bims-meract 2025-03-16 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–03–16
nineteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

CRSP8-driven fatty acid metabolism reprogramming enhances hepatocellular carcinoma progression by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.
WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer.
Medium-Chain Fatty Acids Selectively Sensitize Cancer Cells to Ferroptosis by Inducing CD36 and ACSL4.
NADPH oxidase activator 1 (NOXA1) suppresses ferroptosis and radiosensitization in colorectal cancer.
STX1A regulates ferroptosis and chemoresistance in gastric cancer through mitochondrial function modulation.
Interleukin-16 enhances anti-tumor immune responses by establishing a Th1 cell-macrophage crosstalk through reprogramming glutamine metabolism in mice.
PKM2 knockout facilitates the activation of the AMPK/KLF4/ACADVL pathway, leading to increased oxidative degradation of fatty acids in TNBC.
Upregulated FSP1 by GPD1/1L mediated lipid droplet accumulation enhances ferroptosis resistance and peritoneal metastasis in gastric cancer.
SLC5A3 depletion promotes apoptosis by inducing mitochondrial dysfunction and mitophagy in gemcitabine-resistant pancreatic cancer cells.
SLC7A5/E2F1/PTBP1/PKM2 axis mediates progression and therapy effect of triple-negative breast cancer through the crosstalk of amino acid metabolism and glycolysis pathway.
Thyroid hormones inhibit tumor progression and enhance the antitumor activity of lenvatinib in hepatocellular carcinoma via reprogramming glucose metabolism.
PADI4 facilitates stem-like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma.
PKN2 enhances the immunosuppressive activity of polymorphonuclear myeloid-derived suppressor cells in esophageal carcinoma by mediating fatty acid oxidation.
Protein arginine methyltransferase 6 enhances immune checkpoint blockade efficacy via the STING pathway in MMR-proficient colorectal cancer.
Ironomycin induces mantle cell lymphoma cell death by targeting iron metabolism addiction.
Alterations in PD-L1 succinylation shape anti-tumor immune responses in melanoma.
A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours.
Glycogen drives tumour initiation and progression in lung adenocarcinoma.
Introduction of AGPAT3 gene as a regulator of cisplatin resistance in A2780 ovarian endometrioid carcinoma cell line.

J Exp Clin Cancer Res. 2025 Mar 11. 44(1): 93

CRSP8-driven fatty acid metabolism reprogramming enhances hepatocellular carcinoma progression by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.

Yuxi Lin, Zhixing Liang, Zhiyan Weng, Xiaofang Liu, Feng Zhang, Yutian Chong.

   BACKGROUND: In-depth exploration into the dysregulation of lipid metabolism in hepatocellular carcinoma (HCC) has contributed to the development of advanced antitumor strategies. CRSP8 is a critical component of mediator multiprotein complex involved in transcriptional recruiting. However, the regulatory mechanisms of CRSP8 on fatty acid metabolism reprogramming and HCC progression remain unclear.
METHODS: In-silico/house dataset analysis, lipid droplets (LDs) formation, HCC mouse models and targeted lipidomic analysis were performed to determine the function of CRSP8 on regulating lipid metabolism in HCC. The subcellular colocalization and live cell imaging of LDs, transmission electron microscopy, co-immunoprecipitation and luciferase reporter assay were employed to investigate their potential mechanism.
RESULTS: CRSP8 was identified as a highly expressed oncogene essential for the proliferation and aggressiveness of HCC in vitro and in vivo. The tumor promotion of CRSP8 was accompanied by LDs accumulation and increased de novo fatty acids (FAs) synthesis. Moreover, CRSP8 diminished the colocalization between LC3 and LDs to impair lipophagy in a nuclear-localized PPARα-dependent manner, which decreased the mobilization of FAs from LDs degradation and hindered mitochondrial fatty acid oxidation. Mechanistically, the small ras family GTPase RAN was transcriptionally activated by CRSP8, leading to the reinforcement of RAN/CRM1-mediated nuclear export. CRSP8-induced enhanced formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer orchestrated cytoplasmic translocation of PPARα, attenuated nPPARα-mediated lipophagy and fatty acid catabolism, subsequently exacerbated HCC progression. In CRSP8-enriched HCC, lipid synthesis inhibitor Orlistat effectively reshaped the immunosuppressive tumor microenvironment (TME) and improved the efficacy of anti-PD-L1 therapy in vivo.
CONCLUSION: Our study establishes that CRSP8-driven fatty acid metabolism reprogramming facilitates HCC progression via the RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer and impaired lipophagy-derived catabolism. Targeting the energy supply sourced from lipids could represent a promising therapeutic strategy for treating CRSP8-sufficient HCC.

Keywords:  CRSP8; Fatty acid oxidation; Hepatocellular carcinoma; Lipophagy; PPARα

DOI:  https://doi.org/10.1186/s13046-025-03329-3
Mol Med. 2025 Mar 12. 31(1): 93

WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer.

Yang Wang, Dachuan Qi, Guijie Ge, Ning Cao, Xiangdong Liu, Na Zhu, Feng Li, Xiang Huang, Kui Yu, Jinzhou Zheng, Daoheng Wang, Wenyan Yao, Lili Chen, Ziyang Dong.

