bims-meract 2026-04-26 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–04–26
twenty-one papers selected by
Andrea Morandi, Università degli Studi di Firenze

SLC25A48 promotes colorectal cancer growth by enhancing mitochondrial respiration and conferring ferroptosis resistance.
Creatine uptake promotes dendritic cell activation and enhances antitumor immunity.
Polyploid cancer cells surviving cisplatin reallocate central carbon sources to fuel antioxidant metabolism for survival.
Aurora-A drives sorafenib resistance by scaffolding stress granule assembly via phase separation.
CDC6/THBS1 accelerates pancreatic cancer progression via AKT-mediated glycolytic reprogramming.
AURKA suppresses NCOA4-mediated ferritinophagy to enhance sorafenib resistance in hepatocellular carcinoma.
A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.
Oleic Acid Fuels Cisplatin-Resistant Ovarian Cancer Through FABP4-Driven Lipid Uptake.
PFKP is required for chemoresistant phenotype of breast cancer through modulating the formation of CD133+ cancer stem like cells.
Pharmacological inhibition of the PERK pathway modulates hepatocellular carcinoma growth and immune signaling.
OTUB2/ALYREF axis modulates the docetaxel resistance of castration-resistant prostate cancer via upregulating ABCG4-mediated drug efflux.
CuET promotes cuproptosis and ferroptosis of lung cancer cells by interacting directly with polyunsaturated phospholipids.
RHBDL2 drives lipid metabolic reprogramming in osteosarcoma via USP3-mediated deubiquitination of PPT1.
USP7-mediated deubiquitination of the KEAP1-NRF2-HMOX1 axis enhances radioresistance in non-small cell lung cancer by suppressing ferroptosis.
Targeting RuvBL1 disrupts mitochondrial metabolism and structure in hepatocellular carcinoma.
Senescent cells acquire resistance to cystine deprivation-induced ferroptosis via the PPARα-PDK4-phosphorylated PDH axis.
Monocyte-mediated metabolic rewiring via CD31-CD38 interactions promotes growth and drug-resistance in multiple myeloma.
PDK1 elevation was induced by epigenetic modifications of KDM3A and METTL16 to mediate TKI resistance and cancer development.
TMEM87A suppresses ferroptosis and increases cancer immunotherapy resistance by maintaining the Golgi apparatus pH homeostasis.
Inhibiting Fatty Acid Oxidation Reverses Autophagy-Mediated Acquired Chemotherapy Resistance in Pancreatic Ductal Adenocarcinoma.
Cell Cycle Control of Nuclear Metabolism Couples Phosphatidylinositol Signaling to Histone Methylation.

Free Radic Biol Med. 2026 Apr 20. pii: S0891-5849(26)00427-2. [Epub ahead of print]

SLC25A48 promotes colorectal cancer growth by enhancing mitochondrial respiration and conferring ferroptosis resistance.

Zhen Wang, Jinghu He, E Jifu, Ying Yang, Xiaohong Yang.

  Accumulating evidence indicates that mitochondrial dysfunction is a hallmark of cancer. Nonetheless, the mechanisms linking mitochondrial dysfunction to cancer progression remain largely elusive. SLC25A48 was recently recognized as a transporter involved in mitochondrial choline uptake. Nevertheless, the roles of SLC25A48 in human malignancies remain unexplored. Here, we found that SLC25A48 is elevated in colorectal cancer (CRC) tissues and associates with unfavorable patient outcomes. Functional analyses showed that SLC25A48 accelerates the growth of CRC by enhancing proliferative capacity and preventing cell death. Mechanistically, SLC25A48 exerts its oncogenic function by enhancing the synthesis of choline-derived betaine, which is an important source of one-carbon units for numerous biosynthetic processes. On the one hand, SLC25A48 mitigates oxidative stress-induced ferroptosis by augmenting NADPH availability. On the other hand, it enhances cell proliferation by promoting mitochondrial energy production through upregulating mitochondrial DNA (mtDNA) replication and transcription. Importantly, silencing of SLC25A48 augmented the responsiveness of CRC cells to RSL3-induced ferroptosis and 5-FU-based chemotherapy. Furthermore, increased CTCF expression may contribute, at least in part, to the upregulation of SLC25A48 in CRC. Collectively, our data emphasize that SLC25A48 plays a critical oncogenic role in CRC and holds potential as a druggable target to overcome drug resistance in CRC.

Keywords:  SLC25A48; chemotherapy resistance; colorectal cancer; ferroptosis; mitochondrial metabolism

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.136
iScience. 2026 Apr 17. 29(4): 115436

Creatine uptake promotes dendritic cell activation and enhances antitumor immunity.

Elliot Kang, James Elsten-Brown, Yu-Chen Wang, Ashley Lam, Elise Sanchez, Renee Wen, Tiffany Wang, Jennifer Chiang, Quentin Scarborough, Yan-Ruide Li, Yichen Zhu, Jie Huang, Matthew Williams, Sarah Eckl, Bo Li, Lili Yang.

  Dendritic cells (DCs) are central regulators of antitumor T cell immunity and are highly sensitive to metabolic cues. However, the therapeutic potential of targeting DC metabolism remains underexplored. Here, we report upregulation of the creatine transporter (CrT; Slc6a8) in intratumoral DCs, which facilitates the cellular uptake of creatine, an energy-storage metabolite. DCs from CrT knockout mice exhibited impaired activation and reduced ability to elicit antigen-specific CD8 T cell responses. Conversely, creatine supplementation enhanced mouse DC activation in vitro and in vivo, and suppressed tumor growth in a syngeneic melanoma model. Notably, creatine uptake similarly boosted the activation and immunostimulatory function of human monocyte-derived DCs. Mechanistically, CrT promotes DC activation by preserving intracellular ATP levels and enhancing energy-dependent inflammatory signaling pathways. Together, these findings uncover a previously unrecognized role for creatine metabolism in regulating DC function and support the use of creatine supplementation as a strategy to augment DC-based cancer immunotherapy.

