bims-meract Biomed News
on Metabolic reprogramming and anti-cancer therapy
Issue of 2025–06–22
sixteen papers selected by
Andrea Morandi, Università degli Studi di Firenze
  1. Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis.
  2. GSTP1 knockdown induces metabolic changes affecting energy production and lipid balance in pancreatic cancer cells.
  3. Targeting the NAD+/SIRT1 axis: A metabolic strategy to overcome oxaliplatin resistance in colorectal cancer.
  4. Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications.
  5. Mitochondria-Targeted Microneedles Reverse Doxorubicin Resistance via Apoptosis-Ferroptosis Synergy.
  6. Targeting USP18 overcomes acquired resistance in hepatocellular carcinoma by regulating NCOA4 deISGylation and ferroptosis.
  7. Navigating the role of protein lactylation in prostate cancer and its implications for immunotherapy.
  8. D-mannose augments targeted radioligand-immunotherapy of prostate cancer by enhancing radiosensitivity and reshaping immune microenvironment.
  9. Combined targeting of PRDX6 and GSTP1 as a potential differentiation strategy for neuroblastoma treatment.
  10. Loss of BAP1 defines a unique subtype of TP53-mutated de novo AML and confers sensitivity to BCL-xL inhibitors.
  11. PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer.
  12. Peroxisome proliferator-activated receptor antagonists as emerging therapeutics in cancer treatment.
  13. RSK1-driven TRIM28/E2F1 feedback loop promotes castration-resistant prostate cancer progression.
  14. PARP14-mediated glycolysis enhances Tamoxifen resistance in estrogen receptor + breast cancer cells.
  15. Targeting metabolic reprogramming to overcome immune tolerance in melanoma immunotherapy.
  16. Myeloid-Derived LGALS9-P4HB Immune Interaction Promotes Metastasis in Gastric Cancer Through Enhanced Cell Proliferation and Lipid Metabolism.
  1. Cancer Metab. 2025 Jun 16. 13(1): 28
    Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis.
    Ann-Kathrin Daum, Lisa Schlicker, Marc A Schneider, Thomas Muley, Ursula Klingmüller, Almut Schulze, Michael Thomas, Petros Christopoulos, Holger Sültmann.
       BACKGROUND: Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in patients with ALK-rearranged lung adenocarcinomas, yet resistance occurs almost inevitably. In addition to tumor cell-intrinsic resistance mechanisms, accumulating evidence suggests that cancer-associated fibroblasts (CAFs) within the tumor microenvironment contribute to therapy resistance. This study aimed to investigate CAF-driven molecular networks that shape the therapeutic susceptibility of ALK-driven lung adenocarcinoma cells.
    METHODS: Three-dimensional (3D) spheroid co-cultures comprising ALK-rearranged lung adenocarcinoma cells and CAFs were utilized to model the tumor microenvironment. Single-cell RNA sequencing was performed to uncover transcriptional differences between TKI-treated homotypic and heterotypic spheroids. Functional assays assessed the effects of CAF-conditioned medium and CAF-secreted factors on tumor cell survival, proliferation, lipid metabolism, and downstream AKT signaling. The therapeutic potential of targeting metabolic vulnerabilities was evaluated using pharmacological inhibition of lipid metabolism and by ferroptosis induction.
    RESULTS: CAFs significantly diminished the apoptotic response of lung tumor cells to ALK inhibitors while simultaneously enhancing their proliferative capacity. Single-cell RNA sequencing identified lipogenesis-associated genes as a key transcriptional difference between TKI-treated homotypic and heterotypic lung tumor spheroids. CAF-conditioned medium and the CAF-secreted factors HGF and NRG1 activated AKT signaling in 3D-cultured ALK-rearranged lung tumor cells, leading to increased de novo lipogenesis and suppression of lipid peroxidation. These metabolic adaptations were critical for promoting tumor cell survival and fostering therapy resistance. Notably, both dual inhibition of ALK and the lipid-regulatory factor SREBP-1, as well as co-treatment with ferroptosis inducers such as erastin or RSL3, effectively disrupted the CAF-driven metabolic-supportive niche and restored sensitivity of resistant lung tumor spheroids to ALK inhibition.
