bims-meract 2025-05-18 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–05–18
twenty-one papers selected by
Andrea Morandi, Università degli Studi di Firenze

CHD1 loss reprograms SREBP2-driven cholesterol synthesis to fuel androgen-responsive growth and castration resistance in SPOP-mutated prostate tumors.
Apolipoprotein E promotes primary resistance to AR-targeted therapy via inducing TRIM25-mediated AR ubiquitination and sensitizes immunotherapy in prostate cancer.
Auranofin resensitizes ferroptosis-resistant lung cancer cells to ferroptosis inducers.
NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis.
Targeting GPX4 palmitoylation to boost antitumor immunity.
MYLK-AS1 Enhances Glutamine Metabolism to Promote EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer.
Lysine-specific demethylase 1 deletion reshapes tumour microenvironment to overcome acquired resistance to anti-programmed death 1 therapy in liver cancer.
HSPA9 contributes to tumor progression and ferroptosis resistance by enhancing USP14-driven SLC7A11 deubiquitination in multiple myeloma.
Hypoxia-Activated CBS/H2S Signaling Drives Drug Resistance in AML through CD36-Mediated Fatty Acid metabolism.
Chemotherapy-induced macrophage CXCL7 expression drives tumor chemoresistance via the STAT1/PHGDH-serine metabolism axis and SAM paracrine feedback to M2 polarization.
Sitravatinib targets TYRO3 to augment the anti-tumor immune response of PD-1 blockade in hepatocellular carcinoma.
Dimethyl fumarate abrogates hepatocellular carcinoma growth by inhibiting Nrf2/Bcl-xL axis and enhances sorafenib's efficacy.
Cholesterol metabolism: A strategy for overcoming drug resistance in tumors.
LRP8 Regulates Lipid Metabolism to Stimulate Malignant Progression and Cisplatin Resistance in Bladder Cancer.
Inhibition of Mitochondrial-Associated Protein MAGMAS Resensitizes Chemoresistant Prostate Cancer Cells to Docetaxel.
Sickle cell disease induces chromatin introversion and ferroptosis in CD8+ T cells to suppress anti-tumor immunity.
Glutamine modulates stress granule formation in cancer cells through core RNA-binding proteins.
DEPP1: A prognostic biomarker linked to stroma‑rich and immunosuppressive microenvironment, promoting oxaliplatin resistance in gastric cancer.
CDK5-triggered G6PD phosphorylation at threonine 91 facilitating redox homeostasis reveals a vulnerability in breast cancer.
Using novel oxidative phosphorylation inhibitors to attenuate drug resistance in human gliomas.
Salinomycin inhibits SREBP1 to sensitize ferroptosis and ameliorate sorafenib resistance in clear cell renal cell carcinoma.

Nat Cancer. 2025 May 13.

CHD1 loss reprograms SREBP2-driven cholesterol synthesis to fuel androgen-responsive growth and castration resistance in SPOP-mutated prostate tumors.

Feiyu Chen, Haoyan Li, Yin Wang, Ximing Tang, Kevin Lin, Qidong Li, Chenling Meng, Wei Shi, Javier Leo, Xin Liang, Jie Zhang, Vivien Van, Iqbal Mahmud, Bo Wei, Philip L Lorenzi, Maria G Raso, Ana Aparicio, Yue Lu, Daniel E Frigo, Boyi Gan, Di Zhao.

Despite undergoing castration, most individuals with prostate cancer (PCa) experience progression to castration-resistant PCa (CRPC), in which the androgen receptor (AR) remains an important driver. Concurrent genetic alterations in SPOP and CHD1 define a unique subtype of PCa, but their interactions in tumor progression and therapy response remain unclear. Here, we provide genetic evidence supporting that CHD1 loss accelerates disease progression and confers resistance to castration in males with SPOP-mutated PCa. By leveraging genetic engineering and multiomics, we uncovered a noncanonical function of CHD1 in lipid metabolism reprogramming via repressing the SREBP2 transcriptome. Loss of CHD1 induces cholesterol production, supplies intratumoral androgen biosynthesis and enhances AR activity, leading to castration resistance of SPOP-mutated PCa. Combining anti-androgen therapy with cholesterol-lowering drugs showed synergistic and durable activity against CRPC harboring CHD1 loss and SPOP mutations. These findings advance our understanding of an emerging PCa subtype and offer biomarker-driven combinatorial treatment strategies for men with CRPC.

DOI: https://doi.org/10.1038/s43018-025-00952-z
Theranostics. 2025 ;15(12): 5572-5591

Apolipoprotein E promotes primary resistance to AR-targeted therapy via inducing TRIM25-mediated AR ubiquitination and sensitizes immunotherapy in prostate cancer.

Chaofan Liu, Xi Wang, Qinyu Li, Xintao Gao, Kai Zeng, Beining Li, Jianping Miao, Bolong Zheng, Jihong Liu, Zhihua Wang, Xianglin Yuan, Bo Liu.

