineteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Overexpression of c-Myc triggers p62 aggregation-mediated mitochondrial mitophagy in cabozantinib resistance of hepatocellular carcinoma.
Butyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidation.
Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights.
CRISPR screen reveals a simultaneous targeted mechanism to reduce cancer cell selenium and increase lipid oxidation to induce ferroptosis.
Metabolomic reprogramming of the tumor microenvironment by dual arginase inhibitor OATD-02 boosts anticancer immunity.
Alteration in expression and subcellular localization of the androgen receptor- regulated FAM111A protease is associated with emergence of castration resistant prostate cancer.
Triggering ferroptosis in drug-tolerant cancer cells.
Therapeutic applications of a novel humanized monoclonal antibody targeting chemokine receptor CCR9 in pancreatic cancer.
Prognostic implication of six m6A-modulated genes signature in the ferroptosis for hepatocellular carcinoma patients.
DNA repair and the contribution to chemotherapy resistance.
Laminar shear stress promotes accumulation of polyunsaturated fatty acid in aortic endothelial cells through upregulation of LPCAT3 enzyme activity.
High KYNU Expression Is Associated with Poor Prognosis, KEAP1/STK11 Mutations, and Immunosuppressive Metabolism in Patient-Derived but Not Murine Lung Adenocarcinomas.
Inhibition of TPI1 Sensitizes Cisplatin-Resistant Oral Cancer to Ferroptosis.
Circular Nucleic Acids Act as an Oncogenic MicroRNA Sponge to Inhibit Hepatocellular Carcinoma Progression.
PI3Kδ as a Novel Therapeutic Target for Aggressive Prostate Cancer.
Defining key parameters of therapeutic activity using mouse cancer neoepitopes.
PRPS activity tunes redox homeostasis in Myc-driven lymphoma.
IL-6/KIAA1429 promotes ferroptosis resistance in endometrial cancer through m6A modification of DDIT3.
Inhibition of mitochondrial protein import and proteostasis by a pro-apoptotic lipid.

Mol Med. 2025 May 27. 31(1): 209

Overexpression of c-Myc triggers p62 aggregation-mediated mitochondrial mitophagy in cabozantinib resistance of hepatocellular carcinoma.

Kaibo Yang, Xing Zhang, Kun Yang, Sinan Liu, Jingyao Zhang, Yunong Fu, Tong Liu, Kunjin Wu, Jing Li, Chang Liu, Qichao Huang, Kai Qu.

  Resistance to tyrosine kinase inhibitors (TKIs) poses a significant challenge in the treatment of hepatocellular carcinoma (HCC). Although dysregulation of mitochondrial dynamics has been implicated in the aggressive behaviors of various tumors, the specific role and underlying mechanisms by which this dysregulation contributes to cabozantinib resistance in HCC cells remains insufficiently characterized. By investigating mitochondrial dynamics as central regulators of cabozantinib resistance, this work specifically aims to discover actionable targets for restoring drug sensitivity in treatment-refractory HCC cells. We employed transmission electron microscopy (TEM) and confocal microscopy to analyze mitochondrial morphology in HCC cells resistant to TKIs. Additionally, we utilized an oncogene hydrodynamic injection-induced primary liver cancer mouse model to assess the therapeutic efficacy of combining cabozantinib with other pharmacological agents. Our results demonstrated significant increases in mitochondrial fragmentation, p62 aggregation, and mitophagy in cabozantinib-resistant HCC cells, which correlated with overexpression of c-Myc. Notably, inhibiting mitochondrial fission, p62 aggregation, or autophagy effectively reversed the resistance of HCC cells to cabozantinib. Mechanistically, cabozantinib treatment was shown to induce c-Myc expression, which significantly enhanced mitochondrial fragmentation and p62 aggregation, thereby promoting mitophagy. This mitophagic process selectively eliminated damaged mitochondria, reducing cytochrome C-induced apoptosis in cabozantinib-resistant cells. Ultimately, combining cabozantinib with either the autophagy inhibitor chloroquine or the p62 aggregation inhibitor XRK3F2 resulted in improved anticancer efficacy. In conclusion, c-Myc overexpression facilitates p62 aggregation-mediated mitophagy, leading to cabozantinib resistance in HCC cells. Inhibition of autophagy effectively restores cabozantinib sensitivity in HCC.

Keywords:  C-Myc; Cabozantinib resistance; HCC; Mitophagy; P62 aggregation

DOI:  https://doi.org/10.1186/s10020-025-01263-w
Discov Oncol. 2025 May 27. 16(1): 935

Butyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidation.

Ran Zhu, Shujiang Gu, Yuan Tao, Yan Zhang.