    CONCLUSIONS: This study highlights a critical role for CAFs in mediating resistance to ALK-TKIs by reprogramming lipid metabolism in ALK-rearranged lung cancer cells. It suggests that targeting these metabolic vulnerabilities, particularly through inhibition of lipid metabolism or induction of ferroptosis, could provide a novel therapeutic approach to overcome resistance and improve patient outcomes.
    Keywords:  3D cell culture; Cancer-associated fibroblasts; EML4-ALK; Lipid metabolism; Lung adenocarcinoma; Therapy resistance
    DOI:  https://doi.org/10.1186/s40170-025-00400-7
  2. Mol Cell Oncol. 2025 ;12(1): 2518773
    GSTP1 knockdown induces metabolic changes affecting energy production and lipid balance in pancreatic cancer cells.
    Jenna N Duttenhefner, Katie M Reindl.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options, underscoring the need for novel therapeutic targets. Metabolic reprogramming is a hallmark of PDAC, enabling tumor cells to sustain rapid proliferation and survive under nutrient-deprived conditions. While glutathione S-transferase pi 1 (GSTP1) is a known regulator of redox homeostasis in PDAC, its role in metabolic adaptation remains unclear. Here, we show that GSTP1 knockdown disrupts PDAC metabolism, leading to downregulation of key metabolic enzymes (ALDH7A1, CPT1A, SLC2A3, PGM1), ATP depletion, mitochondrial dysfunction, and phospholipid remodeling. Phospholipid remodeling, including an increase in phosphatidylcholine (PC) levels, further suggests a compensatory response to metabolic stress. Importantly, GSTP1 knockdown led to elevated lipid peroxidation, increasing 4-hydroxynonenal (4-HNE) accumulation. Treatment with the antioxidant N-acetyl cysteine (NAC) partially restored metabolic gene expression, reinforcing GSTP1's role in the interplay between redox regulation and metabolism in PDAC. By disrupting multiple metabolic pathways, GSTP1 depletion creates potential therapeutic vulnerabilities that could be targeted through metabolic and oxidative stress-inducing therapies to enhance treatment efficacy.
    Keywords:  Pancreatic ductal adenocarcinoma; glutathione S-transferase pi 1 (GSTP1); metabolic reprogramming; metabolomics; therapeutic targeting
    DOI:  https://doi.org/10.1080/23723556.2025.2518773
  3. World J Gastroenterol. 2025 Jun 07. 31(21): 106530
    Targeting the NAD+/SIRT1 axis: A metabolic strategy to overcome oxaliplatin resistance in colorectal cancer.
    Md Sadique Hussain, Vikash Jakhmola, Kavita Goyal, Arcot Rekha, Ayesha Sultana, Haider Ali, Gaurav Gupta.
      Oxaliplatin resistance remains a significant clinical challenge in colorectal cancer (CRC), highlighting the urgent need to identify novel molecular targets for therapeutic intervention. Recent findings by Niu et al have elucidated the role of the NAD+/SIRT1 axis in mediating oxaliplatin resistance through metabolic reprogramming. Their study demonstrated that oxaliplatin-induced DNA damage activates PARP, resulting in NAD+ depletion and subsequent downregulation of SIRT1. This reduction in SIRT1 levels enhances glycolysis, as evidenced by increased expression of PKM2 and LDHA, thereby conferring a metabolic advantage to resistant CRC cells. Conversely, restoration of SIRT1 expression reverses resistance, while pharmacological inhibition of glycolysis effectively sensitizes cells to oxaliplatin. These findings underscore the therapeutic potential of targeting the NAD+/SIRT1 pathway as a metabolic vulnerability in CRC. Future studies should investigate the clinical feasibility of combining SIRT1 agonists and glycolysis inhibitors with oxaliplatin to overcome drug resistance and improve patient outcomes.