  Rationale: Prostate cancer (PCa) growth is facilitated by the androgen receptor (AR) and its downstream signaling pathways, making AR-targeted therapy crucial for treating advanced stages. Despite this, the response to AR-targeted therapies is inconsistent, with a significant proportion of patients even exhibiting unresponsiveness to therapy from the outset, known as primary resistance. Therefore, a refined categorization framework is imperative for the timely detection of resistant phenotypes and the exploration of novel therapeutic avenues. Methods: Tissue microarrays and clinical cohorts were employed to delineate the impact of APOE on the prognostic outcomes and therapeutic resistance in PCa patients. Employing flow cytometry, immunoprecipitation, and mass spectrometry, we dissected the molecular underpinnings of APOE's role in conferring resistance to AR-targeted interventions. Single-cell RNA sequencing elucidated the intricate transcriptomic profiles of PCa with elevated APOE expression. Additionally, the therapeutic potential of anti-PD-L1 agents in treating PCa with APOE induction was rigorously assessed. Results: In this study, we elucidated the pivotal role of APOE in mediating primary resistance to AR-targeted therapy in PCa through the suppression of AR signaling pathways. Mechanistically, APOE was found to enhance the ubiquitination and subsequent degradation of AR by mediating the interaction between the E3-ligase TRIM25 and AR, concurrently dampening the transcriptional activity of AR. Additionally, elevated APOE expression was correlated with an augmented response to anti-PD-L1 treatment, hinting at the therapeutic advantage of immunotherapy in APOE-high PCa contexts. Conclusions: APOE expression could serve as a prognostic biomarker, pivotal for forecasting responses to both AR-targeted therapy and immunotherapy, thereby offering an innovative strategy for the personalized selection of treatment modalities in PCa.

Keywords:  AR-targeted therapy; Apolipoprotein E; immunotherapy; precision therapy; prostate cancer

DOI:  https://doi.org/10.7150/thno.109994
Biochem Biophys Res Commun. 2025 May 11. pii: S0006-291X(25)00706-5. [Epub ahead of print]770 151992

Auranofin resensitizes ferroptosis-resistant lung cancer cells to ferroptosis inducers.

Hao Li, Shuran Li, Yohei Kanamori, Saisai Liu, Toshiro Moroishi.

  Lung cancer, a major cause of cancer-related mortality, has limited therapeutic options, especially for advanced cases. Ferroptosis, an iron-dependent form of cell death, is a potential therapeutic strategy for this disease; however, resistance mechanisms in the tumor microenvironment impede its effectiveness. Therefore, in this study, we aimed to investigate the efficacy of sulfasalazine (SAS), a ferroptosis inducer, and auranofin (AUR), a Food and Drug Administration-approved anti-inflammatory agent, combination to counteract ferroptosis resistance in lung cancer. SAS induced ferroptosis in vitro; however, its efficacy in vivo was limited, possibly because of factors, such as nutrient deprivation and high cell density, in the microenvironment that suppressed the activities of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), key regulators of ferroptosis resistance. Screening of 2483 drugs revealed AUR as a compound resensitizing the YAP/TAZ-deficient lung cancer cells to ferroptosis. Moreover, SAS and AUR combination significantly enhanced lipid peroxidation and reactive oxygen species accumulation, further driving ferroptosis in cells. This combination effectively inhibited tumor growth and enhanced survival in a murine lung cancer model. Overall, our findings suggest that AUR potentiates ferroptosis-based therapies, serving as an effective candidate to overcome ferroptosis resistance in lung cancer.

Keywords:  Auranofin; Combination therapy; Drug resistance; Ferroptosis; Lung cancer; Sulfasalazine

DOI:  https://doi.org/10.1016/j.bbrc.2025.151992
Cell Rep. 2025 May 09. pii: S2211-1247(25)00472-3. [Epub ahead of print]44(5): 115701

NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis.

Ziyang Wang, Yuqin Di, Lvlan Ye, Wenzheng Fang, Xiangqiong Wen, Xiang Zhang, Jiale Qin, Youpeng Wang, Kunhua Hu, Zhenxin Zhu, Weiling He, Ying Chen.

  Metastatic colorectal cancer (CRC) cells endure survival challenges, including treatment-induced ferroptosis. While adaptation to ferroptosis stress facilitates metastasis, reciprocal regulatory mechanisms remain unclear. Here, a CRISPR-Cas9 screen identifies N-acetylneuraminate synthase (NANS) as a ferroptosis promoter in CRC, regardless of its metabolic function. NANS expression is downregulated and correlates with poor prognosis in patients with CRC. Under ferroptotic stress, cyclin-dependent kinase 1 (CDK1) phosphorylates NANS at serine 275 (S275), triggering its dissociation from TAK1. Phosphorylated NANS is ubiquitinated by UBE2N at K246, leading to degradation, which activates TAK1-NF-κB signaling and upregulates the ferroptosis inhibitor FTH1, enabling metastasis via ferroptosis resistance. NANS pS275 levels are associated with tumor aggressiveness and clinical outcomes in patients with CRC. These findings indicate that NANS suppresses CRC metastasis by enhancing ferroptosis susceptibility, while CDK1-mediated phosphorylation at S275 drives adaptive resistance. Targeting this phosphorylation axis may improve ferroptosis-inducing therapies to restrict metastatic progression in CRC.

Keywords:  CDK1; CP: Cancer; CP: Molecular biology; NANS; NF-κB signaling; colorectal cancer metastasis; ferroptosis; iron homeostasis

DOI:  https://doi.org/10.1016/j.celrep.2025.115701
Trends Cancer. 2025 May 14. pii: S2405-8033(25)00121-9. [Epub ahead of print]

Targeting GPX4 palmitoylation to boost antitumor immunity.

Daehee Hwang, Whitney S Henry.

  Despite significant milestones in cancer immunotherapy, tumor cells often escape immune surveillance. Zhou et al. revealed that the pivotal ferroptosis suppressor glutathione peroxidase 4 (GPX4) can undergo palmitoylation by zDHHC8, enhancing ferroptosis resistance. This study highlights the potential of targeting GPX4 palmitoylation to enhance cytotoxic T cell-mediated ferroptosis of tumor cells.