  Immunotherapy including anti-PD-1 demonstrated therapeutic promise to colorectal cancer (CRC) patients, but tumor cell resistance limits their efficacy. Butyrate may influence therapeutic outcomes by modulating tumor metabolism, but it remains unclear whether butyrate influences CRC cell resistance to anti-PD-1 therapy. We aimed to investigate whether butyrate promotes resistance to anti-PD-1 therapy in CRC and underlying metabolic and immunologic mechanisms. CRC murine models were established by subcutaneously inoculating MC38 cells or butyrate/anti-PD-1-administered tumor cells of mice, followed by treatment with butyrate, anti-PD-1, or a combination. Therapeutic efficacy was assessed by tumor growth and survival outcomes. In vitro, HCT116 cells were exposed to monotherapy or co-therapy regimens. Carnitine Palmitoyltransferase 1A (CPT1A) knockdown was conducted by shRNA transfection both in vivo and in vitro. Fatty acid oxidation (FAO) was determined by oxygen consumption rate and CPT1A expression. CD8+ T cell cytotoxicity assays and CD8 expression in tumors were performed to evaluate immune cell infiltration. The addition of butyrate into anti-PD-1 treatment combination did not improve survival or reduce tumor volume compared to anti-PD-1 alone, with a marked activation of CPT1A observed in treated tumor tissues. Butyrate significantly elevated FAO, contributing to elevated oxygen consumption rate and reduced CD8+ T cell cytotoxicity. However, in sh-CPT1A models, the combination therapy significantly improved antitumor efficacy and restored CD8+ T cell infiltration. Furthermore, CRC patient samples resistant to anti-PD-1 therapy exhibited elevated CPT1A levels. Butyrate-induced CPT1A-mediated FAO promotes resistance to anti-PD-1 therapy in CRC, suggesting that targeting CPT1A might enhance the efficacy of immunotherapy.

Keywords:  Anti-PD-1 therapy; Butyrate; CPT1A; Colorectal cancer; Fatty acid oxidation; Immune resistance

DOI:  https://doi.org/10.1007/s12672-025-02686-x
Cancer Metab. 2025 May 29. 13(1): 26

Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights.

Shyng-Shiou F Yuan, Anupama Vadhan, Hieu D H Nguyen, Pang-Yu Chen, Chih-Huang Tseng, Ching-Hu Wu, Yu-Chieh Chen, Yi-Chia Wu, Stephen Chu-Sung Hu, Steven Lo, Ming-Feng Hou, Yen-Yun Wang.

Breast cancer remains the most prevalent malignancy among women globally, with its complexity linked to genetic variations and metabolic alterations within tumor cells. This study investigates the role of fumarate hydratase (FH), a key enzyme in the tricarboxylic acid (TCA) cycle, in breast cancer progression. Our findings reveal that FH mRNA and protein levels are significantly upregulated in breast cancer tissues and correlate with poor patient prognosis and aggressive tumor characteristics. Using in vitro and in vivo models, we demonstrate that FH overexpression enhances breast cancer cell proliferation, migration, and invasion through metabolic reprogramming and by increasing reactive oxygen species (ROS) production. Furthermore, we identify matrix metalloproteinase 1 (MMP1) as a downstream effector of FH, linked to p21 downregulation, elucidating a novel regulatory pathway influencing tumor behavior. Interestingly, unlike its tumor-suppressing role in other cancer types, this study highlights FH's oncogenic potential in breast cancer. Our results suggest that FH enhances cancer cell viability and aggressiveness via both catalytic and non-catalytic mechanisms. This work not only underscores the metabolic adaptations of breast cancer cells but also proposes FH as a potential biomarker and therapeutic target for breast cancer management.

DOI: https://doi.org/10.1186/s40170-025-00397-z
Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2502876122

CRISPR screen reveals a simultaneous targeted mechanism to reduce cancer cell selenium and increase lipid oxidation to induce ferroptosis.

Sophia M Lamperis, Kaylin M McMahon, Andrea E Calvert, Jonathan S Rink, Karthik Vasan, Madhura R Pandkar, Eliana U Crentsil, Zachary R Chalmers, Natalie R McDonald, Cameron J Kosmala, Marcelo G Bonini, Daniela Matei, Leo I Gordon, Navdeep S Chandel, C Shad Thaxton.

  Ferroptosis is a cell death mechanism distinguished by its dependence on iron-mediated lipid oxidation. Cancer cells highly resistant to conventional therapies often demonstrate lipid metabolic and redox vulnerabilities that sensitize them to cell death by ferroptosis. These include a unique dependency on the lipid antioxidant selenoenzyme, glutathione peroxidase 4 (GPx4), that acts as a ferroptosis inhibitor. Synthetic high-density lipoprotein-like nanoparticle (HDL NP) targets the high-affinity HDL receptor scavenger receptor class B type 1 (SR-B1) and regulates cell and cell membrane lipid metabolism. Recently, we reported that targeting cancer cell SR-B1 with HDL NP depleted cell GPx4, which is accompanied by increased cell membrane lipid peroxidation and cancer cell death. These data suggest that HDL NP may induce ferroptosis. Thus, we conducted an unbiased CRISPR-based positive selection screen and target validation studies in ovarian clear cell carcinoma (OCCC) cell lines to ascertain the mechanism through which HDL NP regulates GPx4 and kills cancer cells. The screen revealed two genes, acyl-CoA synthetase long chain family member 4 (ACSL4) and thioredoxin reductase 1 (TXNRD1), whose loss conferred resistance to HDL NP. Validation of ACSL4 supports that HDL NP induces ferroptosis as the predominant mechanism of cell death, while validation of TXNRD1 revealed that HDL NP reduces cellular selenium and selenoprotein production, most notably, GPx4. Accordingly, we define cancer cell metabolic targets that can be simultaneously actuated by a multifunctional, synthetic HDL NP ligand of SR-B1 to kill cancer cells by ferroptosis.