Keywords:  cancer; immunological methods; immunology

DOI:  https://doi.org/10.1016/j.isci.2026.115436
Mol Metab. 2026 Apr 18. pii: S2212-8778(26)00054-2. [Epub ahead of print] 102370

Polyploid cancer cells surviving cisplatin reallocate central carbon sources to fuel antioxidant metabolism for survival.

Melvin Li, Bradley Priem, Luke V Loftus, Michael J Betenbaugh, Kenneth J Pienta, Sarah R Amend.

  Therapy resistance is the leading cause of cancer-related deaths. Polyploid cancer cells mediate resistance through adaptive cell states transitions that promote survival and tumor recurrence. Here, we investigate metabolic differences between cisplatin-surviving polyploid cells and parental cancer cells using integrated fluxomics. Transcriptomic and proteomic profiling and extracellular flux analyses revealed that surviving cells upregulate glycolysis and gluconeogenesis while reducing oxidative phosphorylation, indicating a shift in central carbon metabolism. Isotope tracing and metabolic modeling demonstrate that surviving cells utilize glucose to fuel the pentose phosphate pathway (PPP) for NADPH generation and metabolize glutamine to provide carbons for the PPP via gluconeogenesis. Integrating our multi-omic datasets into a genome-scale model identified that surviving cells sustain antioxidant metabolism by decreasing fluxes of other NADPH-consuming reactions upon in silico PPP knockout. In addition, pathway-centric transcriptomic analysis revealed that high PPP and antioxidant gene expression correlated with poor survival outcomes in patients across multiple cancer types, demonstrating the clinical prognostic value of PPP and antioxidant metabolism. These findings reveal a systems-level shift in metabolism that maintains antioxidant activity for cell survival, highlighting potential targets and treatment paradigms to overcome therapy resistance.

Keywords:  (13)C-metabolic flux analysis; Cancer metabolism; Chemotherapy resistance; Genome scale metabolic modeling; Integrated fluxomics

DOI:  https://doi.org/10.1016/j.molmet.2026.102370
Proc Natl Acad Sci U S A. 2026 Apr 28. 123(17): e2516469123

Aurora-A drives sorafenib resistance by scaffolding stress granule assembly via phase separation.

Lingyu Kong, Fumei Zhong, Fazhi Yu, Ting Wang, Gang Wang, Yu Bai, Han Xia, Zihang Pan, Mingxue Liu, Yan Zhang, Rui Feng, Jiahai Zhang, Yingying Du, Kaiguang Zhang, Jing Guo, Ke Ruan, Zhenye Yang.

  The mitotic kinase Aurora-A is frequently overexpressed in cancers and contributes to tumor progression and therapy resistance, yet the mechanisms underlying its role in drug resistance remain unclear. Here, we show that sorafenib treatment triggers Aurora-A phase separation, leading to its recruitment into stress granules (SGs), membraneless organelles that promote cancer cell survival. Aurora-A facilitates robust SGs assembly, thereby conferring sorafenib resistance. Mechanistically, upon sorafenib-induced SGs formation, Aurora-A binds RNA via positively charged lysine/arginine residues within its intrinsically disordered region (IDR). Mutating these K/R residues with IDR of Aurora-A disrupts its RNA binding, impairs SGs assembly, and resensitizes cancer cells to sorafenib. Together, our work identifies Aurora-A as a kinase-activity-independent, RNA-binding scaffold essential for stress-adaptive biomolecular condensation, revealing a druggable phase-separation axis distinct from canonical Aurora-A kinase signaling.

Keywords:  Aurora-A; phase separation; sorafenib; stress granule; tumor therapy

DOI:  https://doi.org/10.1073/pnas.2516469123
Cell Death Dis. 2026 Apr 21.

CDC6/THBS1 accelerates pancreatic cancer progression via AKT-mediated glycolytic reprogramming.

Mengqiu Yin, Xi Chen, Ziyu Liu, Chongyu Wang, Tianyu Chen, Jinhui Zhu.

Pancreatic cancer remains one of the most aggressive malignancies, characterized by early metastatic spread and intrinsic resistance to chemotherapy, which ultimately results in poor treatment outcomes. While the Cell Division Cycle 6 (CDC6) protein has been extensively characterized across multiple cancer types, its functional role in the pathogenesis of pancreatic cancer remains poorly understood. In this study, we performed bioinformatics analysis using RNA-seq data from The Cancer Genome Atlas (TCGA) pancreatic adenocarcinoma cohort, and identified differentially expressed genes through microarray profiling. We conducted a comprehensive functional characterization of CDC6 using CCK-8, colony formation, wound healing, Transwell assays, and flow cytometry, and assessed cellular glycolysis levels based on measurements of ATP production, lactic acid generation, and glucose content. Subcutaneous xenograft mouse models were established to evaluate the impact of CDC6 on tumor growth in vivo, while mechanistic investigations were carried out using co-immunoprecipitation, chromatin immunoprecipitation, dual-luciferase reporter assays, and nucleocytoplasmic fractionation. Our results revealed that CDC6 expression is upregulated in pancreatic cancer, and its elevated expression is significantly correlated with unfavorable patient prognosis. Functional experiments demonstrated that CDC6 promotes the proliferation, migration, and invasion of pancreatic cancer cells. Thrombospondin 1 (THBS1) was identified to be positively correlated with CDC6 expression, and differentially expressed genes were notably enriched in the glucose metabolism pathway. Mechanistically, CDC6 cooperates with E2F1 to facilitate the transcription of THBS1, and the AKT signaling pathway is activated via the CDC6/THBS1 interaction. Overexpression of CDC6 significantly promoted glycolysis and tumor progression in pancreatic cancer, whereas these pro-tumor effects were markedly abrogated by THBS1 knockdown. Collectively, our findings demonstrate that CDC6/THBS1/AKT signaling drives glycolysis and accelerates pancreatic cancer progression, suggesting that the CDC6/THBS1/AKT axis may serve as a promising therapeutic target for pancreatic cancer.