Keywords:  GPX4; ferroptosis; immune-checkpoint blockade (ICB); palmitoylation; tumor microenvironment (TME); zDHHC8

DOI:  https://doi.org/10.1016/j.trecan.2025.05.001
Cancer Res. 2025 May 14.

MYLK-AS1 Enhances Glutamine Metabolism to Promote EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer.

Tianyu Qu, Lei Song, Jiali Xu, Xiyi Lu, Dandan Yin, Jiali Dai, Chen Zhang, Renhua Guo, Erbao Zhang.

Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) limits the efficacy of molecular targeted therapy in non-small cell lung cancer (NSCLC). Metabolic reprogramming is a hallmark of lung cancer that could contribute to TKI resistance. Through systematic screening and verification, we identified a role for the long noncoding RNA (lncRNA) MYLK-AS1 supporting acquired TKI resistance in lung cancer. Elevated expression of MYLK-AS1 correlated with TKI resistance in NSCLC patient samples and cell lines. c-Myc mediated transcriptional activation of MYLK-AS1, and m6A modification promoted post transcriptional upregulation. Mechanistically, MYLK-AS1 bound and directly drove phase separation of interleukin enhancer binding factor 3 (ILF3), thus interacting with the 3'UTR of glutamate dehydrogenase 1 (GLUD1) to post-transcriptionally promote its mRNA stability. MYLK-AS1-mediated GLUD1 upregulation accelerated mitochondrial glutamine catabolism, promoting TKI resistance. Inhibition of GLUD1 with the small-molecule inhibitor R162 in TKI resistant models suppressed cell proliferation in vitro and tumor growth in vivo. Moreover, knockdown of MYLK-AS1 also enhanced drug sensitivity in TKI resistant patient-derived xenograft models, suggesting its therapeutic potential. Collectively, these findings offer insights into the regulation of TKI resistance from the perspective of phase separation and metabolism and highlight targeting the MYLK-AS1/ILF3/GLUD1 axis as a potential strategy for improving the efficacy of EGFR TKIs in NSCLC.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3748
Clin Transl Med. 2025 May;15(5): e70335

Lysine-specific demethylase 1 deletion reshapes tumour microenvironment to overcome acquired resistance to anti-programmed death 1 therapy in liver cancer.

Chen Liang, Mu Ye, Lei Yu, Peng-Fei Zhang, Xiao-Jun Guo, Xian-Long Meng, Hai-Ying Zeng, Shu-Yang Hu, Dao-Han Zhang, Qi-Man Sun, Ying-Hao Shen, Jia-Bin Cai, Shuang-Qi Li, Zhen Chen, Ying-Hong Shi, Ai-Wu Ke, Yujiang G Shi, Jian Zhou, Jia Fan, Fei-Zhen Wu, Xiao-Yong Huang, Guo-Ming Shi, Zheng Tang, Jia-Cheng Lu.

   BACKGROUND: Immune checkpoint blockade, particularly targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), shows promise in treating hepatocellular carcinoma (HCC). However, acquired resistance, especially in patients with 'hot tumours', limits sustained benefits. Lysine-specific demethylase 1 (LSD1) plays a role in converting 'cold tumours' to 'hot tumours', but its involvement in PD-1 inhibitor resistance in HCC is unclear.
METHODS: LSD1 and PD-L1 expression, along with CD8+ T cell infiltration, were assessed using immunohistochemistry in HCC tissues, correlating these markers with patient prognosis. The impact of LSD1 deletion on tumour cell proliferation and CD8+ T cell interactions was examined in vitro. Mouse models were used to study the combined effects of LSD1 inhibition and anti-PD-1 therapy on tumour growth and the tumour microenvironment (TME). The clinical relevance of LSD1, CD74 and effector CD8+ T cells was validated in advanced HCC patients treated with PD-1 blockade.
RESULTS: LSD1 overexpression in HCC patients correlated with reduced PD-L1 expression, less CD8+ T cell infiltration and poorer prognosis. LSD1 deletion increased PD-L1 expression, boosted effector CD8+ T cells in vitro and inhibited tumour growth in vivo. While anti-PD-1 monotherapy initially suppressed tumour growth, it led to relapse upon antibody withdrawal. In contrast, combining LSD1 inhibition with anti-PD-1 therapy effectively halted tumour growth and prevented relapse, likely through TME remodelling, enhanced CD8+ T cell activity and improved CD74-mediated antigen presentation. Clinically, low LSD1 expression was associated with better response to anti-PD-1 therapy.
CONCLUSION: LSD1 deletion reshapes the TME, enhances CD8+ T cell function and prevents acquired resistance to anti-PD-1 therapy in HCC. The combination of LSD1 inhibitors and PD-1 blockade offers a promising strategy for overcoming resistance in advanced HCC.
KEY POINTS: Uncovering the synthetic lethality resulting from LSD1 deletion and PD1 inhibitor co-administration, evaluating their combined effects on tumour growth and TME remodelling. Elucidating the mechanism underlying the combined therapy of LSD1 deletion with PD1 inhibition for HCC. Exploring the implications of LSD1, CD74 and effector CD8+ T cell expression levels in advanced HCC patients undergoing anti-PD1 treatment.

Keywords:  acquired resistance; hepatocellular carcinoma; immune checkpoint blockade; lysine‐specific demethylase 1; programmed death ligand 1; programmed death protein 1; tumour microenvironment

DOI:  https://doi.org/10.1002/ctm2.70335
Cell Rep. 2025 May 14. pii: S2211-1247(25)00491-7. [Epub ahead of print]44(5): 115720

HSPA9 contributes to tumor progression and ferroptosis resistance by enhancing USP14-driven SLC7A11 deubiquitination in multiple myeloma.