    Keywords:  Chemotherapy; Colorectal cancer; Drug resistance; Glycolysis; SIRT1
    DOI:  https://doi.org/10.3748/wjg.v31.i21.106530
  4. Int J Med Sci. 2025 ;22(11): 2852-2876
    Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications.
    Xinyi Chen, Mu Yang, Lu Wang, Jingyao Tu, Xianglin Yuan.
      Metabolic reprogramming enables cancer cells to adapt to the tumor microenvironment, facilitating their survival, proliferation, and resistance to therapy. While glucose has long been considered the primary substrate for cancer cell metabolism, recent studies have highlighted the role of fructose as an alternative carbon source. Fructose metabolism, particularly through key enzymes such as ketohexokinase (KHK) and aldolase B (ALDOB), along with the fructose transporter GLUT5, supports tumor growth, metastasis, and therapeutic resistance. This review explores the mechanisms by which fructose metabolism influences cancer progression, focusing on its metabolic pathways and its impact on the tumor microenvironment. By promoting glycolysis, lipid biosynthesis, and nucleotide production, fructose metabolism enhances the metabolic adaptability of cancer cells, especially in glucose-deprived conditions. A comprehensive understanding of these processes offers potential insights into therapeutic strategies targeting fructose metabolism for cancer treatment. However, further studies are required to fully elucidate the complex role of fructose in various malignancies.
    Keywords:  aldolase; fructose metabolism; glucose transporter; ketohexokinase; metabolic reprogramming; tumor metabolism
    DOI:  https://doi.org/10.7150/ijms.108549
  5. ACS Nano. 2025 Jun 18.
    Mitochondria-Targeted Microneedles Reverse Doxorubicin Resistance via Apoptosis-Ferroptosis Synergy.
    Tianshu Hao, Hanze Guo, Chenyuan Wang, Shisuo Jing, Wen Zhang, Yongnian Zeng, Jinxuan Hou, Zhiyin Song, Wei Li.
      Mitochondrial hyperfunction in doxorubicin (DOX)-resistant breast cancer cells mitigates oxidative stress, contributing to chemoresistance. Here, we present a precise mitochondria-targeted microneedle (MN) delivery strategy incorporating hollow DOX-TPP@ZIF-67 nanoparticles to overcome chemotherapy resistance. This platform was synthesized by loading mitochondria-targeted DOX-TPP into ZIF-67 structures and embedded into fast-dissolving MN patches for localized, organelle-specific drug delivery. Mitochondrial accumulation of DOX-TPP induces ROS overproduction, triggering apoptosis, disrupting cystine-cysteine conversion, depleting glutathione (GSH), and inactivating GPX4. The resulting oxidative imbalance promotes lipid peroxidation and ferroptosis. Additionally, the hydrogen peroxide generated during metabolic reprogramming drives further ferroptosis via the Fenton-like reaction. This approach effectively suppresses the growth of chemoresistant tumors and prolongs survival in DOX-resistant animal models. Our results demonstrate that mitochondria-targeted MN delivery provides a precise strategy to overcome chemoresistance and uncover a mechanism by which enhanced anthracycline efficacy drives the synergistic activation of mitochondrial dysfunction, apoptosis, and ferroptosis.
    Keywords:  ROS; drug-resistant breast cancer; microneedle; organelle-specific drug delivery; targeting mitochondria
    DOI:  https://doi.org/10.1021/acsnano.5c06302
  6. Cell Death Dis. 2025 Jun 13. 16(1): 448
    Targeting USP18 overcomes acquired resistance in hepatocellular carcinoma by regulating NCOA4 deISGylation and ferroptosis.
    Shengtao Ye, Junxin Chen, Ying Zheng, Mengmeng He, Yanqiu Zhang, Yang Cheng, Yingrong Leng, Enyi Wu, Lingyi Kong, Hao Zhang.