Keywords:  cancer; cell death; ferroptosis; lipids; nanoparticles

DOI:  https://doi.org/10.1073/pnas.2502876122
Sci Rep. 2025 May 28. 15(1): 18741

Metabolomic reprogramming of the tumor microenvironment by dual arginase inhibitor OATD-02 boosts anticancer immunity.

Marcin Mikołaj Grzybowski, Yasemin Uçal, Angelika Muchowicz, Tomasz Rejczak, Agnieszka Kikulska, Katarzyna Maria Głuchowska, Małgorzata Szostakowska-Rodzoś, Agnieszka Zagożdżon, Tobias Bausbacher, Agnieszka Tkaczyk, Magdalena Kulma, Paulina Pomper, Michał Mlącki, Adam Konrad Jagielski, Roman Błaszczyk, Carsten Hopf, Zbigniew Zasłona.

  Metabolic reprogramming within the tumor microenvironment (TME) plays a central role in cancer progression and immune evasion, with L-arginine metabolism emerging as a key regulatory axis. Arginase overexpression depletes intratumoral L-arginine, thus suppressing T-cell proliferation while fuelling tumor growth through polyamine biosynthesis. OATD-02, a novel dual arginase (ARG1/ARG2) inhibitor, reprograms tumor metabolism by restoring L-arginine availability and reducing the levels of polyamines, thereby shifting the TME toward a more immunostimulatory state. Unlike ARG1-selective inhibitors with limited intracellular uptake, OATD-02 effectively inhibits both extracellular and intracellular arginases, thereby addressing a major limitation of first-generation arginase inhibitors. To visualize the pharmacodynamic effects of OATD-02 dosing in mice with spatial resolution, we employed MALDI mass spectrometry imaging (MALDI-MSI), thus enabling direct mapping of metabolic changes within tumor tissues. In preclinical models, OATD-02 treatment led to widespread accumulation of intratumoral L-arginine with concomitant depletion of polyamines and resulted in metabolic shifts that correlated with increased immune cell infiltration and an improved response to immune checkpoint blockade. These findings underscore the role of dual arginase inhibition in reshaping tumor metabolism and overcoming immune suppression by restoring the metabolic fitness of immune cells to fight cancer. The metabolic changes caused by OATD-02 treatment resulted in significantly enhanced antitumor immune responses, increased T-cell infiltration in tumors, expansion of CD8⁺ T cells in draining lymph nodes, and systemic upregulation of T-cell activation markers. These effects translated into a substantial survival benefit in the CT26 tumor model, particularly when combined with anti-PD-1 therapy, where OATD-02 improved checkpoint blockade efficacy by relieving metabolic constraints affecting tumor-infiltrating lymphocytes. By leveraging the unique capabilities of MALDI-MSI, this study provides high-resolution metabolic insights into the mechanism of action of OATD-02, reinforcing its potential as a next-generation metabolic-immunotherapeutic agent. The observed metabolic reprogramming, coupled with enhanced immune activation and prolonged survival, supports the clinical development of OATD-02 as a promising strategy for enhancing cancer immunotherapy efficacy. OATD-02 is currently undergoing clinical evaluation in a phase I/II trial (NCT05759923), which will further elucidate its safety and therapeutic impact. These findings highlight the potential of arginase-targeted therapies in cancer treatment and underscore the value of MALDI-MSI as a powerful tool for tracking metabolic responses to therapy.

Keywords:  Anticancer therapy; Arginine metabolism; Dual arginase Inhibition; Immune modulation; MALDI imaging; Metabolic reprogramming; Mitochondrial metabolism; OATD-02; Polyamines; Tumor metabolism

DOI:  https://doi.org/10.1038/s41598-025-03446-1
Neoplasia. 2025 May 29. pii: S1476-5586(25)00060-0. [Epub ahead of print]66 101181

Alteration in expression and subcellular localization of the androgen receptor- regulated FAM111A protease is associated with emergence of castration resistant prostate cancer.

Maria Malvina Tsamouri, Stephen J Libertini, Salma Siddiqui, Maitreyee K Jathal, Blythe P Durbin-Johnson, Clifford G Tepper, Eva Corey, Jun Luo, Kenneth A Iczkowski, Paramita M Ghosh, Maria Mudryj.

  The androgen receptor (AR) is a pivotal regulator of growth and survival of prostate cancer (PCa) and the majority of lethal castration-resistant prostate cancers (CRPC) remain reliant on AR signaling. PCa exhibits variability in progression and responses to treatment suggesting genetic heterogeneity. Two independent studies identified PCa predisposing single nucleotide polymorphisms (SNPs) within the FAM111A protease gene, but the mechanistic basis of this association remained elusive. Our in vitro and in vivo studies uncovered that AR represses FAM111A in castration sensitive and resistant cells via an AR binding site within the FAM111A gene. FAM111A levels are significantly lower in matched castration-resistant than in castration-sensitive cells and xenografts, and lower in metastatic lesions than in primary tumors. We discovered that FAM111A is AR-repressed in castration sensitive PCa xenograft and multiple PCa cells. Additionally, FAM111A subcellular localization changes dramatically with acquisition of castration resistance, where in castration sensitive cells FAM111A is predominantly in the nucleoli, but with castration resistance it becomes more dispersed in the nucleus and in the cytoplasm. FAM111A depletion in castration sensitive and resistant cells enhances the efficacy of PARP1 inhibitors olaparib and niraparib, consistent with its role in DNA repair. Moreover, FAM111A depletion reduces AR target gene prostate specific antigen (PSA) and transmembrane serine protease 2 (TMPRSS2) transcription, indicating that FAM111A modulates AR-dependent gene expression forming a FAM111A-AR co-regulatory loop in PCa. Our studies argue that AR-dependent FAM111A regulation modulates PCa gene expression, acquisition of castration resistance, and sensitivity to agents that target DNA damage repair.