Na Shen, Yuan Xia, Xuxing Shen, Wei Hua, Min Shi, Lijuan Chen.

  Ferroptosis, a regulated cell death triggered by overload-dependent lipid peroxidation, is implicated in multiple human cancers. The mechanisms underlying ferroptosis in multiple myeloma (MM) remain enigmatic. Here, we confirmed that HSPA9 is overexpressed in MM samples and correlates with unfavorable outcomes. Functionally, HSPA9 enhances MM cell viability, ferroptosis resistance, and tumorigenicity, suggesting its oncogenic role. Proteomics screening identified SLC7A11, a key ferroptosis suppressor, as a HSPA9 interactor. Mechanistically, HSPA9 serves as a bridge to strengthen the interaction between USP14 and SLC7A11, modulating USP14-mediated SLC7A11 deubiquitination. Furthermore, the inhibition of USP14 with IU1 enhances the SLC7A11 ubiquitination and degradation, promoting ferroptosis and showing therapeutic efficacy in MM xenograft models. Clinically, HSPA9, USP14, and SLC7A11 expression are positively correlated in MM samples, which have a prognostic value. Our study reveals HSPA9-USP14-SLC7A11 axis as a key regulator of ferroptosis in MM and a potential therapeutic target.

Keywords:  CP: Cancer; HSPA9; SLC7A11; USP14; deubiquitination; multiple myeloma

DOI:  https://doi.org/10.1016/j.celrep.2025.115720
J Leukoc Biol. 2025 May 16. pii: qiaf065. [Epub ahead of print]

Hypoxia-Activated CBS/H2S Signaling Drives Drug Resistance in AML through CD36-Mediated Fatty Acid metabolism.

Qianpeng Li, Qin Li, Haifeng Han, Maowen Liu, Nannan Lyu, Zhiyuan Qiu, Rui Zhang, Xuehong Ran, Xiaofeng Li.

  Hypoxia-associated H2S accumulation promotes chemotherapy resistance in solid tumor cells. This study delved into the mechanism by which CBS/H2S signaling is involved in the development of acute myeloid leukemia (AML) resistance to cytarabine (ara-C) under hypoxic conditions. The levels of CBS and H2S in AML cells and ara-c-resistant AML cells were evaluated. Subsequently, the expression of CBS and H2S under normoxic and hypoxic conditions in ara-c-resistant AML cells were further scrutinized. Sh-CBS or sh-THBS1 was transfected into ara-c-resistant AML cells, which were then exposed to 1% oxygen and/or ara-C. The cell viability, apoptosis, lipid metabolism level were evaluated by CCK-8, flow cytometry, kit and qPCR. Simultaneously, the methylation of THBS1 was detected via methylation-specific PCR analysis. The expression of CBS and H2S is elevated in ara-C-resistant AML cells, rising proportionally with diminishing oxygen concentration. In ara-C-resistant AML cells, hypoxia stimulated cell viability, suppressed apoptosis, augmented total cholesterol and triacylglycerol levels, upregulated the levels of CD36 and CPT1α as well as downregulated SCAD and PPARα levels, while these effects of hypoxia were all reversed by sh-CBS. Sh-CBS notably decreases the hypermethylation level of THBS1 in ara-C-resistant AML cells. Sh-THBS1 reversed the regulatory effect of sh-CBS on lipid metabolism, cell viability, and apoptosis in ara-C-resistant AML cells. Conversely, sh-CD36 effectively overrode the reversal impact of sh-THBS1. Activation of CBS/H2S signaling in a hypoxic environment participates in the ara-C resistance of AML cells by facilitating CD36-mediated fatty acid metabolism through mediation of THBS1 methylation.

Keywords:  Acute myeloid leukemia; cytarabine resistance; hydrogen sulfide; hypoxia; thrombospondin 1

DOI:  https://doi.org/10.1093/jleuko/qiaf065
Cell Death Dis. 2025 May 14. 16(1): 379

Chemotherapy-induced macrophage CXCL7 expression drives tumor chemoresistance via the STAT1/PHGDH-serine metabolism axis and SAM paracrine feedback to M2 polarization.

Shuguang Liu, Hui Gong, Peihang Li, Jiahao Hu, Yixuan Li, Rou Xu, Junchao Cai, Shuqi Wang, Jiayi Cai, Hongmei Ma, Xirong Mi, Yifan Li, Qingbo Zhou, Qiming Zhou, Weiqiang Yang, Riqing Li, Libing Song, Lishan Fang.

Chemotherapy resistance in colorectal cancer (CRC) remains a major obstacle in clinical oncology. Analysis of clinical specimens from chemotherapy-resistant patients revealed elevated CXCL7 expression in tumor-associated macrophages (TAMs). Through integrated in vitro and in vivo studies, we demonstrated that chemotherapy induces tumor cell-macrophage crosstalk, leading to CXCL7 upregulation in TAMs. Using a co-culture system, we observed that CXCL7+ macrophages confer chemoresistance to CRC cells. Mechanistic investigations revealed that CXCL7 activates the CXCR2 receptor on tumor cells, triggering interferon signaling and promoting serine metabolism through STAT1-dependent transcriptional upregulation of phosphoglycerate dehydrogenase (PHGDH), the key enzyme in serine biosynthesis. This metabolic reprogramming enhances the paracrine secretion of S-adenosyl methionine (SAM), which drives chemotherapy resistance. Furthermore, CXCL7-mediated the paracrine secretion of SAM in tumor cells, which in turn promotes M2 macrophage polarization and sustains CXCL7 expression in TAMs. Our findings reveal that a CXCL7-SAM feedback loop between tumor cells and macrophages establishes a chemoresistant niche. This interaction represents a promising therapeutic target for overcoming chemoresistance in CRC.