DOI: https://doi.org/10.1038/s41419-026-08758-2
Cell Death Dis. 2026 Apr 24.

AURKA suppresses NCOA4-mediated ferritinophagy to enhance sorafenib resistance in hepatocellular carcinoma.

Wancui Zhu, Yilin Li, Zizhen Li, Jiajia Huang, Qiaohua Zhu, Huijuan Qiu, Enni Chen, Haohui Sun, Dingbo Shi, Miao Chen, Weining Xie, Wuguo Deng.

Acquired resistance to sorafenib remains a major obstacle in the treatment of advanced hepatocellular carcinoma (HCC). While inducing ferroptosis represents a promising strategy to overcome this resistance, the specific molecular drivers underlying ferroptosis evasion in this context remain poorly defined. Here, we identified Aurora Kinase A (AURKA) as a central, actionable regulator of ferroptosis resistance in sorafenib-resistant HCC. AURKA was significantly upregulated in resistant cells and clinical specimens, which correlated with a suppressed ferroptotic state. Mechanistically, we discovered that AURKA directly interacted with and phosphorylated the ferritinophagy receptor NCOA4 at specific serine residues (S186/S234/S492), thereby competitively disrupting the NCOA4-FTH1 complex. This disruption inhibited ferritinophagic degradation of FTH1, stabilized the iron-storage protein, and limited the intracellular labile iron pool required for ferroptosis execution. Genetic or pharmacological inhibition of AURKA restored NCOA4-mediated ferritinophagy, synergized with ferroptosis inducers (sorafenib or IKE), and potently suppressed tumor growth both in vitro and in vivo. Clinically, high co-expression of AURKA and FTH1 predicted an unfavorable prognosis of HCC patients. Our study delineated the first direct link between AURKA kinase activity and the ferritinophagy machinery, establishing the AURKA-NCOA4-FTH1 axis as a master regulator of ferroptosis resistance in sorafenib-resistant HCC. These findings provide both a novel prognostic biomarker and a mechanistically grounded therapeutic strategy to overcome acquired resistance.

DOI: https://doi.org/10.1038/s41419-026-08774-2
Cell Rep Med. 2026 Apr 23. pii: S2666-3791(26)00187-4. [Epub ahead of print] 102770

A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.

Omid Hajihassani, Asael Roichman, Jacob A Boyer, Michal MacArthur, Ricardo Cordova, Alexander Loftus, Christina S Boutros, Jonathan J Hue, Parnian Naji, Soubhi Tahhan, Peter Gallagher, William Beegan, Danyal Shah, James Choi, Nimat Manzoor, Shihong Lei, Christine Kim, Moeez Rathore, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Craig Hunter, Mehrdad Zarei, Sydney Alibeckoff, Karen Ji, Hallie Graor, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder J Lund, Luke D Rothermel, Joshua D Rabinowitz, Jordan M Winter.

  Pancreatic cancer is the third leading cause of cancer-related death in the United States. Current chemotherapy options provide limited benefits. Emerging evidence suggests that a ketogenic diet (KD) exerts anti-tumor effects by reprogramming tumor metabolism and revealing therapeutic vulnerabilities. Efforts to target glutamine metabolism-an essential pathway in many cancers-have shown promise in preclinical models, but clinical efficacy has remained limited. Here, we show that a KD increases tricarboxylic acid (TCA) cycle activity and elevates reliance on glutamine-related metabolites in murine pancreatic cancer models and in vitro under KD-mimicking conditions. This metabolic adaptation occurs in response to reduced glucose availability. We demonstrate that combining glutamine metabolism inhibitors, such as CB-839 or 6-diazo-5-oxo-L-norleucine (DON), with a KD leads to robust anti-tumor effects in preclinical models of pancreatic cancer. Thus, metabolic vulnerability induced by dietary intervention provides a rationale for combining glutamine-targeted therapies with a ketogenic diet in future clinical studies.

Keywords:  PDAC nutrient flux; chemotherapy; combination therapy; glutamine metabolism; glutamine tracing; ketogenic diet; ketogenic diet media; pancreatic cancer; targeted therapy

DOI:  https://doi.org/10.1016/j.xcrm.2026.102770
Mol Metab. 2026 Apr 21. pii: S2212-8778(26)00058-X. [Epub ahead of print] 102374

Oleic Acid Fuels Cisplatin-Resistant Ovarian Cancer Through FABP4-Driven Lipid Uptake.

Ana Maria Isac, Andres Valdivia, Didi Zha, Yinu Wang, Vanessa Hernandez, Guangyuan Zhao, Chinmayee Vallabh Prabhu Dessai, Ujin Kim, Annapurna Sai Josyula, Wenan Qiang, Sandra Orsulic, Ji-Xin Cheng, Daniela Matei.