Keywords:  Androgen receptor; Castration resistant prostate cancer; FAM111A; Metastases, Nucleoli, Subcellular; Prostate cancer

DOI:  https://doi.org/10.1016/j.neo.2025.101181
Nat Rev Drug Discov. 2025 May 27.

Triggering ferroptosis in drug-tolerant cancer cells.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-025-00090-2
Mol Oncol. 2025 May 28.

Therapeutic applications of a novel humanized monoclonal antibody targeting chemokine receptor CCR9 in pancreatic cancer.

Hannah G McDonald, Anna M Reagan, Charles J Bailey, Mei Gao, Muqiang Gao, Angelica L Solomon, Michael J Cavnar, Prakash K Pandalai, Mautin T Barry-Hundeyin, Megan M Harper, Justin A Rueckert, Ángela Turrero, Araceli Tobio, Anxo Vidal, Daniel Roca-Lema, Elia Álvarez-Coiradas, Pablo Garrido, Laureano Simón, Joseph Kim.

  The relative failure of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) despite having a dense, immunosuppressive tumor microenvironment highlights the need to target alternate/escape pathways. We have previously examined C-C chemokine receptor type 9 (CCR9) as a candidate immune checkpoint and developed a targeted, humanized monoclonal antibody (SRB2). Cytotoxicity of SRB2 was evaluated in vitro and in vivo. CCR9 expression on PDAC cells/tissues, immune components of patient-derived organoids (PDOs), and antibody-dependent cell-mediated cytotoxicity were examined. In PANC-1 and MIA PaCa-2 cell lines, we demonstrated highest CCR9 expression; however, no direct cytotoxic effect was observed with SRB2 treatment. In PANC-1 cells, NK cell-mediated cytotoxicity was promoted by SRB2. Dose-dependent SRB2 cytotoxicity was observed in PDAC PDOs. In patient-derived xenograft mouse models, cytotoxicity of SRB2 monotherapy and in combination with oxaliplatin was also shown. In humanized immune-competent mouse models, SRB2 efficacy was similar to other drugs, but two mice in this cohort had complete tumor regression. Our current studies suggest that therapeutic targeting of CCR9 may improve PDAC outcomes, and additional studies are underway to evaluate SRB2 for clinical use.

Keywords:  chemokine receptor CCR9; immune checkpoint; pancreatic cancer

DOI:  https://doi.org/10.1002/1878-0261.70062
Clin Exp Med. 2025 May 27. 25(1): 180

Prognostic implication of six m6A-modulated genes signature in the ferroptosis for hepatocellular carcinoma patients.

Yu He, Zhilin Zou, Zuyong Lan, Ming Chang, Xiao Zhang, Risheng Lin, Wen Zhang, Guangtao Zhang, Ting Wang, Erbao Chen.

  Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal malignancies worldwide, with survival rates still falling short of expectations. Emerging evidence highlights the pivotal roles of both m6A methylation and ferroptosis-related genes (FRGs) in HCC progression. However, the prognostic significance of m6A-modulated FRGs remains largely unexplored. In this study, we developed a novel prognostic signature based on m6A-regulated FRGs, identifying six key genes (VEGFA, FANCD2, ZFP69B, EIF2S1, SLC7A11, and SRXN1) through multivariate and LASSO Cox regression analyses. A high m6A-FRGs score was strongly associated with poor prognosis, and multivariate analysis confirmed it as an independent prognostic factor. Notably, the high-risk group exhibited increased expression of immune checkpoint genes and a higher frequency of gene mutations. Functional assays further demonstrated that silencing ZFP69B significantly suppressed liver cancer cell proliferation, migration, and invasion. Clinical validation in 144 HCC samples revealed that elevated ZFP69B expression correlated with worse patient outcomes. Moreover, qPCR analysis confirmed CLSPN and HNRNPR as downstream targets of ZFP69B. Collectively, our findings establish the m6A-FRGs signature as a powerful prognostic tool for HCC and identify ZFP69B as a promising therapeutic target, warranting further investigation.

Keywords:  Ferroptosis; Hepatocellular carcinoma; Immunotherapy; M6-methyladenosine; Prognostic signature; ZFP69B

DOI:  https://doi.org/10.1007/s10238-025-01700-4
Genome Med. 2025 May 26. 17(1): 62

DNA repair and the contribution to chemotherapy resistance.

Ksenija Nesic, Phoebe Parker, Elizabeth M Swisher, John J Krais.