      Targeted therapy resistance has become a major challenge for hepatocellular carcinoma (HCC) treatment. Triggering ferroptosis emerges as a promising strategy to overcome therapeutic resistance. Here, we have identified ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating enzyme family, contributing to HCC resistance by inhibiting sorafenib-induced ferroptosis. Nuclear receptor coactivator 4 (NCOA4), a crucial regulator of ferroptosis, turned out to be a novel downstream effector of USP18 and is posttranslationally suppressed. Such regulation is based on the USP18-mediated deISGylation and degradation process. Additionally, we have demonstrated that sorafenib promotes USP18 accumulation in HCC via the STING/IRF3/ISG15 axis. Importantly, we screened and identified hyperoside (HYP) as a new USP18 enzyme activity inhibitor, which sensitizes cancer cells to existing targeted therapies (sorafenib and regorafenib) by inhibiting USP18 and following deISGylation of NCOA4. Collectively, our study has uncovered a novel mechanism of acquired sorafenib resistance and offers a promising combination therapy strategy for overcoming therapeutic resistance in HCC.
    DOI:  https://doi.org/10.1038/s41419-025-07772-0
  7. J Cancer. 2025 ;16(8): 2706-2719
    Navigating the role of protein lactylation in prostate cancer and its implications for immunotherapy.
    Dongzhang Li, Kaifeng Wang, Guantao Lou, Wangjian Li, Quan Ma, Yu'e Liu, Yongliang Chen.
      Prostate cancer is an aggressive malignancy with high prevalence and significant mortality, characterized by its remarkable metabolic adaptability and immune complexity. Emerging evidence has highlighted the critical role of post-translational modifications (PTMs) in cancer biology, with protein lactylation gaining attention as a novel PTM with profound implications. Lactylation, derived from lactate, links the altered metabolic processes of tumor cells to diverse cellular functions, including epigenetic regulation and protein dynamics. It significantly influences tumor progression, immune evasion, and therapeutic resistance by modulating key immune cells within the tumor microenvironment. The immunosuppressive conditions created by lactate and lactylation favor tumor survival in prostate cancer. Thus, targeting lactylation offers innovative strategies for treating prostate cancer. By leveraging lactylation modulation, particularly in combination with immune checkpoint inhibitors, there is potential to enhance anti-tumor immune responses and improve treatment outcomes. This review explores the intersection of metabolic alterations and immune modulation, underscoring lactylation as a promising therapeutic avenue in prostate cancer.
    Keywords:  immune checkpoints; immunotherapy; lactylation; prostate cancer; tumor microenvironment
    DOI:  https://doi.org/10.7150/jca.114137
  8. Drug Deliv Transl Res. 2025 Jun 14.
    D-mannose augments targeted radioligand-immunotherapy of prostate cancer by enhancing radiosensitivity and reshaping immune microenvironment.
    Lei Tao, Bin Xu, Juan Sun, Jiangtao Yang, Fenghua Meng, Zhiyuan Zhong.
      Targeted radioligand therapy (TRT) is an emerging therapeutic modality for advanced tumors like metastatic castration-resistant prostate cancer. The patients bare, however, varying degrees of resistance to TRT, which would greatly lessen the treatment efficacy and response rate. Here, we find that oral medication of D-mannose effectively enhances the radiosensitivity of PSMA-positive murine RM1-hPSMA prostate cancer cells to TRT by suppressing glucose metabolism. This metabolic disruption not only impeded the proliferation of RM1-hPSMA cells but also augmented DNA damage within tumor cells subjected to TRT, co-promoting cell apoptosis. Interestingly, TRT-D-mannose combination strongly boosted the anti-tumor immune responses by inducing immunogenic cell death, disrupting the immune evasion mechanisms employed by tumor cells, and reducing immunosuppressive cells in the tumor. D-mannose significantly improved the TRT efficacy for highly aggressive murine RM1-hPSMA and human LNCaP Clone FGC models, without causing adverse effects. Hence, D-mannose is potentially a safe radio-sensitizer and a potent immune activator for TRT.
