bims-meract 2025-12-14 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–12–14
fourteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Potent synergy of DHODH and SREBP inhibition in acute myeloid leukemia via disruption of cholesterol and lipid metabolism.
The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival.
ACSL5 Regulates Glucose Metabolism and Chemotherapy Sensitivity in Colorectal Cancer Cells under Glutamine Deficiency.
BE screen reveals METTL3 S2 dephosphorylation sensitizes gastric cancer cells to oxaliplatin by interfering METTL3-eIF3H interaction.
Adaptation of redox metabolism in drug-tolerant persister cells is a vulnerability to prevent relapse in pancreatic cancer.
Identification and targeting oxidative phosphorylation/glycolysis to overcome anti-CSF-1R therapy resistance in glioblastoma.
YAP/TEAD-activated TAG synthesis and peroxidation in lipid droplets confer ROS resistance in cancer stem cells.
Targeting ferroptosis in cancer.
High-fat diet induced ECM remodeling attenuates chemosensitivity in prostate cancer via activating Piezo1-dependent mitochondria-ER contacts.
The microbial metabolite I3A inhibits ferroptosis and the effectiveness of redox-based cancer therapy.
Enhanced lipid metabolism serves as a metabolic vulnerability to polyunsaturated fatty acids in glioblastoma.
Chloroquine Overcomes Chemotherapy Resistance and Suppresses Cancer Metastasis by Eradicating Dormant Cancer Cells.
Fasting boosts breast cancer therapy efficacy via glucocorticoid activation.
P4HA3 drives cervical cancer lymphatic metastasis by facilitating ACLY-mediated ferroptosis resistance.

Haematologica. 2025 Dec 11.

Potent synergy of DHODH and SREBP inhibition in acute myeloid leukemia via disruption of cholesterol and lipid metabolism.

Shanna M Hogeling, Dominique Sternadt, Nikita La Rose, Marjan Geugien, Diego Pereira-Martins, Fiona A J Van den Heuvel, Anna Kuchnio, Christine E Pietsch, Ulrike Philippar, Gerwin Huls, Jan Jacob Schuringa.

Acute myeloid leukemia (AML) remains difficult to cure, in part related to strong genetic and functional heterogeneity between and within individual patients. Metabolic reprogramming is emerging as an important feature of AML cells, allowing to explore alternative treatment strategies. Here, we describe a novel DHODH inhibitor, JNJ-74856665, that showed strong efficacy in a subset of AML samples. In a multi-omics approach, by combining label-free quantitative proteome data with drug sensitivity data in bone marrow stromal cocultures in a large cohort of primary AML patient samples we identified that sensitivity to DHODH inhibition (DHODHi) is linked to cholesterol and lipid metabolism. DHODHi resulted in an accumulation of cholesterol, mitochondrial ROS and lipid peroxidation. LC-MS/MS-based lipidomics studies revealed that DHODHi resulted in a strong increase in polyunsaturated fatty acids (PUFAs) and triglycerides (TGs), which are the primary lipid species stored in lipid droplets (LDs). We hypothesized that this might be the consequence of increased ROS and lipid peroxidation levels, prompting the cell to detoxify such toxic lipid species by storing them in LDs. Indeed, we could observed a marked increase in LD formation upon DHODHi. The transcriptional regulator SREBF2, known to control cholesterol and lipid metabolism, was upregulated in DHODHi sensitive AMLs, and a strong synergy was observed between combination of both DHODHi and the SREBP inhibitor dipyridamole. Our data indicate that combined DHODH and SREBP inhibition is of interest to explore further as a therapeutic target option in AML.

DOI: https://doi.org/10.3324/haematol.2025.287918
Cancer Res. 2025 Dec 11.

The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival.

Bruna Martins Garcia, Patricia Altea-Manzano.

The tumor microenvironment imposes diverse metabolic challenges to cancer cells. Overcoming these challenges is essential for survival, proliferation, and dissemination. However, how cancer cells cope with the harsh environment and how the different coexisting stresses affect the tumor in vivo is unknown. Recently, Groessl, Kalis and colleagues published their findings in Science showing that acidosis outweighs all other stresses and plays a major role in the adaptation to them. Mechanistically, acidosis inhibits the ERK-DRP1 pathway, resulting in mitochondria elongation, which triggers a metabolic shift from glycolysis to oxidative phosphorylation. These findings highlight the plasticity of cancer cell mitochondria and refute the previous belief that cancer mitochondria are inherently dysfunctional. Indeed, inhibition of mitochondrial fusion or oxidative phosphorylation in acidic tumors is sufficient to promote cell death. Thus, enhancing respiration under acidosis comes to light as an essential metabolic adaptation to cancer survival and proliferation and targeting how cancer cells adapt to acidosis emerges as a new avenue for therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5633
Adv Sci (Weinh). 2025 Dec 08. e10801

ACSL5 Regulates Glucose Metabolism and Chemotherapy Sensitivity in Colorectal Cancer Cells under Glutamine Deficiency.