  Chemoresistance continues to pose a significant challenge in managing colorectal cancer (CRC), resulting in unfavorable outcomes for patients. Recent findings indicate that ferroptosis, an innovative type of regulated cell death, might influence chemoresistance. In this research, we explored how WW domain-binding protein 1 (WBP1) affects mitochondrial function, cell growth, ferroptosis, and chemoresistance in CRC cells. By employing both genetic and pharmacological methods, we found that WBP1 is essential for maintaining mitochondrial respiration in CRC cells. WBP1 depletion impaired mitochondrial function, leading to reduced cell proliferation and increased ferroptosis. Exogenous mitochondria from wild-type cells restored mitochondrial function, cell proliferation, and suppressed ferroptosis in WBP1-deficient cells, indicating that mitochondrial function acts downstream of WBP1. Importantly, we demonstrated that targeting WBP1 or its mediated mitochondrial function sensitized chemoresistant CRC cells to 5-fluorouracil and oxaliplatin by inducing ferroptosis. Furthermore, we analyzed transcriptome data from CRC patients, which indicated that increased WBP1 expression correlated with poor outcomes for patients receiving chemotherapy, thus highlighting the clinical significance of our observations. Collectively, our results pinpoint WBP1 as a significant modulator of mitochondrial function and ferroptosis in CRC cells and imply that targeting WBP1 may represent a viable approach to tackling chemoresistance. These insights offer a deeper understanding of the molecular pathways underlying CRC chemoresistance and may guide the development of new treatment options.

Keywords:  Chemoresistance; Colorectal cancer; Ferroptosis; Mitochondrial function

DOI:  https://doi.org/10.1186/s10020-025-01151-3
Nutrients. 2025 Feb 25. pii: 794. [Epub ahead of print]17(5):

Medium-Chain Fatty Acids Selectively Sensitize Cancer Cells to Ferroptosis by Inducing CD36 and ACSL4.

Kai Han, Jiaxuan Li, Shutao Yin, Hongbo Hu, Chong Zhao.

   BACKGROUND: Inducing ferroptosis in cancer cells is a promising therapeutic strategy. It has been shown that certain types of fatty acids can induce ferroptosis in multiple types of cancer cells.
METHODS: Here, we employed crystal violet staining and CCK8 to assess cell viability, a Liperfluo probe and commercial kit to measure lipid peroxides, and western blotting and RNA interference to detect protein levels.
RESULTS: This study demonstrates for the first time that the medium-chain fatty acids lauric acid (LA-m), octanoic acid (OA-m), and decanoic acid (DA-m) selectively sensitize various cancer cell types to ferroptosis induced by either RSL3, a well-known inducer of ferroptosis, or linoleic acid (LA-l), a ω-6 polyunsaturated fatty acid (PUFA). Mechanistically, the ferroptosis-sensitizing effect of medium-chain fatty acids is associated with their ability to upregulate cluster of differentiation 36 (CD36) and acyl-CoA synthetase long-chain family member 4 (ACSL4) expression.
CONCLUSIONS: These findings suggest that medium-chain fatty acids could be developed as novel ferroptosis sensitizers to enhance ferroptosis-based cancer therapy.

Keywords:  ACSL4; CD36; cancer; ferroptosis; medium-chain fatty acids

DOI:  https://doi.org/10.3390/nu17050794
Int J Med Sci. 2025 ;22(6): 1301-1312

NADPH oxidase activator 1 (NOXA1) suppresses ferroptosis and radiosensitization in colorectal cancer.

Qingyu Jiang, Qianping Chen, Quanquan Sun, Dong Liu, Ji Zhu, Wei Mao.

  Radiotherapy is one of the main treatments for colorectal cancer (CRC), but due to the intrinsic resistance of cells or resistance caused by long-term radiotherapy, the effectiveness of this treatment is limited for some CRC patients. Consequently, identifying novel sensitization strategies is essential. This study identifies Noxa1 as a marker linked to radiotherapy resistance in CRC, suggesting its potential as a prognostic biomarker for patients with CRC. The study found that Noxa1 was significantly overexpressed in radiotherapy-resistant colorectal cancer patients, correlating with a poor prognosis. Additionally, we discovered that the high expression of Noxa1 was negatively correlated with ferroptosis and primarily played a role through the glutathione metabolic pathway, as indicated by GSVA analysis. Experimental data indicated that the expression levels of NOXA1, SLC7A11, and GPX4 were significantly elevated in CRC cell lines resistant to radiotherapy. The expression of SLC7A11 and GPX4 decreased after the knockdown of Noxa1, leading to an increase in cellular ROS levels, which induced ferroptosis and sensitized the cells to radiotherapy. Therefore, Noxa1 might influence the radiotherapy sensitivity of CRC via regulating ferroptosis. Targeting Noxa1 could enhance radiotherapy sensitization and improve the prognosis of CRC patients.