    Keywords:  Immune response; Prostate cancer; Radio-sensitizer; Targeted radioligand therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s13346-025-01886-w
  9. Proc Natl Acad Sci U S A. 2025 Jun 24. 122(25): e2427211122
    Combined targeting of PRDX6 and GSTP1 as a potential differentiation strategy for neuroblastoma treatment.
    Judit Liaño-Pons, Elisa Garde-Lapido, Fenja L Fahrig, Merle Jäckering, Ye Yuan, Stina Andersson, Lea Schort, Maria Esteve, Sofie Mohlin, Oscar C Bedoya-Reina, Marie Arsenian-Henriksson.
      Neuroblastoma (NB) is a heterogeneous childhood cancer, characterized by the amplification of the MYCN oncogene in 40% of the high-risk cases. Our previous work demonstrated that MYCN drives metabolic reprogramming in NB, including upregulation of antioxidant enzymes. Here, we identify peroxiredoxin 6 (PRDX6) as a promising therapeutic target in NB. Pharmacological inhibition of PRDX6 reduces MYCN levels, induces apoptosis, and promotes neuronal differentiation accompanied by lipid droplet accumulation, essential for the phenotypic reprogramming. Moreover, combined inhibition of PRDX6 and glutathione S-transferase Pi 1 (GSTP1), a key antioxidant enzyme needed for PRDX6 activation, demonstrated synergistic effects both in vitro and in vivo. This strategy results in neuronal maturation as well as activity and initiates downstream pathways distinct from the ones triggered by retinoic acid, the differentiation-inducing agent currently used in clinical practice for NB. Notably, both PRDX6 and GSTP1 are highly expressed in the developing murine adrenal gland, as well as in high-risk, MYCN-amplified NB, correlating with an undifferentiated state and poor prognosis. Together, our results provide insights into the potential of PRDX6 and GSTP1 as therapeutic targets for differentiation induction for children with NB.
    Keywords:  antioxidants; childhood cancer; differentiation-inducing therapy; neuroblastoma; oxidative stress
    DOI:  https://doi.org/10.1073/pnas.2427211122
  10. Blood. 2025 Jun 20. pii: blood.2024026417. [Epub ahead of print]
    Loss of BAP1 defines a unique subtype of TP53-mutated de novo AML and confers sensitivity to BCL-xL inhibitors.
    Jaclyn Andricovich, Coen Johannes Lap, Alexandros Tzatsos.
      Mutations in TP53 are mutually exclusive with other known drivers of myeloid transformation and define a distinct molecular subtype within de novo Acute Myeloid Leukemia (AML) that is associated with a complex karyotype, resistance to chemotherapy, and poor prognosis. Although TP53 defects are rare in de novo AML, biallelic mutations are a defining molecular feature of erythroleukemia. The genetic alterations that cooperate with defective TP53 to transform erythroid progenitors remain unknown. We found that loss of BAP1 (BRCA1 Associated Protein-1) co-occurs in one-third of patients with TP53-mutated AML, is associated with an erythroid-primed gene expression signature, and confers an additional adverse effect on overall survival. BAP1 is a tumor suppressor involved in the DNA damage response as well as epigenetic regulation through histone H2AK119 de-ubiquitination. While Bap1KO mice develop myelodysplasia with prominent dyserythropoiesis, combined deletion of Bap1 and Trp53 caused transplantable erythroleukemia, and occasionally mixed AML, mirroring the heterogeneity of human disease. Bulk and single-cell RNA-seq coupled to ChIP-seq in hematopoietic progenitors revealed that Bap1 loss triggers a proinflammatory response and cooperates with Trp53 deficiency to transform erythroid-primed multipotent progenitors. Mechanistically, genomic instability led to the development of erythroleukemia, while epigenetic deregulation caused myelomonocytic skewing suggesting a dichotomous and context dependent role for BAP1. We also demonstrate that BAP1 deficient erythroleukemia is dependent on BCL2L1 expression and is sensitive to BCL-xL inhibitors in vivo.