BACKGROUND: Ovarian cancer (OC) depends on lipids as fuel for metastasis and growth. We previously showed that cisplatin resistant (Pt-R) OC cells uptake higher amounts of fatty acids (FAs) compared to sensitive (Pt-S) cells, a process which facilitates cancer cell survival under cisplatin-induced oxidative stress.
METHODS: Isogenic pairs of Pt-S and Pt-R OC cell lines were cultured in low serum conditions supplemented with either 50 μM oleic acid (OA, unsaturated) or 50 μM palmitic acid (PA, saturated) and used for viability assays, RNA-Sequencing, and cell cycle analysis. The effects of an OA enriched diet were assessed in intraperitoneal ovarian xenografts. The FABP inhibitor BMS-309403 was used to block lipid import in vitro and in vivo.
RESULTS: Pt-R cells were less viable than Pt-S cells under serum depletion and OA rescued starvation induced inhibition of cell proliferation, with more significant effects in Pt-R compared to Pt-S cells. RNA-sequencing showed that OA promoted upregulation of cell cycle-related pathways, including G2/M checkpoints, driven by the transcription factor E2F1. Supplementation with OA increased S- and G2/M phase cell populations in both Pt-S and Pt-R cells (p<0.05) and E2F1 inhibition reduced OA-induced cell proliferation. An OA enriched diet promoted the growth and peritoneal dissemination of Pt-R ovarian xenografts. When co-cultured with adipocytes, Pt-R cells expressed higher levels of FA transporter proteins FABP4 and CD36 compared to sensitive cells and FABP4 expression was upregulated in paired metastatic and recurrent vs. primary human ovarian tumors (p<0.05). An FABP inhibitor sensitized OC cells to cisplatin and suppressed the in vivo growth of Pt-R xenografts and patient derived xenografts.
CONCLUSIONS: Pt-R OC cells harbor heightened dependence on unsaturated FAs compared to Pt-S cells and upregulate key transporters to increase FAs uptake. OA supports the proliferation of Pt-R cells in vitro and in vivo and a combination of carboplatin and FABP4 inhibitor reduces OC growth in vivo. These findings suggest that lipid composition may influence therapeutic response and raise important considerations for dietary guidance in patients with cancer.

DOI: https://doi.org/10.1016/j.molmet.2026.102374
Mol Biomed. 2026 Apr 23. pii: 56. [Epub ahead of print]7(1):

PFKP is required for chemoresistant phenotype of breast cancer through modulating the formation of CD133+ cancer stem like cells.

Kai Fang, Yue Ma, Lihua Li, Yan Yue, Hang Ruan, Sidong Xiong.

  Breast cancer is the foremost cause of cancer-related death in women globally, and taxane-anthracycline (TA) combination regimens represent standard frontline chemotherapy. Although widely administered, the pathological complete response rate to TA therapy is less than 30%, and chemoresistance remains a major barrier to effective disease control, frequently leading to relapse and poor survival. Both metabolic reprogramming and tumor microenvironmental remodeling are closely associated with treatment failure, yet how they interact to drive TA resistance remains largely unclear. Here we show that phosphofructokinase platelet (PFKP), a key glycolytic enzyme, is highly expressed in breast cancer. PFKP drives glycolysis and promotes CD133+ cancer stem-like cells (CSLCs) that are inherently TA-resistant. Moreover, PFKP-overexpressing cancer cells stimulate cancer-associated fibroblasts (CAFs), which in turn augment CD133+ CSLC formation via the CXCL16/CXCR6 axis, establishing a feedforward loop that reinforces chemoresistance. These results reveal a previously unappreciated mechanism by which a glycolytic enzyme in cancer cells orchestrates stromal crosstalk to sustain a chemotherapy-refractory niche. By identifying PFKP as a key driver and the PFKP-CSLC-CAF axis as an actionable target, our work moves the field beyond the traditional view of metabolic reprogramming as a cell-autonomous event. Disrupting this axis-for instance, by PFKP inhibition or CXCL16/CXCR6 blockade-may restore TA sensitivity in aggressive basal-type breast cancer, offering a promising strategy to improve long-term outcomes for hard-to-treat patients.

Keywords:  Breast cancer; Cancer stem-like cells; Cancer-associated fibroblasts; Chemoresistance; Glycolysis; PFKP

DOI:  https://doi.org/10.1186/s43556-026-00454-z
FEBS Open Bio. 2026 Apr 21.

Pharmacological inhibition of the PERK pathway modulates hepatocellular carcinoma growth and immune signaling.

Ada Lerma-Clavero, Maria Kopsida, Nathalie Arendt, Hans Lennernäs, Markus Sjöblom, Femke Heindryckx.

  The unfolded protein response (UPR) plays an important role in tumor progression and cellular stress adaptation. In hepatocellular carcinoma (HCC), pharmacological inhibition of the protein kinase R-like endoplasmic reticulum kinase (PERK) is a potential therapeutic strategy, yet its effects on tumor growth and the microenvironment remain unclear. We investigated the selective PERK inhibitor AMG PERK 44 in a diethylnitrosamine (DEN)-induced mouse model of advanced HCC. Tumor burden, proliferation, fibrosis, immune-related gene expression, and ER stress signaling were assessed alongside analyses of single-cell RNA-sequencing data from HCC mouse models and liver-specific PERK knockout mice. Our results show that AMG PERK 44 did not alter tumor number nor cause a decrease in tumor area and proliferation. Furthermore, fibrotic burden was unchanged, although fibrosis architecture and stromal gene expression (TGF-β, CTGF, F4/80) were modified. Despite PERK inhibition, the expression of ER stress associated genes (CHOP, EIF2AK3, ERdj4) increased. Single-cell analysis revealed context-dependent PERK activity, highest in dendritic cells and macrophages under inflammatory and tumor conditions, while PERK knockout livers showed impaired UPR responses after tunicamycin treatment. Finally, AMG PERK 44 did not enhance idarubicin efficacy and caused no major off-target effects. These findings highlight the context-dependent role of PERK in the HCC microenvironment and its implications for targeting UPR pathways in liver cancer. Impact statement This study provides an evaluation of PERK as a therapeutic target in hepatocellular carcinoma by demonstrating that its inhibition does not produce the anticipated anti-tumor effects in advanced disease, but instead exerts nuanced, context-dependent influences on the tumor microenvironment.