Keywords:  Noxa1; ROS; colorectal cancer; ferroptosis; radiotherapy sensitization

DOI:  https://doi.org/10.7150/ijms.107038
Hum Cell. 2025 Mar 08. 38(3): 66

STX1A regulates ferroptosis and chemoresistance in gastric cancer through mitochondrial function modulation.

Yan Niu, Chunyu Liu, Lizhou Jia, Fangxin Zhao, Yixiao Wang, Lu Wang, Weiyi Chen, Yanzi Gan, Yongjun Wen.

  Gastric cancer is one of the leading causes of cancer-related deaths worldwide, and chemoresistance remains a major obstacle to effective treatment. Ferroptosis, a novel form of regulated cell death, has emerged as a potential therapeutic strategy to treat cancer. However, the molecular mechanisms regulating ferroptosis in gastric cancer remain largely unknown. In this study, we identified syntaxin 1A (STX1A) as a novel regulator of mitochondrial function and ferroptosis in gastric cancer. We found that STX1A is overexpressed in gastric cancer cell lines and tissues and that its knockdown inhibits cell proliferation and induces ferroptosis. Notably, we made the novel discovery that STX1A is localized to the mitochondria, providing a direct link between STX1A and mitochondrial function. Mechanistically, we demonstrated that STX1A depletion impairs mitochondrial respiration, leading to increased oxidative stress and ferroptosis. Furthermore, we showed that targeting STX1A or directly inhibiting mitochondrial function can reverse acquired resistance to 5-fluorouracil and cisplatin in gastric cancer cells by inducing ferroptosis. Our findings provide new insights into the regulation of ferroptosis in gastric cancer and suggest that the STX1A-mitochondria-ferroptosis axis may be a promising therapeutic target for overcoming chemoresistance and improving patient outcomes.

Keywords:  Chemoresistance; Ferroptosis; Gastric cancer; Mitochondrial function

DOI:  https://doi.org/10.1007/s13577-025-01195-x
Nat Commun. 2025 Mar 10. 16(1): 2362

Interleukin-16 enhances anti-tumor immune responses by establishing a Th1 cell-macrophage crosstalk through reprogramming glutamine metabolism in mice.

Zhenzhen Wen, Tong Liu, Xutao Xu, Nandini Acharya, Zhida Shen, Yunkun Lu, Junjie Xu, Ke Guo, Shuying Shen, Yuening Zhao, Pinli Wang, Shumin Li, Weiyu Chen, Hui Li, Yimin Ding, Min Shang, Hongshan Guo, Yu Hou, Bijun Cui, Manlu Shen, Youling Huang, Ting Pan, Wang Qingqing, Qian Cao, Kai Wang, Peng Xiao.

Overcoming immunosuppression in the tumor microenvironment (TME) is crucial for developing novel cancer immunotherapies. Here, we report that IL-16 administration enhances the polarization of T helper 1 (Th1) cells by inhibiting glutamine catabolism through the downregulation of glutaminase in CD4+ T cells and increases the production of Th1 effector cytokine IFN-γ, thus improving anti-tumor immune responses. Moreover, we find that establishing an IL-16-dependent, Th1-dominant TME relies on mast cell-produced histamine and results in the increased expression of the CXCR3 ligands in tumor-associated macrophages (TAM), thereby improving the therapeutic effectiveness of immune checkpoint blockade (ICB). Cancer patients exhibit impaired production of IL-16, which correlates with poorer prognosis. Additionally, low IL-16 production is associated with unresponsiveness to immunotherapy in cancer patients. Collectively, our findings provided new insights into the biological function of IL-16, emphasizing its potential clinical significance as a therapeutic approach to augment anti-tumor immunity and sensitize ICB-based cancer immunotherapy.

DOI: https://doi.org/10.1038/s41467-025-57603-1
Med Oncol. 2025 Mar 12. 42(4): 102

PKM2 knockout facilitates the activation of the AMPK/KLF4/ACADVL pathway, leading to increased oxidative degradation of fatty acids in TNBC.

Linghan Zhang, Li Cheng, Yingchao Ma, Junlin Li, Yue Zhong, Xiuzhi Zhu, XiaoMin Leng, Fuhua Xie.

  This study unveils PKM2 as a master metabolic coordinator in triple-negative breast cancer (TNBC), governing the glycolysis-lipolysis balance through the AMPK/KLF4/ACADVL axis. We demonstrate stage-specific PKM2 upregulation in TNBC, with CRISPR/Cas9 knockout inducing dual metabolic reprogramming-suppressed glycolysis and activated lipid catabolism. Mechanistically, PKM2 ablation triggers AMPK-dependent nuclear translocation of KLF4, which directly activates ACADVL (mitochondrial β-oxidation rate-limiting enzyme), explaining lipid droplet depletion. Therapeutically, synergistic lethality emerges from combining PKM2 knockout with ACADVL inhibition, suggesting metabolic redundancy disruption strategies. Unlike PKM2-SCAP-mediated lipogenesis reported elsewhere, our work establishes a KLF4-driven lipid catabolic pathway specific to TNBC. Crucially, this AMPK/KLF4/ACADVL network operates independently of BRCA status, proposing targeted therapy for chemoresistant non-BRCA mutant TNBC. Our findings redefine TNBC metabolic plasticity through transcriptional-metabolic crosstalk, offering combinatorial therapeutic paradigms against metabolic adaptation.