    DOI:  https://doi.org/10.1182/blood.2024026417
  11. Oncogene. 2025 Jun 18.
    PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer.
    Fan Liu, Weixiao Liu, Yawen Tan, Yaxin Shang, Sihui Ling, Xiaokun Jiang, Zhen Zhang, Shiyao Sun, Ping Xie.
      The gradual emergence of a novel therapeutic approach lies in the restoration of tumor suppressive machinery. PTEN is a crucial negative regulator of the PI3K/Akt signaling pathway. Protein neddylation modification contributes to PTEN inactivation and fuels breast cancer progression. Here, we highlight that an elevated level of PTEN neddylation is markedly associated with resistance to palbociclib, a CDK4/6 inhibitor used in luminal subtype breast cancer patients. Mechanistically, PTEN neddylation activates the PI3K/Akt signaling pathway, and more notably, upregulates the activity of the AP-1 transcription factor. Our data showed that PTEN neddylation stabilizes JUND, a transcription factor involved in the AP-1 complex, by disrupting its interaction with the E3 ubiquitin ligase ITCH. Consequently, activated JUND leads to the release of cytokines and chemokines, which in turn may drive an inflammatory tumor microenvironment, potentially contributing to drug resistance. Then, we identified Echinacoside as a potent inhibitor of PTEN neddylation both in vivo and in vitro by disrupting its interaction with XIAP, the E3 ligase responsible for PTEN neddylation. Combination of Echinacoside effectively overcome resistance to palbociclib in breast cancer treatment. These findings highlight targeting PTEN neddylation as a promising strategy for restoring tumor suppressor activity and overcoming resistance.
    DOI:  https://doi.org/10.1038/s41388-025-03468-z
  12. Bioorg Chem. 2025 Jun 16. pii: S0045-2068(25)00573-5. [Epub ahead of print]163 108693
    Peroxisome proliferator-activated receptor antagonists as emerging therapeutics in cancer treatment.
    Snehal Misal, Vijay M Patil, C S Ramaa, Antonio Lavecchia.
      Cancer remains one of the leading causes of mortality worldwide, driving the need for novel therapeutic strategies. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate lipid metabolism, inflammation, and tumor progression. While PPAR agonists have been widely explored for their anticancer potential, recent evidence highlights PPAR antagonists as promising therapeutic candidates. These antagonists selectively modulate oncogenic pathways by disrupting metabolic and signaling networks that support tumor growth, survival, and metastasis. PPARα antagonists, such as N-(2-bromophenyl)-2-[[(3-chlorophenyl)amino]thioxomethyl]acetamide (GW6471) and TPST-1120, impair tumor metabolism and angiogenesis, reducing cancer progression. Their combination with immunotherapy has shown enhanced antitumor effects in preclinical models. PPARβ/δ antagonists, including 4-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy]benzoic acid (GSK0660) and methyl 3-(N-(4-(hexylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (ST247), suppress β-catenin-driven oncogenic transcription, modulating cell proliferation and invasion. PPARγ antagonists, such as 2-Chloro-5-nitro-N-phenylbenzamide (T0070907) and 2-Chloro-5-nitro-N-phenylbenzamide (GW9662), interfere with cancer cell metabolism, apoptosis, and migration, thereby enhancing their antitumor efficacy. Combination strategies involving chemotherapy, radiotherapy, or targeted therapies have shown synergistic effects, improving treatment response and overcoming resistance. Beyond direct tumor suppression, PPAR antagonists modulate immune responses and reshape the tumor microenvironment, offering a multifaceted therapeutic approach. Despite promising results, clinical translation remains limited and requires further studies to improve selectivity, pharmacokinetics, and drug delivery strategies. This review provides a comprehensive analysis of the medicinal chemistry, molecular mechanisms, and pharmacological development of PPAR antagonists, highlighting their potential clinical applications. Future efforts should refine drug design, develop personalized treatments, and conduct well-designed clinical trials to unlock their role in precision oncology.