Keywords:  AMG PERK44; ER stress; PERK; carcinogenesis; fibrosis; hepatocellular carcinoma; idarubicin; inflammation

DOI:  https://doi.org/10.1002/2211-5463.70252
Int J Biol Sci. 2026 ;22(7): 3342-3366

OTUB2/ALYREF axis modulates the docetaxel resistance of castration-resistant prostate cancer via upregulating ABCG4-mediated drug efflux.

Zhi-Bin Ke, Jia-Yin Chen, Bin Lin, Chao-Ran Chen, Yu-Ting Xue, Jiang-Bo Sun, Zi-Heng Yan, Yu-Xuan Zhao, Meng-Xin Liu, Zhen Wang, Xue-Yi Xue, Qing-Shui Zheng, Yong Wei, Ning Xu.

  Docetaxel (DTX) is a standard chemotherapy agent for castration-resistant prostate cancer (CRPC); however, DTX resistance remains a major clinical challenge, and the underlying molecular mechanisms are not fully understood. In our study, it was found that OTUB2 was highly expressed in DTX-resistant CRPC and could be served as a key driver of DTX resistance. Mechanistically, OTUB2 stabilizes the m5C reader ALYREF by removing its K48-linked polyubiquitin chains, leading to increased ALYREF protein levels. And then, ALYREF enhances the mRNA stability and expression of ABCG4, thereby promoting ATP-dependent efflux of DTX. Moreover, the expression of OTUB2 mRNA and protein could be regulated by FOXD3-AS1 derived from cancer-associated fibroblasts (CAFs). More importantly, treatment with OTUB2 inhibitor (OTUB2-IN-1) resensitized resistant CRPC to DTX. Together, our findings establish OTUB2 as a novel driver of DTX resistance in CRPC and highlight the role of CAFs-derived FOXD3-AS1 and OTUB2/ALYREF/ABCG4 axis in modulating DTX resistance of CRPC.

Keywords:  cancer-associated fibroblasts; castration-resistant prostate cancer; de-ubiquitination; docetaxel resistance; m5C modification

DOI:  https://doi.org/10.7150/ijbs.126319
iScience. 2026 Apr 17. 29(4): 115438

CuET promotes cuproptosis and ferroptosis of lung cancer cells by interacting directly with polyunsaturated phospholipids.

Jie Zhang, Chengying Lei, Guangzhe Zheng, Bingxue Nie, Yiju Wei, Yanqin Lu, Shuping Zhang.

  The FDA-approved disulfiram (DSF) is metabolized to diethyldithiocarbamate-copper (CuET) in vivo, exhibiting excellent anti-tumor activity in various types of tumors. Although cuproptosis and ferroptosis are both reported to be involved in the tumor-killing effects of CuET, the specific crosstalk mechanism remains poorly understood. Herein, we found that CuET increased the concentration of copper ions significantly in non-small cell lung cancer (NSCLC) cells, thereby triggering the process of cuproptosis. Simultaneously, we observed an increase in lipid peroxidation (LPO) and ferroptosis. Mechanistically, CuET interacts directly with polyunsaturated phospholipids to generate free radicals, leading to LPO and ferroptosis, with limited dependence on iron accumulation. Additionally, lipid composition changes induced by CuET might also contribute to ferroptosis. In vivo anti-tumor experiments verified copper-mediated cell death. We uncovered that CuET induced ferroptosis through a copper-triggered, non-canonical, and radical-dependent pathway. Therefore, our data elucidate a therapeutic approach for NSCLC by co-targeting cuproptosis and ferroptosis.

Keywords:  biochemistry; cancer; cell biology

DOI:  https://doi.org/10.1016/j.isci.2026.115438
Cell Death Dis. 2026 Apr 24.

RHBDL2 drives lipid metabolic reprogramming in osteosarcoma via USP3-mediated deubiquitination of PPT1.

Li Fan, Cheng Tao, Xiangwei Zeng, Jianpeng Liu, Rubo Cao, Kewei Zhu.

Osteosarcoma (OS) is characterized by high malignancy and profound metabolic reprogramming, yet the upstream regulators of its lipid metabolic adaptations remain largely elusive. Here, we report that RHBDL2 is significantly overexpressed in OS tissues, correlating with advanced clinical stage and poor patient prognosis. Mechanistically, multi-omics and structural analyses reveal that RHBDL2 functions as a non-proteolytic scaffold to stabilize the deubiquitinase USP3. This interaction is mediated by a compact hydrophobic core anchored by the Val245 residue of RHBDL2 and occurs independently of its protease activity. Stabilized USP3 subsequently prevents the proteasomal degradation of Palmitoyl-Protein Thioesterase 1 (PPT1) through deubiquitination. We further identify PPT1 as a metabolic rheostat that fuels OS malignancy by orchestrating FASN-dependent de novo lipogenesis, a requirement that can be partially bypassed by exogenous lipid supplementation. This RHBDL2-USP3-PPT1 axis promotes OS cell proliferation, migration, and epithelial-mesenchymal transition while suppressing apoptosis. Pharmacological screening identified Epigallocatechin gallate (EGCG) as a potent inhibitor that competitively disrupts the RHBDL2-USP3 interaction interface, thereby suppressing the downstream lipogenic program and inhibiting tumor growth and bone destruction in vivo. Collectively, our findings delineate a novel signaling cascade linking post-translational protein stabilization to metabolic adaptation, highlighting the RHBDL2-USP3 structural interface as a promising therapeutic vulnerability in osteosarcoma.