DOI: https://doi.org/10.1038/s41419-025-07712-y
Clin Cancer Res. 2025 May 12.

Sitravatinib targets TYRO3 to augment the anti-tumor immune response of PD-1 blockade in hepatocellular carcinoma.

Hongkai Zhuang, Chenwei Tang, Wentao Wang, Bo Chen, Bingkun Wang, Yonglin Hua, Xiaowu Ma, Qingbin Wang, Wenliang Tan, Lei Yang, Zhiqin Xie, Yajin Chen, Changzhen Shang.

PURPOSE: Tyrosine kinase inhibitors (TKIs) combined with immune checkpoint blockades (ICBs) produce enhanced anti-tumor activity in the treatment of advanced hepatocellular carcinoma (HCC). Sitravatinib is a novel multi-target TKI that targets TYRO3, AXL, MERTK (TAM) receptors, c-MET, etc. This study aimed to investigate the anti-tumor efficacy and immunomodulatory activity of sitravatinib in HCC.
EXPERIMENTAL DESIGN: Human HCC cell lines and xenograft models were used to explore the anti-tumor activity of sitravatinib. Subcutaneous and orthotopic immunocompetent murine HCC models were used to assess the therapeutic efficacy of sitravatinib and PD-1 blockade combination therapy. Co-cultures for tumor cells and T cells were performed to verify the immunomodulatory effect of sitravatinib in tumors.
RESULTS: Sitravatinib showed potent anti-tumor activity and immunomodulatory capabilities from in vitro to in vivo. Sitravatinib treatment synergized with PD-1 blockade to generate an increased anti-tumor efficacy, leading to significant enrichment of cytotoxic CD8+ T cells as well as reduction of Treg cells infiltration in tumors. Mechanically, on one hand, sitravatinib reinforced MHC-I expression by blocking TYRO3-STAT1 axis, thereby sensitizing tumor cells to T cell liking. On the other hand, sitravatinib suppressed tumor-secreted IL33 by inhibiting TYRO3 activity in HCC cells, resulting in reduced Treg cells differentiation and consequently liberating CD8+ T cell cytotoxic capacity. In the clinic, one advanced HCC patient treated with Sitravatinib plus PD-1 blockade achieved near complete response and remains disease progression-free for more than two years.
CONCLUSIONS: Collectively, we demonstrated a rationale for combining sitravatinib with PD-1 blockade in the treatment for HCC.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-4338
Sci Rep. 2025 May 14. 15(1): 16724

Dimethyl fumarate abrogates hepatocellular carcinoma growth by inhibiting Nrf2/Bcl-xL axis and enhances sorafenib's efficacy.

Oluwasijibomi Damola Faleti, Moyed Alsaadawe, Jingyi Long, Qingshuang Luo, Longtai Hu, Yuanbin Zhang, Simin Deng, Gongfa Wu, Weiyi Fang, Mingliang He, Xiaoming Lyu.

  Hepatocellular carcinoma (HCC) is characterized by poor prognosis and remains a leading cause of cancer mortality worldwide. Advanced HCC is managed with several first-line therapies, including tyrosine kinase inhibitors (TKI) and immunotherapy (mAb-PD-1 and mAb-VEGF). However, the efficacy of HCC therapeutics is often short-lived. Recent studies have demonstrated that the activation of the Nrf2-Bcl-xL pathway contributes to poor prognosis in a subset of HCC patients. Here, we found that dimethyl fumarate (DMF), a drug used for treating psoriasis and multiple sclerosis, regulates the Nrf2-Bcl-xL signaling axis to inhibit HCC growth in a mice xenograft model. Mechanistically, the downregulation of the Nrf2-Bcl-xL axis led to mitochondria stress and apoptosis in vitro and in vivo. Enforced Nrf2 or Bcl-xL expression in HCC cells markedly reversed the antitumor effects of DMF in HCC cells. Importantly, DMF enhanced sorafenib's antitumor effects. Collectively, our results demonstrate new mechanism insights into the antitumor effects of DMF and that Nrf2-targeted therapy might improve HCC treatment outcomes.

Keywords:  B-cell lymphoma-extra large (Bcl-xL); Chemoresistance; Dimethyl fumarate; Hepatocellular carcinoma

DOI:  https://doi.org/10.1038/s41598-025-00832-7
Biochem Pharmacol. 2025 May 10. pii: S0006-2952(25)00236-9. [Epub ahead of print]238 116974

Cholesterol metabolism: A strategy for overcoming drug resistance in tumors.

Jiahui Li, Yinping Guo, Wenjie Zhang, Min Xia, Gaohua Liu, Yan Sun, Chang Liu, Jing Zhong.

  Despite significant advancements in targeted tumor therapies, the emergence of drug resistance remains a complex challenge. Cholesterol accumulation within tumor cells plays a crucial role in mediating drug resistance through various mechanisms, including altered membrane dynamics, enhanced drug efflux, and activation of survival signaling pathways. Targeting cholesterol metabolism presents an innovative strategy to enhance therapeutic sensitivity, particularly in breast cancer. Consequently, ongoing preclinical studies and clinical trials involving cholesterol-lowering agents indicate a promising direction for improving treatment outcomes in tumors. The combination of these agents with existing therapeutic regimens may lead to enhanced efficacy, highlighting the necessity for continued research in this vital area. This review examines the impact of cholesterol metabolism on drug resistance in tumors, particularly solid tumors, identifies therapeutic targets in this metabolic pathway (with a special focus on breast cancer), and discusses recent advances in cholesterol-lowering drugs in preclinical, as well as those that have entered clinical trials.