  The DNA damage response comprises a set of imperfect pathways that maintain cell survival following exposure to DNA damaging agents. Cancers frequently exhibit DNA repair pathway alterations that contribute to their intrinsic genome instability. This, in part, facilitates a therapeutic window for many chemotherapeutic agents whose mechanisms of action often converge at the generation of a double-strand DNA break. The development of therapy resistance occurs through countless molecular mechanisms that promote tolerance to DNA damage, often by preventing break formation or increasing repair capacity. This review broadly discusses the DNA damaging mechanisms of action for different classes of chemotherapeutics, how avoidance and repair of double-strand breaks can promote resistance, and strategic directions for counteracting therapy resistance.

Keywords:  Chemotherapy resistance; DNA damage response; DNA repair

DOI:  https://doi.org/10.1186/s13073-025-01488-8
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 May 23. pii: S1388-1981(25)00046-0. [Epub ahead of print] 159638

Laminar shear stress promotes accumulation of polyunsaturated fatty acid in aortic endothelial cells through upregulation of LPCAT3 enzyme activity.

Delphine Bousquet, Nicolas Guillot.

   OBJECTIVE: Endothelial cells (ECs) play an important role in tissue homeostasis. Hemodynamic laminar shear stress are involved in both the physiological and pathological function of endothelial cells EC. Lipid metabolism has emerged as a potential regulator of EC function. Here, we aim to decipher the role of laminar shear stress in the regulation of lipid metabolism in human aortic endothelial cells.
APPROACH AND RESULTS: Human aortic endothelial cells (HAOEC) were exposed to laminar shear stress, and lipid metabolism was analyzed. We found that laminar flow increased polyunsaturated fatty acid (PUFA) content in both neutral and polar lipids. These changes in fatty acid composition were dependent on lysophosphatidylcholine acyltransferase 3 (LPCAT3), which was specifically upregulated by laminar shear stress at both the mRNA and activity levels. Fatty acid uptake was also modulated by shear stress, partly via the LXR pathway. Notably, mechanical stimulation did not alter de novo fatty acid synthesis. However, fatty acid oxidation was upregulated in response to laminar shear stress, involving AMPK and ACC phosphorylation. These modifications in HAOEC fatty acid composition ultimately led to the release of a distinct pattern of lipid metabolites.
CONCLUSION: Overall these data revealed that laminar shear stress increased the turnover of FA acid and in human aortic endothelial cells through the activation of the LPCAT 3 enzyme.

Keywords:  Endothelial cells; LPCAT3; Lipids; Metabolism; Shear stress

DOI:  https://doi.org/10.1016/j.bbalip.2025.159638
Cancers (Basel). 2025 May 16. pii: 1681. [Epub ahead of print]17(10):

High KYNU Expression Is Associated with Poor Prognosis, KEAP1/STK11 Mutations, and Immunosuppressive Metabolism in Patient-Derived but Not Murine Lung Adenocarcinomas.

Ling Cai, Thomas J Rogers, Reza Mousavi Jafarabad, Hieu Vu, Chendong Yang, Nicole Novaresi, Ana Galán-Cobo, Luc Girard, Edwin J Ostrin, Johannes F Fahrmann, Jiyeon Kim, John V Heymach, Kathryn A O'Donnell, Guanghua Xiao, Yang Xie, Ralph J DeBerardinis, John D Minna.

  Background/Objectives: We aimed to discover genes with bimodal expression linked to patient outcomes, to reveal underlying oncogenotypes and identify new therapeutic insights in lung adenocarcinoma (LUAD). Methods: We performed meta-analysis to screen LUAD datasets for prognostic genes with bimodal expression patterns. Kynureninase (KYNU), a key enzyme in tryptophan catabolism, emerged as a top candidate. We then examined its relationship with LUAD mutations, metabolic alterations, immune microenvironment states, and expression patterns in human and mouse models using bulk and single-cell transcriptomics, metabolomics, and preclinical model datasets. Pan-cancer prognostic associations were also assessed. Results: Model-based clustering of KYNU expression outperformed median-based dichotomization in prognostic accuracy. KYNU was elevated in tumors with KEAP1 and STK11 co-mutations but remained a strong independent prognostic marker. Metabolomic analysis showed that KYNU-high tumors had increased anthranilic acid, a catalytic product, while maintaining stable kynurenine levels, suggesting a compensatory mechanism sustaining immunosuppressive signaling. Single-cell and bulk data showed KYNU expression was cancer cell-intrinsic in immune-cold tumors and myeloid-derived in immune-infiltrated tumors. In murine LUAD models, Kynu expression was predominantly immune-derived and uncoupled from Nrf2/Lkb1 signaling, indicating poor model fidelity. KYNU's prognostic associations extended across cancer types, with poor outcomes in pancreatic and kidney cancers but favorable outcomes in melanoma, underscoring the need for lineage-specific considerations in therapy development. Conclusions:KYNU is a robust prognostic biomarker and potential immunometabolic target in LUAD, especially in STK11 and KEAP1 co-mutated tumors. Its cancer cell-intrinsic expression and immunosuppressive metabolic phenotype offer translational potential, though species-specific expression patterns pose challenges for preclinical modeling.