Keywords:  ACADVL; AMPK; KLF4; PKM2; Triple-negative breast cancer

DOI:  https://doi.org/10.1007/s12032-025-02671-y
Cell Commun Signal. 2025 Mar 12. 23(1): 132

Upregulated FSP1 by GPD1/1L mediated lipid droplet accumulation enhances ferroptosis resistance and peritoneal metastasis in gastric cancer.

Guoliang Lin, Qingnan Liu, Chengjie Xie, Ke Ding, Guanghua Mo, Lu Zeng, Fan Zhang, RuiXuan Liu, Lei Lu, Wei Hong, Yuling Mao, Haibo Su, Shuai Li.

  To successfully metastasize, cancer cells must evade detachment induced cell death, known as anoikis. Unraveling the mechanisms that gastric cancer (GC) circumvent anoikis and achieve peritoneal metastasis especially during unanchored growth, could significantly improve patient outcomes. Our study reveals that GC cells exhibit increased lipid peroxidation, MDA production, and cell death during suspension culture, which can be mitigated by the intervention with liproxstatin-1 and ferrostatin-1. We discovered that oleic acid (OA) or adipocytes stimulate lipid accumulation in GC cells, thereby inhibiting lipid peroxidation and cell death. Lipid mass spectrometry confirmed an upregulation of triglyceride synthesis, indicating that the accumulation of lipid droplet may confer resistance to ferroptosis during suspension growth. In vitro assays demonstrated that OA not only induces lipid droplet accumulation but also upregulates the expression of ferroptosis suppressor protein 1 (FSP1), a process that can be abrogated by the double knockout of GPD1/1L genes. Additionally, we have demonstrated that a decrease in the ubiquitination of FSP1 in GC cells upon lipid droplet accumulation, as well as silencing or pharmacological targeting FSP1, promotes ferroptosis and disrupts the peritoneal metastatic potential of GC cells. Collectively, our findings highlight the potential of FSP1 as a promising therapeutic target for metastatic gastric cancer.

Keywords:  FSP1; Ferroptosis; Gastric cancer; Lipid droplet

DOI:  https://doi.org/10.1186/s12964-025-02126-x
Cell Death Dis. 2025 Mar 07. 16(1): 161

SLC5A3 depletion promotes apoptosis by inducing mitochondrial dysfunction and mitophagy in gemcitabine-resistant pancreatic cancer cells.

Minsoo Kim, Woosol Chris Hong, Hyeon Woong Kang, Ju Hyun Kim, Dongyong Lee, Jae-Ho Cheong, Hye-Sol Jung, Wooil Kwon, Jin-Young Jang, Hyo Jung Kim, Joon Seong Park.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis, largely due to the rapid development of chemoresistance in patients. Mitochondrial dynamics play a crucial role in cancer cell survival. Currently, the specific mechanisms underlying gemcitabine resistance in PDAC remain unknown. In this study, we identified the sodium/myo-inositol co-transporter solute carrier family 5 member 3 (SLC5A3) as a key modulator promoting chemoresistance in PDAC. SLC5A3 levels were significantly upregulated in gemcitabine-resistant PDAC cells, enhancing their cell survival by stabilizing the mitochondrial functions and inhibiting apoptosis. Mitochondrial analysis showed that SLC5A3 inhibition disrupted the mitochondrial dynamics, leading to increased reactive oxygen species production, mitochondrial fission, and impaired oxidative phosphorylation. Moreover, SLC5A3 inhibition activated the PTEN-induced kinase 1/Parkin-mediated mitophagy pathway, resulting in the excessive removal of damaged and healthy mitochondria, thereby depleting the mitochondrial reserves and sensitizing the cells to apoptosis. In vivo studies revealed that targeting SLC5A3 enhanced the efficacy of gemcitabine and significantly reduced the tumor growth. Collectively, these results suggest SLC5A3-mediated mitochondrial regulation as a promising therapeutic strategy to overcome gemcitabine resistance in PDAC.

DOI: https://doi.org/10.1038/s41419-025-07476-5
Cancer Lett. 2025 Mar 05. pii: S0304-3835(25)00176-4. [Epub ahead of print]617 217612

SLC7A5/E2F1/PTBP1/PKM2 axis mediates progression and therapy effect of triple-negative breast cancer through the crosstalk of amino acid metabolism and glycolysis pathway.

Chengfei Jiang, Yingchen Qian, Xiaoming Bai, Shuangya Li, Liyuan Zhang, Yunxia Xie, Yifan Lu, Zhimin Lu, Bingjie Liu, Bing-Hua Jiang.