Keywords:  ABC transporter; Cholesterol metabolism; Drug resistance; Lipid raft; Tumor

DOI:  https://doi.org/10.1016/j.bcp.2025.116974
Kaohsiung J Med Sci. 2025 May 15. e70042

LRP8 Regulates Lipid Metabolism to Stimulate Malignant Progression and Cisplatin Resistance in Bladder Cancer.

Gang-Feng Wu, Zhen-Gang Luo, Ke Gao, Yu Ren, Chong Shen, Xiang-Rong Ying.

  Low-density lipoprotein receptor-related protein 8 (LRP8) is a crucial regulator of lipid metabolism and is implicated in the development and treatment of various cancers. However, its role in bladder cancer (BCa) remains unknown. We analyzed LRP8 expression in BCa using the TCGA database and clinical samples. We manipulated LRP8 expression in tumor cell lines using siRNA or overexpression plasmid transfection. Cell proliferation, migration, invasion, apoptosis, and drug resistance were assessed through CCK-8, transwell, flow cytometry, and IC50 assays. Additionally, a rescue experiment confirmed the association between LRP8 and lipid metabolism. LRP8 was significantly upregulated in BCa tissues and cells. Knockdown of LRP8 reduced tumor cell proliferation, migration, invasion, and increased apoptosis while enhancing cisplatin sensitivity. Overexpression of LRP8 boosted malignant progression and cisplatin resistance in tumor cells. The expression level of LRP8 is positively linked with the expression of lipid metabolism-related genes, phospholipid accumulation, and triglyceride accumulation. Notably, inhibiting lipid metabolism reversed the malignant progression and cisplatin resistance induced by LRP8 overexpression. LRP8 could promote BCa malignant progression and cisplatin resistance through lipid metabolism regulation.

Keywords:  LRP8; bladder cancer; cisplatin resistance; lipid metabolism

DOI:  https://doi.org/10.1002/kjm2.70042
Cancers (Basel). 2025 Apr 30. pii: 1535. [Epub ahead of print]17(9):

Inhibition of Mitochondrial-Associated Protein MAGMAS Resensitizes Chemoresistant Prostate Cancer Cells to Docetaxel.

Alfonso M Durán, Kristen Whitley, Krystal Santiago, Christian Yoo, Giancarlo Valdez, Kai Wen Cheng, Pedro Ochoa, David de Semir, Joanne Xiu, Parthiban Chokkalingam, Sasmita Das, Eric S Schaefer, Steven P Rowe, Bhaskar C Das, Carlos A Casiano, Frankis Almaguel.

   BACKGROUND/OBJECTIVES: Metastatic prostate cancer (PCa) is the leading cause of cancer-related deaths and a major contributor to cancer mortality in men. Most patients with metastatic PCa eventually develop metastatic castration-resistant prostate cancer (mCRPC), characterized by resistance to treatment with androgen-deprivation therapy, and often later the development of resistance to other types of agents. MAGMAS, a 13.8 kDa mitochondrial-associated protein, facilitates the import of nuclear-encoded proteins into the mitochondrial matrix. Overexpression of MAGMAS has been observed in several aggressive cancers, including breast, glioblastoma, and prostate cancer. When overexpressed, MAGMAS acts as a cytoprotective protein by scavenging reactive oxygen species (ROS), maintaining ROS levels that support cell proliferation while avoiding the induction of apoptosis. This study investigates the role of MAGMAS in therapy resistance in PCa cells.
METHODS/RESULTS: Quantitative immunoblotting revealed that MAGMAS is endogenously upregulated in docetaxel-resistant (DR) PCa cell lines compared to their docetaxel-sensitive parental counterparts. While MAGMAS depletion alone did not affect the survival of DR cells, it significantly sensitized them to docetaxel (DTX), as indicated by a marked reduction in clonogenic potential. Additionally, transient knockdown of MAGMAS in these resistant cells significantly decreased the levels of ABCB1 protein. Consistent with these findings, sub-therapeutic inhibition of MAGMAS using the novel BT#9 inhibitor, in combination with increasing concentrations of DTX, enhanced the sensitivity of DR cells to DTX, as demonstrated by proliferation and clonogenic assays. Lastly, RNA tumor expression predicts overall survival (OS).
CONCLUSIONS: These results implicate MAGMAS in PCa chemoresistance and suggest that targeting this protein could provide a novel therapeutic strategy for treating DR tumors.

Keywords:  MAGMAS; chemoresistance; docetaxel; mitochondria; prostate cancer

DOI:  https://doi.org/10.3390/cancers17091535
Immunity. 2025 May 08. pii: S1074-7613(25)00183-9. [Epub ahead of print]

Sickle cell disease induces chromatin introversion and ferroptosis in CD8+ T cells to suppress anti-tumor immunity.

Zilong Zhao, Benxia Hu, Yalan Deng, Melinda Soeung, Jun Yao, Lanxin Bei, Yaohua Zhang, Pengju Gong, Lisa A Huang, Zhou Jiang, Jian Gao, Shuang Peng, Tina K Nguyen, Menuka Karki, Bora Lim, Cassian Yee, Jared K Burks, Qing Zhang, Li Ma, Jianjun Gao, Nizar M Tannir, Leng Han, Dihua Yu, Linghua Wang, Michael A Curran, Maria A Gubbiotti, Giannicola Genovese, Boyi Gan, Wenbo Li, Pavlos Msaouel, Liuqing Yang, Chunru Lin.