Keywords:  KEAP1; KYNU; NAD metabolism; STK11; immune suppression; kynureninase; kynurenine pathway; lung adenocarcinoma; mouse model limitations; prognostic biomarker; tryptophan catabolism

DOI:  https://doi.org/10.3390/cancers17101681
Biomedicines. 2025 May 19. pii: 1225. [Epub ahead of print]13(5):

Inhibition of TPI1 Sensitizes Cisplatin-Resistant Oral Cancer to Ferroptosis.

Dandan Wang, Huimin Zheng, Yumin Chen, Jialin Hao, Yuan Zhou, Nan Li.

  Background: Iron metabolism has emerged as a critical factor in cancer biology, with elevated intracellular iron levels contributing to increased oxidative stress and tumorigenesis. However, the molecular determinants governing ferroptosis sensitivity remain incompletely understood. Triosephosphate isomerase 1 (TPI1), a key glycolytic enzyme, has been implicated in cancer progression, but its role in ferroptosis regulation, particularly in the context of chemoresistance, is largely unexplored. In this study, we investigated the impact of TPI1 silencing on ferroptosis in cisplatin-resistant oral squamous cell carcinoma (OSCC), aiming to elucidate its mechanistic role and therapeutic potential. Methods: We conducted in vitro and in vivo analyses to evaluate the functional consequences of TPI1 knockdown in cisplatin-resistant OSCC cell lines and tumor xenograft models. The effects of TPI1 silencing and/or cisplatin treatment were assessed with respect to cell proliferation, migration, and invasion, along with ferroptosis-associated markers, including lipid ROS, free iron levels, lipid peroxidation, and the expression of key ferroptosis-related genes. Additionally, we analyzed the clinical relevance of TPI1 expression in human OSCC tissue samples, examining its association with clinicopathological features and patient prognosis. Results: TPI1 was found to be significantly upregulated in both OSCC tissues and cell lines, and high TPI1 expression correlated with poor clinical outcomes. Multivariate analysis identified TPI1 as an independent prognostic factor for tumor progression. Functionally, TPI1 knockdown suppressed OSCC cell proliferation, migration, and invasion, while its overexpression enhanced these oncogenic behaviors. Mechanistically, silencing TPI1 led to increased intracellular ROS accumulation, elevated free iron, and enhanced lipid peroxidation, collectively promoting ferroptotic cell death in cisplatin-resistant OSCC cells. In vivo, TPI1 depletion resulted in marked tumor growth inhibition and synergized with cisplatin to further suppress tumor burden in xenograft models. Moreover, TPI1 silencing disrupted the epithelial-mesenchymal transition (EMT), a key driver of cancer metastasis and drug resistance. Conclusions: Our study reveals a previously unrecognized role of TPI1 in protecting oral cancer cells from ferroptosis, especially in the setting of cisplatin resistance. These findings suggest that TPI1 not only contributes to tumor aggressiveness but also mediates resistance to ferroptosis. Targeting TPI1 may therefore represent a promising therapeutic strategy to overcome chemoresistance and enhance ferroptosis-based therapies in oral cancer.

Keywords:  TPI1; cisplatin-resistant; ferroptosis; oral cancer

DOI:  https://doi.org/10.3390/biomedicines13051225
Biomedicines. 2025 May 11. pii: 1171. [Epub ahead of print]13(5):

Circular Nucleic Acids Act as an Oncogenic MicroRNA Sponge to Inhibit Hepatocellular Carcinoma Progression.

Qianyi Zhang, Pengcheng Sun, Guang Hu, Xuanyao Yu, Wen Zhang, Xuan Feng, Lan Yu, Pengfei Zhang.

  Background: Aberrant expression of microRNAs in neoplastic lesions may serve as potential personalized therapeutic targets. To inhibit oncogenic microRNAs (oncomiRs) expression and restore tumor suppressor proteins, linear miRNA sponges have been developed, leading to several drugs in clinical trials. Despite their efficacy, chemically synthesized miRNA inhibitors face challenges with sustained inhibition and high production costs, hindering widespread clinical adoption. Additionally, single-stranded circular RNAs (circRNAs) act as miRNA sponges, enhancing protein expression and demonstrating stability and therapeutic potential in cancer treatment. Our approach involves the use of synthetic single-stranded circular nucleic acids, including circDNA and circRNA, to selectively target and inhibit a variety of aberrantly overexpressed oncomiRs in tumors. The objective of this strategy is to restore the expression levels of multiple tumor suppressor factors and to suppress the malignant progression of tumors. Methods: Our methodology comprises a two-step process. First, we identified tumor suppressor genes (TSGs) with abnormally low expression in hepatocellular carcinoma (HCC) tumor cells by transcriptomic analysis and targeted the upstream cancer miRNA clusters of these TSGs. Second, we designed and validated a fully complementary circDNA or circRNA construct, ligated by T4 DNA ligase or T4 RNA ligase, respectively, that specifically targets the sponge oncomiRs both in vitro and in vivo to inhibit the malignant progression of HCC. Results: CircNAs demonstrated superior, long-lasting therapeutic efficacy against HCC compared to inhibitors. Furthermore, we compared the immune effects in vivo of three different nucleic acid adsorption carriers, including commercial miRNA inhibitor, circDNA, and circRNA. We found that the miRNA inhibitor activates a more robust inflammatory response compared to circDNA and circRNA. Conclusions: These findings underscore the substantial therapeutic potential of circDNA in tumorigenesis and provide novel insights for the formulation of personalized treatment plans for malignant tumors, such as HCC.