DOI: https://doi.org/10.1038/s41419-026-08788-w
Oncogene. 2026 Apr 23.

USP7-mediated deubiquitination of the KEAP1-NRF2-HMOX1 axis enhances radioresistance in non-small cell lung cancer by suppressing ferroptosis.

Jianwei Tang, Lei Xu, Zetian Gong, Liang Chen.

Radioresistance remains the primary cause of radiotherapy failure in non-small cell lung cancer (NSCLC). This study investigated the regulatory role of HMOX1-mediated ferroptosis in NSCLC radiosensitivity. Radioresistant cell models (H1650R/H1975R) were established through fractionated irradiation of parental H1650/H1975 cells. Transcriptomic analysis by RNA sequencing revealed significant HMOX1 suppression in resistant cells. Functional validation demonstrated that HMOX1 overexpression enhanced radiation sensitivity via ferroptosis induction, whereas HMOX1 knockdown aggravated radioresistance. Mechanistic investigations identified USP7 as a key deubiquitinating enzyme that stabilizes KEAP1 through K48-linked polyubiquitin chain cleavage, thereby promoting NRF2 ubiquitination and suppressing HMOX1 transcription. Pharmacological inhibition using KI696 blocked KEAP1-NRF2 interaction, restoring HMOX1 expression. Notably, the USP7 inhibitor GNE-6640 destabilized KEAP1, upregulated NRF2/HMOX1 axis activity, and triggered ferroptosis in resistant cells. In vivo studies confirmed that GNE-6640 synergized with radiotherapy to suppress tumor growth and pulmonary metastasis in xenograft and NSG mouse models, as monitored by bioluminescence imaging. These findings establish the USP7-KEAP1-NRF2-HMOX1 axis as a critical determinant of radioresistance, demonstrating that targeted USP7 inhibition with GNE-6640 reactivates ferroptosis and restores radiosensitivity. This dual-mechanistic approach provides a novel therapeutic strategy to overcome treatment resistance in NSCLC.

DOI: https://doi.org/10.1038/s41388-026-03783-z
JHEP Rep. 2026 Apr 17. pii: S2589-5559(26)00129-1. [Epub ahead of print] 101858

Targeting RuvBL1 disrupts mitochondrial metabolism and structure in hepatocellular carcinoma.

Tommaso Mello, Irene Simeone, Alice Guida, Dimitri Papini, Francesca Begnozzi, Alice Santi, Daniele Guasti, Patrizia Nardini, Simone Polvani, Matteo Lulli, Oxana Bereshchenko, Elisabetta Ceni, Armando Curto, Paolo Pinton, Massimo Bonora, Andrea Galli.

   BACKGROUND & AIMS: The AAA+ ATPase RuvBL1 takes part in several biological processes, including chromatin remodelling and DNA repair, ribosome biogenesis, mTOR signalling, and oncogenic transformation. RUVBL1 overexpression correlates with poor survival in hepatocellular carcinoma patients. We previously found that RuvBL1 is a key regulator of liver glucose metabolism in mice. Here, we aimed at disentangling the metabolic function of RuvBL1 in HCC cells.
METHODS: Non-transformed AML-12, primary mouse hepatocytes, HCC cell lines, and RuvBL1hep-/- mice were used (n=3). RuvBL1 was targeted by RNAi and by inhibition with CB-6644. Metabolomic profiling and mitochondrial functions were assessed by targeted GC/MS, Seahorse analysis, and ATP synthase activity. Mitochondrial morphology and membrane potential were investigated by fluorescence microscopy, High-Content Imaging, and TEM. Mitochondrial RuvBL1 was detected by WB, super-resolution microscopy, TEM, and PLA. Human HCC and normal liver samples from TCGA and GTEx databases were used for in silico analysis (T=369, N=160).
RESULTS: Targeting RuvBL1 impairs mitochondria-centred metabolic processes, including amino acid metabolism, TCA cycle, and OXPHOS. Inhibition of RuvBL1/2 activity induces loss of cristae integrity, mitochondrial hyperpolarization and fragmentation, a phenotype paralleled by the hepatocytes of RuvBL1hep-/- mice. We detected RuvBL1 in proximity to mitochondrial ATP synthase, a previously unreported localization for this protein. Mechanistically, CB-6644 reduces ATP synthase-RuvBL1 interaction and impairs complex V activity even under a fuelled TCA cycle. In human HCC, higher RUVBL1 expression correlates with gene signatures associated with mitochondrial oxidative phosphorylation (FDR=5.64e-03), ATP synthase complex (FDR=6.03e-03), and poorer outcome (p=2e-07).
CONCLUSIONS: Targeting RuvBL1 impairs complex V activity, disrupting mitochondrial metabolic functions and structural integrity. The mitochondrial functions of RuvBL1 may inform novel therapeutic strategies in the fight against hepatocellular carcinoma.
IMPACT AND IMPLICATIONS: Metabolic reprogramming is a key feature driving HCC onset, progression, and plasticity, contributing to treatment resistance and poor prognosis. RUVBL1 overexpression correlates with reduced survival of HCC patients and has emerged as a potential metabolic modulator. In this study, we found that targeting RuvBL1 impairs its interaction with mitochondrial ATP synthase, disrupting mitochondrial metabolism and cristae structure. In human HCC samples, RUVBL1 expression correlates with hallmark mitochondrial metabolic processes. These findings may inform the development of targeted therapeutic approaches aimed at impairing the metabolic rewiring and plasticity of HCC.

Keywords:  ATP synthase; OXPHOS; TCA cycle; amino acids metabolism; ketogenesis; liver cancer; metabolic reprogramming

DOI:  https://doi.org/10.1016/j.jhepr.2026.101858
FEBS Lett. 2026 Apr 19.