  Understanding how genetic disorders affect CD8+ T cells in the tumor microenvironment is key to improving cancer immunotherapy. Individuals with sickle cell disease (SCD), the most prevalent inherited blood disorder, have a higher risk of developing certain cancers than the general population, but the mechanisms driving this increased risk remain unclear. Our study revealed that SCD altered CD8+ T cell 3D genome architecture, triggering ferroptosis and weakening anti-tumor immunity, thereby promoting tumor growth. Using murine and humanized SCD models, we found that disrupted chromosomal interactions in CD8+ T cells reduced the expression of anti-ferroptotic genes, including SLC7A11 and hydrogen sulfide (H2S) biogenesis genes, thereby increasing susceptibility to ferroptosis. Therapeutic restoration of H2S concentration in SCD mice rescued SLC7A11 expression, mitigated ferroptosis, and enhanced immune and anti-tumor responses. These findings highlight the impact of inherited disorders on cancer immunity and suggest precision immunotherapy strategies for affected individuals.

Keywords:  CD8(+) T cells; H(2)S; Hi-C; SLC7A11; SMARCB1; ferroptosis; genomic architecture alteration; immune checkpoint inhibitors; renal medullary carcinoma; sickle cell disease

DOI:  https://doi.org/10.1016/j.immuni.2025.04.020
J Cell Sci. 2025 May 16. pii: jcs.263679. [Epub ahead of print]

Glutamine modulates stress granule formation in cancer cells through core RNA-binding proteins.

Gabriel P Faber, Gilad Gross, Oz Mualem, Matan Y Avivi, Hiba Waldman Ben-Asher, Orly Yaron, Orit Shefi, Rakefet Ben-Yishay, Dana Ishay-Ronen, Yaron Shav-Tal.

  Cytoplasmic stress granules (SGs) induced by various stresses have been linked to cancer and other disorders. Which active energy pathways are required for SG formation remains unclear. We used nutrient deprivation to show that glutamine is the sole amino acid source governing whether cancer cells form SGs. Metabolic profiling revealed the essential functions of glutamine and glucose in SG formation under limiting metabolic conditions. Providing glutamine during metabolic stress restored ATP levels in cancer cells and revived many essential gene expression patterns. Myc, a known regulator of the shift between glucose and glutamine metabolism, showed increased expression as cells moved to glutamine uptake. Inhibition of MYC prevented SG formation even with glutamine present and increased cell death after arsenite exposure. The RNA-binding proteins G3BP1/2 were required for glutamine utilization, with G3BP1/2 knockout cells displaying a heavier reliance on glucose, yielding reduced cell survival and inability to properly utilize glutamine. Altogether, we show that cancer cells require glutamine for SG formation under nutrient deprivation, and its absence reduces cell survival, lowering ATP levels below an energy threshold required for SG formation.

Keywords:  Glutamine; Myc; RNA FISH; Stress granules

DOI:  https://doi.org/10.1242/jcs.263679
Oncol Rep. 2025 Jul;pii: 82. [Epub ahead of print]54(1):

DEPP1: A prognostic biomarker linked to stroma‑rich and immunosuppressive microenvironment, promoting oxaliplatin resistance in gastric cancer.

Xudong Qiu, Tao Pan, Tian Kuang, Yanying Shen, Yihan Zheng, Haigang Geng, Bo Ni, Xiang Xia, Chunchao Zhu, Zizhen Zhang, Hui Cao, Lin Tu.

  Decidual protein induced by progesterone (DEPP1) was identified to exert heterogeneous functions in several cancers, whereas its role in gastric cancer (GC) remains elusive. In the present study, differential expression analysis was conducted using three Gene Expression Omnibus datasets (GSE54129, GSE26942 and GSE3438). Validation of DEPP1 expression was performed using reverse transcription‑quantitative PCR, western blotting and immunofluorescence. Kaplan‑Meier survival and Cox regression analyses were employed to assess the association between DEPP1 expression and the prognosis of patients with GC. Immune infiltration analysis was conducted to explore the correlation between DEPP1 and the tumor microenvironment. The potential of DEPP1 to promote oxaliplatin resistance was assessed using flow cytometry, western blotting, and subcutaneous mouse models. DEPP1 was found to be significantly upregulated in the aforementioned cohorts, which was consistent with the clinical specimens of the present study, and it emerged as an independent risk factor for poor overall survival in patients with GC. A prognostic nomogram was developed to improve prognosis prediction. High DEPP1 expression correlated with increased infiltration of cancer‑associated fibroblasts, endothelial cells, and M2 macrophages, contributing to the development of a stroma‑rich and immunosuppressive microenvironment in GC. Furthermore, high DEPP1 expression was associated with reduced sensitivity to chemotherapy drugs in patients with GC. In vitro and in vivo experiments highlighted DEPP1's crucial role in promoting oxaliplatin resistance in GC. In conclusion, DEPP1 is identified as a promising prognostic biomarker linked to a stroma‑rich and immunosuppressive microenvironment, and it is critical in driving oxaliplatin resistance in GC. These findings may inform personalized therapeutic strategies for patients with GC.

Keywords:  chemotherapy resistance; decidual protein induced by progesterone 1; gastric cancer; prognostic biomarker; tumor microenvironment

DOI:  https://doi.org/10.3892/or.2025.8915
Acta Pharm Sin B. 2025 Mar;15(3): 1608-1625

CDK5-triggered G6PD phosphorylation at threonine 91 facilitating redox homeostasis reveals a vulnerability in breast cancer.

Yuncheng Bei, Sijie Wang, Rui Wang, Owais Ahmad, Meng Jia, Pengju Yao, Jianguo Ji, Pingping Shen.