Keywords:  HCC; cancer therapy; circular single-stranded nucleic acids; miRNA sponges

DOI:  https://doi.org/10.3390/biomedicines13051171
Cancers (Basel). 2025 May 09. pii: 1610. [Epub ahead of print]17(10):

PI3Kδ as a Novel Therapeutic Target for Aggressive Prostate Cancer.

Bi-Dar Wang, Alyssa Lucero, Siyoung Ha, Reyhaneh Yarmohammadi.

  Phosphoinositide 3-kinases (PI3Ks) signaling represents an important pathway regulating cell proliferation, survival, invasion, migration, and metabolism. Notably, PI3K/AKT/mTOR signaling is frequently dysregulated in the majority of malignancies. Among the class IA PI3Ks (PI3Kα/β/δ), emerging evidence has implicated that PI3Kδ is not only overexpressed in leukocytes but also in solid tumors, including prostate cancer. The critical role of PI3Kδ in tumorigenesis and in the creation of a suppressive tumor microenvironment, along with the recent finding of PI3Kδ splice isoforms in promoting tumor aggressiveness and resistance, further demonstrates the potential of developing novel PI3Kδ-targeted cancer therapies. In this review, we comprehensively describe the functional mechanisms underlying the PI3Kδ-driven tumor progression and immune regulation in prostate cancer diseases. Furthermore, the recent preclinical and clinical studies on the development of PI3Kδ-/PI3K-targeted inhibitors as single agents and in combination therapies (with chemotherapy, radiation, hormone therapy, or immunotherapy) are summarized. Finally, we discuss the potential novel therapies for improving the treatment efficacies, as well as the current limitations and challenges of PI3Kδ-based therapies for prostate cancer.

Keywords:  PI3K/AKT/mTOR signaling; PI3Kδ and pan-PI3K inhibitors; androgen receptor inhibitors; combination therapies; immune checkpoint blockers; phosphoinositide 3-kinases delta (PI3Kδ); splice isoforms; tumor immune microenvironment

DOI:  https://doi.org/10.3390/cancers17101610
J Immunol. 2025 May 30. pii: vkaf090. [Epub ahead of print]

Defining key parameters of therapeutic activity using mouse cancer neoepitopes.

Summit Singhaviranon, Joseph P Dempsey, Hakimeh Ebrahimi-Nik, Pramod Kumar Srivastava.

  Cancer neoepitopes have emerged as strong candidates as cancer vaccines. Mouse models of cancer neoepitopes often test their activity in models of prophylaxis, while the human setting is always in therapy of preexisting disease. We have previously identified 7 MHC I-presented cancer neoepitopes of the BALB/c sarcoma Meth A by mass spectrometry; 3 of the 7 neoepitopes showed anti-tumor activity in assays of prophylaxis. Here, we test these neoepitopes for activity in treatment of preexisting 3-, 10- and 17-d old cancers, and observe that: (i) activity in prophylaxis is not predictive of efficacy in treatment of preexisting cancers. (ii) The higher activity of a neoepitope in therapy, albeit not in prophylaxis, correlates well with the high precursor frequency of CD8 T cells. (iii) Co-immunization with CD4 and CD8 neoepitopes is essential for optimal therapeutic efficacy. CD4 help can be obtained from an MHC II-restricted neoepitope of the tumor, or from an irrelevant MHC II-epitope. (iv) The CTL and helper epitopes, linked or un-linked to each other, are equally effective. These insights stress and stretch some of our current suppositions and shall inform designs for use of neoepitopes in cancer treatment.

Keywords:  CD4 T cells; CD8 T cells; antigens; precursor frequency; tumor immunity

DOI:  https://doi.org/10.1093/jimmun/vkaf090
Redox Biol. 2025 Apr 25. pii: S2213-2317(25)00162-4. [Epub ahead of print]84 103649

PRPS activity tunes redox homeostasis in Myc-driven lymphoma.

Austin C MacMillan, Bibek Karki, Juechen Yang, Karmela R Gertz, Samantha Zumwalde, Jay G Patel, Maria F Czyzyk-Krzeska, Jarek Meller, John T Cunningham.

  Myc hyperactivation coordinately regulates numerous metabolic processes to drive lymphomagenesis. Here, we elucidate the temporal and functional relationships between the medley of pathways, factors, and mechanisms that cooperate to control redox homeostasis in Myc-overexpressing B cell lymphomas. We find that Myc overexpression rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleotide synthesis, and mitochondrial respiration, which collectively steers cellular equilibrium to a more oxidative state. We identify Myc-dependent hyperactivation of the phosphoribosyl pyrophosphate synthetase (PRPS) enzyme as a primary regulator of redox status in lymphoma cells. Mechanistically, we show that genetic inactivation of the PRPS2 isozyme, but not PRPS1, in Myc-driven lymphoma cells leads to elevated NADPH levels and reductive stress-mediated death. Employing a pharmacological screen, we demonstrate how targeting PRPS1 or PRPS2 elicits opposing sensitivity or resistance, respectively, to chemotherapeutic agents affecting the thioredoxin and glutathione network, thus providing a therapeutic blueprint for treating Myc-driven lymphomas.