  Triple-negative breast cancer (TNBC) is one of the most challenging malignancies with the highest mortality rates among women. TNBC relies on both amino acid metabolism and glycolysis to fuel its bioenergetic and biosynthetic demands. However, the potential crosstalk between these two metabolic pathways and its impact on TNBC progression remain largely unexplored. In this study, we observed that SLC7A5, a key amino acid transporter, was upregulated in TNBC and strongly associated with poor patient prognosis. We demonstrated that the elevated SLC7A5 expression activated the amino acid pathway and promoted cell proliferation, tumor growth, and therapeutic resistance by inducing the switch from PKM1 to PKM2 expression, thereby mediating the crosstalk between amino acid metabolism and glycolysis. We further identified that the upregulation of SLC7A5 resulted from miR-152 suppression, which regulates TNBC cellular function and tumor growth. In addition, the miR-152/SLC7A5 axis mediated the expression of PTBP1, which maintains the balance between PKM1 and PKM2, linking amino acid signaling with the glycolysis pathway. To further understand the mechanism of PTBP1 upregulation, we identified that E2F1 transcriptionally activated PTBP1 expression through direct binding at the seed site, while E2F1 expression was also induced by SLC7A5 in TNBC. This novel SLC7A5/E2F1/PTBP1 axis plays a crucial role in regulating the crosstalk between amino acid signaling and glycolysis in TNBC and is essential for TNBC progression and therapeutic effectiveness. Our findings offer valuable insights into the molecular mechanisms underlying TNBC metabolic reprogramming and highlight potential targets for future therapeutic interventions.

Keywords:  Amino acid pathway; Glucose metabolism; Metabolic reprogramming; MicroRNAs; Solute carrier family 7 member 5; Therapy resistance; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.canlet.2025.217612
Cell Death Discov. 2025 Mar 08. 11(1): 92

Thyroid hormones inhibit tumor progression and enhance the antitumor activity of lenvatinib in hepatocellular carcinoma via reprogramming glucose metabolism.

Chun-Cheng Yang, Yu-Chuan Yan, Guo-Qiang Pan, Guang-Xiao Meng, Xiao Zhang, Lun-Jie Yan, Zi-Niu Ding, Dong-Xu Wang, Rui-Zhe Li, Guang-Zhen Li, Zhao-Ru Dong, Tao Li.

Thyroid hormones (THs) dysfunctions have been demonstrated to be associated with the risk of developing different types of cancers. The role of THs in regulating hepatocellular carcinoma (HCC) progression is still controversial. We demonstrated that T3 can inhibit HCC progression by enhancing the expression of THRSP. Mechanistically, T3 can activate tumor suppressor LKB1/AMPK/Raptor signaling as well as oncogenic PI3K/Akt signaling in HCC. Interestingly, T3-induced THRSP can augment the activation of LKB1/AMPK/Raptor signaling, yet inhibit T3-induced PI3K/Akt signaling activation, thereby preventing mTOR-induced nuclear translocation of HIF-1α, and ultimately suppressing ENO2-induced glycolysis and HCC progression. More importantly, the exogenous T3 enhances the antitumor effect of multikinase inhibitor lenvatinib in vitro and in vivo by regulating glycolysis. Our findings reveal the role and mechanism of THs in HCC progression and glucose metabolism and provide new potential therapeutic strategies for HCC treatment and drug resistance reversal.

DOI: https://doi.org/10.1038/s41420-025-02378-z
Clin Transl Med. 2025 Mar;15(3): e70272

PADI4 facilitates stem-like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma.

Zeyu Wang, Hao Wu, Zhaoxing Li, Zhukai Chen, Anqi Feng, Yuan Chu, Kang Fang, Zehua Zhang, Ziying Zhao, Zhuyun Leng, Shihan Zhang, Xiaoyuan Wang, Lingnan He, Tao Chen, Meidong Xu.

   BACKGROUND: Oesophageal squamous cell carcinoma (OSCC) is a highly lethal cancer characterized by its aggressive nature and chemotherapy resistance. Peptidylarginine deiminase 4 (PADI4) regulates protein citrullination and is associated with various cancer developments. The role of PADI4 in OSCC progression and chemoresistance remains unexplored.
METHODS: The protein interactions were conducted by immunoprecipitation assays. Quantitative real-time PCR and western blotting were utilized to quantifyexpression levels in cancer cells. The stem-like properties were assessed through spheroid growth assays and Cancer Stem Cells (CSCs) markers. Additionally, the resistance of cancer cells to cisplatin was evaluated using CCK8 assay.
RESULTS: This study shows that PADI4 promotes cellular stemness, contributing to the progression and chemoresistance of OSCC. Mechanistically, PADI4 facilitates the citrullination of protein arginine methyltransferase 2 (PRMT2), a process essential for the stabilization of PRMT2 expression and the enhancement of its function in promoting the transcription of IDs family (ID1 and ID2) via histone arginine methylation. This mechanism subsequently increases tumour stemness and contributes to the cisplatin resistance observed in OSCC. Mutations at the R312 site or inhibition by GSK484 can attenuate tumour stemness in OSCC, thereby reducing cisplatin resistance.
CONCLUSION: PADI4 promotes citrullination and stabilization of PRMT2, enhancing its function in upregulating ID1 and ID2 expression via histone arginine methylation, which increases stemness and contributes to cisplatin resistance in OSCC; this effect can be mitigated by R312 mutations or GSK484 inhibition, reducing stemness and cisplatin resistance.
KEY POINTS: The role of citrullinization in cisplatin resistance of OSCC. PADI4 citrullinate of PRMT2 and stabilize PRMT2. PADI4 citrullinate of PRMT2 promoting the transcription of IDs family (ID1, ID2 and ID3) via histone arginine methylation. PADI4 citrullinated PRMT2 affected the combination of PRMT2 and USP7. PADI4 citrullinate of PRMT2 at R312 site. PADI4 inhibitor GSK484 can affect the stemness of OSCC and cisplatin resistance.