  Glucose-6-phosphate dehydrogenase (G6PD), the first rate-limiting enzyme of the pentose phosphate pathway (PPP), is aberrantly activated in multiple types of human cancers, governing the progression of tumor cells as well as the efficacy of anticancer therapy. Here, we discovered that cyclin-dependent kinase 5 (CDK5) rewired glucose metabolism from glycolysis to PPP in breast cancer (BC) cells by activating G6PD to keep intracellular redox homeostasis under oxidative stress. Mechanistically, CDK5-phosphorylated G6PD at Thr-91 facilitated the assembly of inactive monomers of G6PD into active dimers. More importantly, CDK5-induced pho-G6PD was explicitly observed specifically in tumor tissues in human BC specimens. Pharmacological inhibition of CDK5 remarkably abrogated G6PD phosphorylation, attenuated tumor growth and metastasis, and synergistically sensitized BC cells to poly-ADP-ribose polymerase (PARP) inhibitor Olaparib, in xenograft mouse models. Collectively, our results establish the crucial role of CDK5-mediated phosphorylation of G6PD in BC growth and metastasis and provide a therapeutic regimen for BC treatment.

Keywords:  Breast cancer; CDK5; Drug resistance; Glucose-6-phosphoate dehydrogenase; Intracellular redox homeostasis; Isotopomer spectral analysis; Olaparib; Pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.apsb.2024.12.019
EXCLI J. 2025 ;24 433-449

Using novel oxidative phosphorylation inhibitors to attenuate drug resistance in human gliomas.

Chia-Kuang Tsai, Chin-Yu Lin, Yung-Lung Chang, Fu-Chi Yang, Chung-Hsing Chou, Yu-Chian Huang, Dueng-Yuan Hueng.

  Glioblastoma multiforme (GBM) is an aggressive brain tumor with a poor prognosis, worsened by resistance to temozolomide (TMZ). TMZ-induced DNA damage is counteracted by the repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT), promoting tumor recurrence. Targeting oxidative phosphorylation (OXPHOS), essential for cellular energy production, offers a potential therapeutic strategy to overcome TMZ resistance and improve GBM treatment outcomes. Gboxin, a small-molecule drug, selectively inhibits OXPHOS by targeting complex V, with minimal toxicity to normal cells. It accumulates in the mitochondria of GBM cells, exploiting their high membrane potential and pH, thereby inhibiting cell proliferation. This study evaluates Gboxin's efficacy in TMZ-resistant (TMZ-R) GBM. Results show that Gboxin suppresses the growth of both TMZ-sensitive and TMZ-R GBM cells by inhibiting proliferation, inducing apoptosis, and reducing OXPHOS activity. These findings were confirmed in an in vivo model, highlighting Gboxin as a promising therapeutic for both TMZ-sensitive and TMZ-R GBM. See also the graphical abstract(Fig. 1).

Keywords:  Gboxin; PLK2; glioblastoma; oxidative phosphorylation capacity

DOI:  https://doi.org/10.17179/excli2025-8193
Biochim Biophys Acta Mol Cell Res. 2025 May 11. pii: S0167-4889(25)00094-1. [Epub ahead of print] 119989

Salinomycin inhibits SREBP1 to sensitize ferroptosis and ameliorate sorafenib resistance in clear cell renal cell carcinoma.

Yu Su, Xuan Liu, Dekun Wang, Gang Li, Xue Mi, Yuying Zhang, Shijing Yue, Zhujun Zhang, Tianyu Shen, Xiaoyue Tan.

  Backgrounds Resistance to sorafenib, a frontline therapy for advanced ccRCC, is associated with decreased sensitivity to ferroptosis. Our research focuses on elucidating the mechanisms underlying ccRCC's resistance to sorafenib-induced ferroptosis and identifying potential new agents that could overcome this resistance.
METHODS: The silencing of SREBP1 was employed to evaluate the role of this key transcription factor in lipid synthesis and its contribution to ferroptosis resistance in sorafenib-treated ccRCC cells. The ATF4-mediated induction of SREBP1 following Salinomycin treatment was assessed by western blot, RT-PCR, immunohistochemistry, chromatin immunoprecipitation, and dual-luciferase reporter assays. In cultured ccRCC cells, the combined effects of Salinomycin and sorafenib on ferroptosis induction were evaluated by assessing cell viability, glutathione levels, malondialdehyde levels, BODIPY fluorescence, and intracellular Fe2+ concentration. In an orthotopic ccRCC mouse model, the synergistic effects of Salinomycin and sorafenib on both ferroptosis and tumor progression were examined.
RESULTS: Overexpression of SREBP1 was observed in ccRCC tumor tissue, and induced by sorafenib treatment. Silencing SREBP1 reduced the resistance of ccRCC cells to ferroptosis induced by sorafenib. Salinomycin decreased ATF4 level, which in turn inhibited SREBP1 transcription. Treatment with salinomycin enhanced the sensitivity of ccRCC cells to sorafenib-induced ferroptosis. In the orthotopic xenograft mouse model of ccRCC, the combination of salinomycin and sorafenib showed a synergistic effect in inducing ferroptosis inhibiting tumor growth.
CONCLUSIONS: Salinomycin treatment mitigates resistance to sorafenib-induced ferroptosis by inhibiting SREBP1. The combination of salinomycin and sorafenib synergistically enhances ferroptosis and suppresses ccRCC growth.

Keywords:  Clear cell renal cell carcinoma; Ferroptosis resistance; Salinomycin; Sorafenib; Sterol regulatory element binding protein 1

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119989