    Keywords:  Apoptosis; Cancer therapy; Inflammation; Metabolic reprogramming; PPAR antagonists; Signal transduction; Tumor metabolism
    DOI:  https://doi.org/10.1016/j.bioorg.2025.108693
  13. J Clin Invest. 2025 Jun 16. pii: e185119. [Epub ahead of print]135(12):
    RSK1-driven TRIM28/E2F1 feedback loop promotes castration-resistant prostate cancer progression.
    Miyeong Kim, Jinpeng Liu, Yanquan Zhang, Ruixin Wang, Ryan Goettl, Jennifer Grasso, Derek B Allison, Chi Wang, Tianyan Gao, Xiaoqi Liu, Ka-Wing Fong.
      Castration-resistant prostate cancer (CRPC) marks the advanced and lethal stage of prostate cancer (PCa). TRIM28, also known as KAP1, is a transcriptional regulator recently shown to promote CRPC cell proliferation and xenograft tumor growth. Nonetheless, knowledge gaps persist regarding the mechanisms underlying TRIM28 upregulation in CRPC as well as the genomic targets regulated by TRIM28. Here, we report that TRIM28 is a E2F1 target in CRPC. Using an integrated genomic approach, we have demonstrated that TRIM28 forms a positive feedback loop to promote the transcriptional activation and genomic function of E2F1 independent of retinoblastoma (Rb) status. Furthermore, we identified RSK1 as a kinase that directly phosphorylates TRIM28 at S473, and, as such, RSK1 drives the TRIM28/E2F1 feedback loop. Accordingly, pS473-TRIM28 promotes CRPC progression, which is mitigated by RSK inhibition. In summary, our study reveals a critical role of the RSK1-TRIM28-E2F1 axis in CRPC progression, which may be exploited as a vulnerability in treating Rb-deficient CRPC.
    Keywords:  Cell biology; Endocrinology; Prostate cancer
    DOI:  https://doi.org/10.1172/JCI185119
  14. Discov Oncol. 2025 Jun 17. 16(1): 1135
    PARP14-mediated glycolysis enhances Tamoxifen resistance in estrogen receptor + breast cancer cells.
    Wenju Mo, Fanrong Zhang, Chen Wang, Xiaowen Ding, Lili Ren.
       BACKGROUND: Resistance to Tamoxifen is a major challenge in the therapeutic management of estrogen receptor (ER) + breast cancer (BC). Glycolysis, as reported, exerts a crucial influence on the regulation of Tamoxifen resistance in BC, highlighting the need for further investigation into the mechanisms by which it contributes to Tamoxifen resistance in ER + BC.
    METHOD: Bioinformatics was employed to analyze the differential expression of PARP14 between Tamoxifen-responsive and -resistant ER + BC tissues. Poly (ADP-ribose) polymerase family member 14 (PARP14) expression in Tamoxifen-resistant cell lines (T47D/TAMR) was quantified through quantitative real time polymerase chain reaction (qRT-PCR). A subsequent Gene Set Enrichment Analysis (GSEA) was conducted to determine the relationship between PARP14 and glycolysis-related genes. The assessment of glycolytic activity included measurements of hexokinase II (HK2) expression, extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glucose uptake, lactate secretion, and adenosine Triphosphate (ATP) synthesis. Cellular proliferation was evaluated using a colony formation assay, cell viability was assessed with the Cell Counting Kit-8 (CCK-8) assay to establish the half maximal inhibitory concentration (IC50) value, and apoptosis was measured by flow cytometry.