Keywords:  OSCC; PADI4; PRMT2; cisplatin; citrullination

DOI:  https://doi.org/10.1002/ctm2.70272
Mol Med. 2025 Mar 11. 31(1): 92

PKN2 enhances the immunosuppressive activity of polymorphonuclear myeloid-derived suppressor cells in esophageal carcinoma by mediating fatty acid oxidation.

Xiao Fu, GuoQing Zhang, ZhiChao Hou, TingTing Fu, GuangHui Cui.

   BACKGROUND: Myeloid-derived suppressor cells (MDSCs) in tumor microenvironment reduce the efficacy of immunotherapy. PKN2 plays a role in colon cancer, but its function in esophageal cancer (EC) remains unclear. This study investigated PKN2 expression in MDSCs derived from EC tissues and determined whether PKN2 regulates immunosuppressive activity of MDSCs by mediating fatty acid oxidation (FAO).
MATERIALS AND METHODS: PKN2 expression was determined in GEO database, EC patients, and 4-NQO-induced EC mice, as well as in different types of immune cells. The effect of PKN2 on the function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) was investigated by co-culture of PMN-MDSCs and CD4+/CD8+ T cells. The co-culture of patient-derived organoids and autologous immune cells was performed to observe the effect of PKN2 on the immunosuppressive function of PMN-MDSCs.
RESULTS: PKN2 is highly expressed in EC tumor tissues compared to normal tissues, especially in tumor-infiltrated PMN-MDSCs. Overexpressing PKN2 in PMN-MDSCs contributes to the immunosuppressive activity of PMN-MDSCs in vitro. PKN2-overexpressing PMN-MDSCs inhibited the killing ability of cytotoxic T lymphocytes and promoted EC organoid growth. PKN2 promotes FAO in PMN-MDSCs via CPT1B (a key enzyme of FAO). Mechanistically, PKN2 promotes CPT1B transcription by upregulating STAT3 phosphorylation.
CONCLUSIONS: PKN2 expression was increased in PMN-MDSCs derived from human and mouse EC tissues. PKN2 plays a role in enhancing the immunosuppressive activity of PMN-MDSCs by facilitating STAT3 phosphorylation and CPT1B transcription, which in turn leads to increased CPT1B-mediated FAO in PMN-MDSCs. Targeted inhibition of PKN2 is expected to improve immunotherapeutic efficacy in EC patients.

Keywords:  Fatty acid oxidation; Immunosuppressive activity; Myeloid-derived suppressor cells; Organoid; PKN2

DOI:  https://doi.org/10.1186/s10020-025-01132-6
J Immunother Cancer. 2025 Mar 13. pii: e010639. [Epub ahead of print]13(3):

Protein arginine methyltransferase 6 enhances immune checkpoint blockade efficacy via the STING pathway in MMR-proficient colorectal cancer.

Jinlin Duan, Tao Chen, Qiwei Li, Yu Zhang, Ting Lu, Junyan Xue, Yang Sun, Ling Gao, Yonglong Zhang.

   BACKGROUND: The emergence of immunotherapy has revolutionized the paradigm of cancer treatment with immune checkpoint blockades (ICB) in solid cancers, including colorectal cancer (CRC). However, only a small subset of CRC patients harboring deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) benefits from ICB therapy. A very limited response to ICB therapy has been achieved in MMR-proficient CRC, representing a significant challenge limiting the clinical application of immunotherapy. MMR is the critical DNA repair pathway that maintains genomic integrity by correcting DNA mismatches, which is mediated by the MutSα or MutSβ complex consisting of MSH2 with MSH6 and MSH3, respectively. Given that MMR status directs effective immune response, we sought to determine whether targeting MMR capacity boosts ICB efficacy.
METHODS: Azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC and xenograft model were used to evaluate the function of PRMT6 and response to PRMT6 inhibitor EPZ020411 and combination therapy of PD1 and EPZ020411. Biochemical assays were performed to elucidate the underlying mechanism of PRMT6-mediated MSH2 methylation and immune evasion.
RESULTS: We have identified PRMT6 as a crucial regulator of MMR capacity via MSH2 dimethylation at R171 and R219. Such a modification abrogates its MMR capacity and prevents the recruitment of MSH3 and MSH6. PRMT6 loss or inhibition triggers cytosolic DNA accumulation and cGAS-STING signaling activation, leading to enhanced immune response in PRMT6-deficient colon tumors or xenografts. Pharmacological inhibition of PRMT6 using EPZ020411 promotes mutagenesis and destabilizes MutSα or MutSβ assembly, and prolonged EPZ020411 exposure maintains an MSI-like phenotype in microsatellite stability (MSS) cells. EPZ020411 treatment sensitizes ICB efficacy of MSS cells, but not MSI cells in vivo. Similar effects have been observed in MSS colon tumors induced by AOM/DSS.
CONCLUSIONS: Our study provides a preclinical proof of concept to overcome resistance to immunotherapy by targeting PRMT6 in CRC with MSS.