Senescent cells acquire resistance to cystine deprivation-induced ferroptosis via the PPARα-PDK4-phosphorylated PDH axis.

Shiho Machii, Kazushi Morimoto, Pakawit Lerksaipheng, Mirinthorn Jutanom, Ken-Ichi Yamada.

  Cellular senescence, a state of irreversible cell cycle arrest, is implicated in age-related diseases. While it is well known that senescent cells resist apoptosis, studies on their resistance to ferroptosis are limited and not fully understood. Senescent cells remain sensitive to ferroptosis induced by direct inhibition of glutathione peroxidase 4 (GPX4) but resist ferroptosis from cystine starvation, suggesting a role for mitochondrial metabolism. Here, we found that this resistance is mediated by peroxisome proliferator-activated receptor α (PPARα)-dependent upregulation of pyruvate dehydrogenase kinase 4 (PDK4), which inactivates pyruvate dehydrogenase (PDH) and suppresses mitochondria-derived reactive oxygen species, a key driver of ferroptosis. Our findings identify the PPARα-PDK4-PDH axis as a metabolic switch regulating ferroptosis sensitivity in senescent cells and provide insight into the senescence-ferroptosis interaction.

Keywords:  PDH; PDK4; PPARα; cellular senescence; cystine deprivation; ferroptosis; mitochondrial function

DOI:  https://doi.org/10.1002/1873-3468.70332
Hemasphere. 2026 Apr;10(4): e70358

Monocyte-mediated metabolic rewiring via CD31-CD38 interactions promotes growth and drug-resistance in multiple myeloma.

Ramin Raoof, Giada Dal Collo, Helga Simon-Molas, Panagiota Tzortzi, Konxhe Kulaj, Elif N Demirez, Crescenzo Massaro, Renée Poels, Charlotte L B M Korst, Chloe A O'Neill, Wassilis S C Bruins, Marloes E C Broekmans, Payam Behradkia, Maria Krevvata, Sonja Zweegman, Arnon P Kater, Serena R Baglio, Tuna Mutis, Niels W C J van de Donk.

Multiple myeloma (MM) cells interact with different components of the bone marrow (BM) microenvironment, which plays a critical role in MM progression and confers resistance to therapy. Here, we report that monocytes actively control MM cell metabolism by transferring mitochondria to MM cells, thereby increasing their mitochondrial content. Transfer of mitochondria required the expression of CD38 on the surface of MM cells and its ligand CD31 (PECAM-1) on monocytes. The mitochondrial increase in MM cells induced a boost in oxidative phosphorylation (OXPHOS). This monocyte-mediated metabolic adjustment promoted growth, motility, and drug-resistance in both MM cell lines and primary MM cells. Notably, the CD38-targeting monoclonal antibody daratumumab prevented mitochondrial transfer via blocking CD38 on MM cells. Furthermore, in the presence of daratumumab, monocytes acquired a divergent role and obtained mitochondria from MM cells through the process of trogocytosis. Daratumumab-mediated disruption of mitochondrial transfer reduced the mitochondrial content in MM cells, prevented the boost in OXPHOS, significantly impaired MM cell growth and migration, and mitigated drug-resistance. In conclusion, we reveal a crucial metabolic interplay between monocytes and MM cells within the BM microenvironment that promotes tumor growth and induces therapy resistance, providing the rationale for treatment strategies that combine targeting tumor metabolism with existing anti-MM agents.

DOI: https://doi.org/10.1002/hem3.70358
Genes Dis. 2026 Jul;13(4): 101947

PDK1 elevation was induced by epigenetic modifications of KDM3A and METTL16 to mediate TKI resistance and cancer development.

Zhihao Zhou, Ruike Zhang, Zhaoyang Zhang, Liyuan Zhang, Wei Wang, Wenjing Liu, Chunyang Zhang, Gen Lin, Weimiao Yu, Bo Xu, Lin Wang, Bing-Hua Jiang.

  Lung cancer is the leading cause of cancer-related death and has the second-highest incidence worldwide. For patients with advanced EGFR-mutated non-small cell lung cancer, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment option; however, acquired resistance to TKIs is inevitable. Gefitinib and osimertinib, the first-generation and third-generation EGFR-TKI, have shown promising results in patients with EGFR-mutated lung cancer in clinical treatment. Here, we identified that pyruvate dehydrogenase kinase 1 (PDK1) was up-regulated in gefitinib- and osimertinib-resistant cell lines, and PDK1 knockdown rendered cells more sensitive to TKI treatment. PDK1 expression levels were significantly increased in lung, colon, liver, and breast cancer tissues compared with those in normal tissues. Histone demethylase KDM3A was also induced in TKI-resistant cell lines, and demethylated histone H3 lysine 9 to facilitate PDK1 expression to regulate TKI resistance. Further study demonstrated that METTL16 promoted the m6A modification of PDK1 mRNA, and the m6A reader IGF2BP1 directly recognized and enhanced PDK1 mRNA stability. Interestingly, KDM3A also induced METTL16 expression. Moreover, PDK1 inhibitor JX06 rendered cancer cells more sensitive to gefitinib treatment in vivo, and JX06 and gefitinib combination treatments have a synergic effect to inhibit tumor growth. In conclusion, the KDM3A/METTL16/PDK1 axis plays an important role in cancer development and TKI resistance, which may offer new prognostic biomarkers and therapeutic targets for TKI resistance in the future.

Keywords:  KDM3A; METTL16; PDK1; Prognostic biomarkers; TKI resistance; Tumorigenesis

DOI:  https://doi.org/10.1016/j.gendis.2025.101947
Nat Cancer. 2026 Apr 21.

TMEM87A suppresses ferroptosis and increases cancer immunotherapy resistance by maintaining the Golgi apparatus pH homeostasis.