    RESULTS: PARP14 exhibited elevated expression in Tamoxifen-resistant tissues and cells such as T47D/TAMR, where its knockdown increased responsiveness to Tamoxifen. PARP14 was also notably associated with the glycolysis pathway, showing a positive correlation with genes that enhance glycolysis, and its suppression led to decreased glycolysis in T47D/TAMR cells. Overexpression of PARP14 in vitro induced Tamoxifen resistance in these cells, but co-administration of the glycolytic inhibitor 2-DG could recover their sensitivity to Tamoxifen.
    CONCLUSION: PARP14 facilitates Tamoxifen resistance in ER + BC cells via the activation of the glycolysis pathway. We suspect that targeting PARP14 or the glycolytic pathway could be a viable therapeutic option for ER + BC that has developed resistance to Tamoxifen.
    Keywords:  Drug resistance; ER + BC; Glycolysis; PARP14; Tamoxifen
    DOI:  https://doi.org/10.1007/s12672-025-02404-7
  15. Front Immunol. 2025 ;16 1597770
    Targeting metabolic reprogramming to overcome immune tolerance in melanoma immunotherapy.
    Qinchen Wang, Lei Shi, Daoming Shi, Ningzheng Tai, Xu Wang.
      Significant advances in the treatment of melanoma, the most aggressive form of skin cancer, have been achieved via immunotherapy. Despite these improvements, therapeutic resistance remains a formidable challenge, compromising the treatment efficacy and patient outcomes. This review delves into the intricate mechanisms driving immunotherapy resistance in melanoma, emphasizing alterations in key metabolic pathways, changes within the tumor microenvironment, and the critical role of the gut microbiota. This review also examines how metabolic reprogramming supports tumor proliferation and immune evasion, it highlights the impact of extracellular acidification and angiogenic processes on resistance development. By synthesizing current insights, this review emphasizes the importance of targeting these multifaceted interactions to overcome resistance, thereby paving the way for more effective and durable therapeutic strategies in melanoma treatment.
    Keywords:  gut microbiota; immune tolerance; immunotherapy; melanoma; metabolic pathways; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1597770
  16. J Cell Mol Med. 2025 Jun;29(12): e70661
    Myeloid-Derived LGALS9-P4HB Immune Interaction Promotes Metastasis in Gastric Cancer Through Enhanced Cell Proliferation and Lipid Metabolism.
    Xiaobin Zhu, Yating Zhang, Aiping Yu, Xiao Xiao.
      Metastasis remains the primary cause of mortality in gastric cancer patients; however, the underlying mechanisms driving this process remain incompletely understood. Here, we performed an integrated single-cell analysis of gastric cancer primary tumours and their corresponding liver and lymph node metastases to identify critical intercellular communication networks driving the metastatic process. Notably, gene expression analysis of metastatic tissues showed significant upregulation of cholesterol metabolism and PPAR signalling pathway (a nuclear receptor-mediated regulatory system that orchestrates lipid metabolism, adipogenesis and energy homeostasis) genes compared to primary tumours. Our analysis revealed that myeloid cell-derived Galectin-9 (LGALS9) and its receptor beta-subunit of prolyl 4-hydroxylase (P4HB) on epithelial cells constitute a previously uncharacterized ligand-receptor interaction involved in gastric cancer metastasis. Functional experiments confirmed that the activation of P4HB by LGALS9 significantly enhanced proliferation, epithelial-mesenchymal transition (EMT) and lipid metabolism in gastric cancer cells, while pharmacological inhibition of P4HB reversed these effects. Collectively, our findings establish the myeloid-derived LGALS9-P4HB interaction as a crucial mediator of gastric cancer metastatic colonisation through modulation of lipid metabolism, suggesting a potential therapeutic target for metastatic gastric cancer.
    Keywords:  LGALS9; P4HB; cellular communication; gastric cancer; lipid metabolism; metastasis; tumour microenvironment
    DOI:  https://doi.org/10.1111/jcmm.70661
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