Keywords:  Colorectal Cancer; Immune Checkpoint Inhibitor; Immunotherapy

DOI:  https://doi.org/10.1136/jitc-2024-010639
Theranostics. 2025 ;15(7): 2834-2851

Ironomycin induces mantle cell lymphoma cell death by targeting iron metabolism addiction.

Sara Ovejero, Laura Alibert, Julie Devin, Tatiana Cañeque, Valentin Jacquier, Andrea Romero, Salome Amar, Matthieu Abouladze, Elvira Garcia de Paco, Ouissem Karmous Gadacha, Guilhem Requirand, Nicolas Robert, Miss Leriem Zellagui, Hugues de Boussac, Guillaume Cartron, Johanna Chiche, Jean-Ehrland Ricci, Charles Herbaux, Raphael Rodriguez, Jerome Moreaux, Caroline Bret.

  Rationale: Mantle-cell lymphoma (MCL) remains an aggressive and incurable cancer. Accumulating evidence reveals that abnormal iron metabolism plays an important role in tumorigenesis and in cancer progression of many tumors. Based on these data, we searched to identify alterations of iron homeostasis in MCL that could be exploited to develop novel therapeutic strategies. Methods: Analysis of the iron metabolism gene expression profile of a cohort of patients with MCL enables the identification of patients with a poor outcome who might benefit from an iron homeostasis-targeted therapy. We analyzed the therapeutic interest of ironomycin, known to sequester iron in the lysosome and to induce ferroptosis. Results: In a panel of MCL cell lines, ironomycin inhibited MCL cell growth at nanomolar concentrations compared with conventional iron chelators. Ironomycin treatment resulted in ferroptosis induction and decreased cell proliferation rate, with a reduced percentage of cells in S-phase together with Ki67 and Cyclin D1 downregulation. Ironomycin treatment induced DNA damage response, accumulation of DNA double-strand breaks, and activated the Unfolded Protein Response (UPR). We validated the therapeutic interest of ironomycin in primary MCL cells of patients. Ironomycin demonstrated a significant higher toxicity in MCL cells compared to normal cells from the microenvironment. We tested the therapeutic interest of combining ironomycin with conventional treatments used in MCL. We identified a synergistic effect when ironomycin is combined with Ibrutinib, Bruton's tyrosine kinase (BTK) inhibitor, associated with a strong inhibition of B-Cell receptor (BCR) signaling. Conclusion: Altogether, these data underline that MCL patients my benefit from targeting iron homeostasis using ironomycin alone or in combination with conventional MCL treatments.

Keywords:  B-cell receptor signaling; drug combination; iron metabolism; ironomycin; mantle cell lymphoma

DOI:  https://doi.org/10.7150/thno.101821
Nat Genet. 2025 Mar;57(3): 680-693

Alterations in PD-L1 succinylation shape anti-tumor immune responses in melanoma.

Long Liang, Xinwei Kuang, Yi He, Lin Zhu, Poyee Lau, Xin Li, Dingan Luo, Lan Gong, Wenbin Zhou, Fanglin Zhang, Xiaowei Liang, Zhuofeng Li, Bin Hu, Dandan Liu, Tao Ding, Hui Li, Shuang Zhao, Juan Su, Mien-Chie Hung, Jing Liu, Hong Liu, Xiang Chen.

Tumors undergo metabolic reprogramming to meet the energetic, synthetic and redox demands essential for malignancy, often characterized by increased glycolysis and lactate production. However, the role of mitochondrial metabolism in tumor immunity remains unclear. The present study integrates spatial transcriptomics, bulk transcriptomics and proteomics, revealing a strong link between the metabolite succinyl-CoA and tumor immunity as well as the efficacy of anti-programmed cell death protein-1 (PD-1) therapy in patients with melanoma. Elevated succinyl-CoA levels, through α-ketoglutarate or succinate supplementation, enhanced T cell-mediated tumor elimination, both in vitro and in vivo. Mechanistically, succinylation of the ligand of PD-1 (PD-L1) at lysine 129 led to its degradation. Increased carnitine palmitoyltransferase 1A (CPT1A), identified as a succinyltransferase for PD-L1, boosted anti-tumor activity. Preclinically, bezafibrate, a hyperlipidemia drug, upregulated CPT1A and synergized with CTLA-4 monoclonal antibody to inhibit tumor growth. Clinically, higher PD-L1 and lower CPT1A levels in tumors correlated with better anti-PD-1 therapy responses, suggesting potential biomarkers for prediction of treatment efficacy.

DOI: https://doi.org/10.1038/s41588-025-02077-6
Nat Metab. 2025 Mar 10.

A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours.