Keywords:  Enzymatic regulation; Mitochondrial respiration; Oxidative/reductive stress; Pentose phosphate pathway; Purine metabolism; Redox metabolism

DOI:  https://doi.org/10.1016/j.redox.2025.103649
Cell Signal. 2025 May 26. pii: S0898-6568(25)00321-3. [Epub ahead of print] 111906

IL-6/KIAA1429 promotes ferroptosis resistance in endometrial cancer through m6A modification of DDIT3.

Xiaoyu Shen, Wan Shu, Jun Zhang, Ting Zhou, Kejun Dong, Jiarui Zhang, Yuwei Yao, Haojia Li, Shuangshuang Cheng, Tangansu Zhang, Guanxiao Chen, Shuyang Yu, Qi Zhang, Hongbo Wang, Yan Liu.

  Endometrial cancer (EC) exhibits significant resistance to ferroptosis. Interleukin (IL)-6 is a pleiotropic cytokine that is a regulator of the expression of various oncogenes and tumour suppressor genes. Notably, N6-methyladenosine (m6A) modification has been demonstrated to play a significant role in tumour occurrence and development. However, IL-6 regulatory role in ferroptosis during carcinogenesis and whether it affects m6A modification in EC remain unclear. The present study aimed to investigate the effect of IL-6 on m6A modification in EC. The degree of ferroptosis of EC in vitro and in vivo was evaluated using a cell proliferation assay, western blotting, total reactive oxygen species (ROS) detection, a lipid peroxidation assay, and a subcutaneous xenograft tumour model. The regulation of downstream molecules by KIAA1429 was confirmed using dot blot, RNA and methylated RNA immunoprecipitation (RIP), a RNA stability assay, and fluorescence in situ hybridisation (FISH). IL-6 upregulated overall m6A levels in EC cells, with the KIAA1429 expression upregulation being the most significant. Functionally, IL-6 inhibited EC cell ferroptosis and promoted proliferation. The downregulation of KIAA1429 triggered ferroptosis, subsequently suppressing the proliferation of EC cells in vitro and tumour growth in vivo. Mechanistically, IL-6 activated KIAA1429 expression through the JAK1/STAT3 pathway. KIAA1429 regulated DDIT3 expression and promoted its degradation through m6A modification. IL-6 is crucial in EC cell ferroptosis resistance. Overall, the IL-6/KIAA1429/DDIT3 axis is a novel pathway that promotes EC progression and provides novel directions for targeted EC therapy.

Keywords:  Endometrial cancer; Ferroptosis; Interleukin-6; KIAA1429

DOI:  https://doi.org/10.1016/j.cellsig.2025.111906
Elife. 2025 May 30. pii: RP93621. [Epub ahead of print]13

Inhibition of mitochondrial protein import and proteostasis by a pro-apoptotic lipid.

Josep Fita-Torró, José Luis Garrido-Huarte, Lucía López-Gil, Agnès H Michel, Benoit Kornmann, Amparo Pascual-Ahuir, Markus Proft.

  Mitochondria-mediated cell death is critically regulated by bioactive lipids derived from sphingolipid metabolism. The lipid aldehyde trans-2-hexadecenal (t-2-hex) induces mitochondrial dysfunction from yeast to humans. Here, we apply unbiased transcriptomic, functional genomics, and chemoproteomic approaches in the yeast model to uncover the principal mechanisms and biological targets underlying this lipid-induced mitochondrial inhibition. We find that loss of Hfd1 fatty aldehyde dehydrogenase function efficiently sensitizes cells for t-2-hex inhibition and apoptotic cell death. Excess of t-2-hex causes a profound transcriptomic response with characteristic hallmarks of impaired mitochondrial protein import, like activation of mitochondrial and cytosolic chaperones or proteasomal function and severe repression of translation. We confirm that t-2-hex stress induces rapid accumulation of mitochondrial pre-proteins and protein aggregates and subsequent activation of Hsf1- and Rpn4-dependent gene expression. By saturated transposon mutagenesis, we find that t-2-hex tolerance requires an efficient heat shock response and specific mitochondrial and ER functions and that mutations in ribosome, protein, and amino acid biogenesis are beneficial upon t-2-hex stress. We further show that genetic and pharmacological inhibition of protein translation causes t-2-hex resistance, indicating that loss of proteostasis is the predominant consequence of the pro-apoptotic lipid. Several TOM subunits, including the central Tom40 channel, are lipidated by t-2-hex in vitro and mutation of accessory subunits Tom20 or Tom70 confers t-2-hex tolerance. Moreover, the Hfd1 gene dose determines the strength of t-2-hex mediated inhibition of mitochondrial protein import, and Hfd1 co-purifies with Tom70. Our results indicate that the transport of mitochondrial precursor proteins through the outer mitochondrial membrane is sensitively inhibited by the pro-apoptotic lipid and thus represents a hotspot for pro- and anti-apoptotic signaling.

Keywords:  S. cerevisiae; apoptosis; biochemistry; chemical biology; genetics; genomics; lipid signaling; mitochondrial protein import; proteostasis; sphingolipid metabolism; yeast

DOI:  https://doi.org/10.7554/eLife.93621