Jing Li, Yuhan Zhou, Xiong Li, Songlin Yin, Yuan Gao, Haotian Shang, Yongfeng Lai, Liguo Yang, Ying Xue, Xiaoxiao Li, Yan Li, Zhenzhen Chang, Jing Chen, Xiang Cheng, Xiaoyan Zhang, Qian Chu, Fujia Lu, Weimin Wang.

Most membrane-bound organelles have been linked to the initiation and execution of ferroptosis. However, the role of the Golgi apparatus and its resident proteins in ferroptosis remain elusive. Here we show that ferroptosis inducer triggers rapid oxidation of Golgi membrane lipids in the early phase of ferroptosis, resulting in disruption of Golgi pH. The Golgi-localized transmembrane protein TMEM87A is identified to mediate ferroptosis resistance through buffering Golgi pH. Depletion of TMEM87A leads to Golgi overacidification, which impairs FSP1-mediated reduction of coenzyme Q. In vivo, TMEM87A ablation suppresses the progression of multiple murine tumors including melanoma, colorectal cancer and liver cancer. TMEM87A ablation also enhances antitumor T cell responses and potentiates PD1 blockade therapy. Clinically, tumoral TMEM87A expression negatively correlates with immunotherapy response and treatment outcome. Our study reveals that TMEM87A functions as a suppressor of tumoral ferroptosis by maintaining Golgi pH homeostasis and targeting TMEM87A is potent to augment cancer immunotherapy.

DOI: https://doi.org/10.1038/s43018-026-01156-9
Cancer Res. 2026 Apr 20.

Inhibiting Fatty Acid Oxidation Reverses Autophagy-Mediated Acquired Chemotherapy Resistance in Pancreatic Ductal Adenocarcinoma.

Sang Myung Woo, Joon Hee Kang, Wonyoung Choi, Ho Lee, Hyonchol Jang, Sung Hoon Sim, Jung Won Chun, Eun-Byeol Koh, Chaeyoung Kim, Woojin Ham, Woosol Hong, Mingyu Kang, JeongHwan Park, Suji Han, Jong Woo Kim, Eun-Woo Lee, Woo Jin Lee, Soo-Youl Kim.

In pancreatic ductal adenocarcinoma (PDAC), irinotecan chemotherapy triggers a dual-phase autophagy process that drives drug resistance. Although mTOR and autophagy exert suppressive effects on each other, co-activation of mTOR and autophagy has been observed when PDAC cells begin to regrow after treatment. Therefore, we hypothesized that the distinct temporal phases of autophagy are governed by independent upstream pathways. Initially, DNA damage activated AMPK, inducing early autophagy within 24 hours that fueled fatty acid oxidation (FAO), boosting ATP production. After 48 hours, elevated ATP levels inactivated AMPK and activated mTOR, which typically suppresses autophagy. However, autophagy and FAO activity persisted beyond 72 hours of irinotecan treatment via the JNK1-Beclin-1 pathway. This created a paradoxical state in which mTOR and autophagy were co-activated, promoting cell survival under irinotecan treatment. Irinotecan combined with FAO inhibition using KN510713 (a combination of KN510 targeting the carnitine-acylcarnitine transporter and KN713 targeting acetyl-CoA acyltransferase1/2) or FAO gene knockdown blocked autophagy flux and cell growth. FAO inhibition-induced fatty acid accumulation impaired autophagy flux and induced cytotoxicity, leading to cancer cell death. In xenograft models, combining irinotecan with KN510713 significantly prevented tumor regrowth compared with irinotecan alone. These findings suggest that targeting FAO induced by autophagy activation may overcome acquired drug resistance in PDAC while minimizing the toxic side effects associated with systemic inhibition of autophagy in healthy cells.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4517
Adv Sci (Weinh). 2026 Apr 21. e01083

Cell Cycle Control of Nuclear Metabolism Couples Phosphatidylinositol Signaling to Histone Methylation.

Antoni Gañez-Zapater, Savvas Kourtis, Camilla Reiter Elbæk, Lorena Espinar, Carolina Toro-Márquez, Albert Coll-Manzano, Alfredo Smiriglia, Laura García-López, Laura Wiegand, Maria Guirola, Frédéric Fontaine, Andrea Morandi, André C Müller, Sara Sdelci.

  Progression through the cell cycle requires coordinated regulation of transcription, chromatin state, and cellular metabolism. While metabolic enzymes are known to localize the nucleus and influence chromatin states, how nuclear metabolism itself oscillates during the cell cycle remains unexplored. Here, we combine a customized FUCCI-3 reporter with chromatome mass spectrometry and high-throughput imaging to systematically resolve nuclear and chromatin-associated metabolic changes across cell cycle phases. We identify phosphatidylinositol metabolism as a nuclear pathway that oscillates with the cell cycle, with PIP5K1A, PLCD3, and PLD2 showing phase-specific nuclear and chromatin dynamics. Nuclear PIP2 levels redistribute within the nucleus depending on cell cycle stage. Downregulation of PIP5K1A reduces nuclear PIP2 levels, whereas nuclear enrichment of PIP5K1A increases PIP2 abundance in the nucleus and nucleolus, functionally linking PIP5K1A nuclear localization to nuclear PIP2 synthesis. Moreover, perturbation of nuclear PIP2 synthesis alters chromatin methylation, with a pronounced impact on H4K20 monomethylation. Together, our results reveal that nuclear phosphatidylinositol metabolism is cell cycle regulated and functionally linked to chromatin methylation, establishing nuclear lipid metabolism as a previously unrecognized layer of cell cycle control.

Keywords:  cell cycle; chromatin; epigenetics; nuclear metabolism; proteomics

DOI:  https://doi.org/10.1002/advs.202501083