Samantha Pretto, Qian Yu, Pierre Bourdely, Sarah Trusso Cafarello, Heleen H Van Acker, Joren Verelst, Elena Richiardone, Lotte Vanheer, Amir Roshanzadeh, Franziska Schneppenheim, Charlotte Cresens, Maria Livia Sassano, Jonas Dehairs, Martin Carion, Shehab Ismail, Patrizia Agostinis, Susana Rocha, Tobias Bald, Johan Swinnen, Cyril Corbet, Sophia Y Lunt, Bernard Thienpont, Mario Di Matteo, Massimiliano Mazzone.

Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8+ T cells, we identified 83 targets and we applied single-cell RNA sequencing to disclose transcriptome changes associated with each metabolic perturbation in the context of pancreatic cancer. This revealed elongation of very long-chain fatty acids protein 1 (Elovl1) as a metabolic target to sustain effector functions and memory phenotypes in CD8+ T cells. Accordingly, Elovl1 inactivation in adoptively transferred T cells combined with anti-PD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumours. The accumulation of saturated long-chain fatty acids in Elovl1-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T cell receptor signalling. Elovl1-deficient T cells increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumour microenvironment. Finally, ELOVL1 in CD8+ T cells correlated with anti-PD-1 response in patients with melanoma. Altogether, Elovl1 targeting synergizes with anti-PD-1 to promote effective T cell responses.

DOI: https://doi.org/10.1038/s42255-025-01233-w
Nat Metab. 2025 Mar 11.

Glycogen drives tumour initiation and progression in lung adenocarcinoma.

Harrison A Clarke, Tara R Hawkinson, Cameron J Shedlock, Terrymar Medina, Roberto A Ribas, Lei Wu, Zizhen Liu, Xin Ma, Yi Xia, Yu Huang, Xing He, Josephine E Chang, Lyndsay E A Young, Jelena A Juras, Michael D Buoncristiani, Alexis N James, Anna Rushin, Matthew E Merritt, Annette Mestas, Jessica F Lamb, Elena C Manauis, Grant L Austin, Li Chen, Pankaj K Singh, Jiang Bian, Craig W Vander Kooi, B Mark Evers, Christine F Brainson, Derek B Allison, Matthew S Gentry, Ramon C Sun.

Lung adenocarcinoma (LUAD) is an aggressive cancer defined by oncogenic drivers and metabolic reprogramming. Here we leverage next-generation spatial screens to identify glycogen as a critical and previously underexplored oncogenic metabolite. High-throughput spatial analysis of human LUAD samples revealed that glycogen accumulation correlates with increased tumour grade and poor survival. Furthermore, we assessed the effect of increasing glycogen levels on LUAD via dietary intervention or via a genetic model. Approaches that increased glycogen levels provided compelling evidence that elevated glycogen substantially accelerates tumour progression, driving the formation of higher-grade tumours, while the genetic ablation of glycogen synthase effectively suppressed tumour growth. To further establish the connection between glycogen and cellular metabolism, we developed a multiplexed spatial technique to simultaneously assess glycogen and cellular metabolites, uncovering a direct relationship between glycogen levels and elevated central carbon metabolites essential for tumour growth. Our findings support the conclusion that glycogen accumulation drives LUAD cancer progression and provide a framework for integrating spatial metabolomics with translational models to uncover metabolic drivers of cancer.

DOI: https://doi.org/10.1038/s42255-025-01243-8
PLoS One. 2025 ;20(3): e0318740

Introduction of AGPAT3 gene as a regulator of cisplatin resistance in A2780 ovarian endometrioid carcinoma cell line.

Hadi Alizadeh, Sana Kerachian, Sadegh Babashah, Bahram M Soltani.

Ovarian cancer therapy remains a challenge for human health, partly due to chemotherapy resistance. Understanding the molecular mechanisms underlying this resistance is crucial. Therefore, to identify genes involved in cisplatin resistance in ovarian cancer, RNA-seq analysis of A2780cp (cisplatin-resistant) and A2780 (cisplatin-sensitive) cell lines was performed, revealing 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) as a differentially expressed candidate gene. First, MTT analysis confirmed the drug resistance of A2780cp and the sensitivity of A2780 cell lines. Subsequent reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting analyses revealed elevated AGPAT3 and mTOR expression in A2780cp cells compared with A2780 cells. Additionally, western blotting showed increased p-mTOR (phospho-mTOR)/mTOR and p-S6K (phospho-S6K)/S6K ratios in A2780cp cells. The overexpression of AGPAT3 in A2780 cells led to increased p-mTOR/mTOR and p-S6K/S6K ratios and increased IC50 values, as shown by RT-qPCR, western blotting, and MTT analysis. Conversely, shRNA-mediated downregulation of AGPAT3 resulted in reduced p-mTOR/mTOR and p-S6K/S6K ratios. At the cellular level, AGPAT3 overexpression in A2780 cells increased survival rates, decreased apoptosis, and caused G2/M cell cycle arrest under cisplatin treatment, as detected by apoptosis assay, and cell cycle flow cytometry analysis. Overall, we conclude that AGPAT3 is involved in cisplatin resistance in A2780cp cells and propose that targeting this gene or its enzymatic product could help overcome drug resistance.

DOI: https://doi.org/10.1371/journal.pone.0318740