Shuai Tian, Qiaoxia Zhang, Xuedan Sun, Rick Francis Thorne, Zeyuan Shi, Qiang Ji, Zhangran Sun, Yuanxiang Lu, Qun Zhao, Xianjun Yu, Wanglai Hu, Mian Wu.

  Glutamine metabolism is crucial for sustaining tumor cell viability and growth, broadly promoting prospects for the therapeutic targeting of glutamine dependence. However, further research is needed to address key translational issues, particularly to better understand the adaptive survival responses employed by cancer cells in overcoming nutrient deficiency. Long-chain acyl-CoA synthetase 5 (ACSL5) is found to be upregulated under glutamine deprivation, acting to sustain tumor cell viability by enhancing both glycolytic flux and oxidative phosphorylation. ACSL5 operates within a p53 regulatory loop: p53 transcriptionally upregulates ACSL5, while ACSL5 competes with MIB1 to stabilize MDM2, suppressing p53 expression. Mechanistically, ACSL5 relieves p53-mediated inhibition of PGAM1 to drive glycolysis, while its mitochondrial localization promotes IDH2 activation to accelerate the TCA cycle. Nonetheless, these metabolic increases also generate reactive oxygen species (ROS), inducing DNA damage and significantly enhancing colorectal cancer cell sensitivity to oxaliplatin. The latter provides an explanation as to why colorectal tumors with high ACSL5 expression display preferentially improved patient outcomes from chemotherapy. Collectively, the findings reveal a new pathway for non-genetic chemotherapy resistance mechanisms, deepen the understanding of metabolic reprogramming in tumor cells, and offer potential therapeutic targets for future treatment strategies.

Keywords:  ACSL5; DNA damage; chemotherapy sensitivity; glucose metabolism; glutamine deficiency; p53

DOI:  https://doi.org/10.1002/advs.202510801
Sci Adv. 2025 Dec 12. 11(50): eady7259

BE screen reveals METTL3 S2 dephosphorylation sensitizes gastric cancer cells to oxaliplatin by interfering METTL3-eIF3H interaction.

Xiaoran Xu, Wanyu Tao, Yixin Liu, Tangxi Guo, Yu Zhang, Dongyi Wei, Picheng Yan, Xingxu Huang, Yongchang Wei.

The resistance to oxaliplatin (OXA)-based chemotherapies may lead to poor prognosis in patients with gastric cancer (GC). Emerging evidence suggests that resistance is closely associated with phosphorylation modifications. In GC cell line AGS, high-throughput base editor screen identified key phosphorylation sites associated with OXA response. Methyltransferase-like 3 (METTL3) S2 emerged as a notable negative hit. Further investigation revealed that dephosphorylation of METTL3 S2 disrupted the METTL3-eukaryotic translation initiation factor 3 subunit H (eIF3H) interaction, thereby suppressing the translation of oncogenes involved in replication stress responses, including bromine domain protein 4 (BRD4) and serpin family E member 2 (SERPINE2), ultimately enhancing sensitivity to OXA. In addition, clinical investigation showed that METTL3 S2 phosphorylation was highly correlated with the response to GC OXA chemotherapy. In summary, base editor screen provides a versatile approach for exploring the role of phosphorylation sites in cancer chemotherapy. The METTL3-eIF3H interaction may serve as a potential therapeutic target.

DOI: https://doi.org/10.1126/sciadv.ady7259
Oncogenesis. 2025 Dec 09. 14(1): 48

Adaptation of redox metabolism in drug-tolerant persister cells is a vulnerability to prevent relapse in pancreatic cancer.

Nadine Abdel Hadi, Gabriela Reyes-Castellanos, Tristan Gicquel, Scarlett Gallardo-Arriaga, Emma Cosialls, Emeline Boet, Jean-Emmanuel Sarry, Rawand Masoud, Juan Iovanna, Alice Carrier.

Pancreatic Ductal Adenocarcinoma (PDAC) remains a major unresolved disease because of its remarkable therapeutic resistance. Even patients who respond to initial therapy experience relapse in most cases. The mechanisms underlying therapy-acquired resistance supporting relapse are poorly understood. In this study, we aimed to determine the metabolic features of PDAC during relapse, specifically adaptations of mitochondrial oxidative metabolism. We used preclinical PDAC mouse models (patient-derived xenografts and murine syngeneic allografts) that present regression under initial chemotherapeutic treatment but relapse after a certain time. Relapsed tumors were analyzed ex vivo by flow cytometry to measure mitochondrial and redox characteristics. Molecular mechanisms were investigated by quantification of ATP and antioxidants levels, bulk RNA-sequencing and RT-qPCR. We show increased mitochondrial mass, ATP levels, mitochondrial superoxide anions, and total ROS levels, in relapsed compared to control tumors in both models; mitochondrial membrane potential is increased in the xenografts model only. These metabolic features are also observed in tumors during treatment-induced regression and at relapse onset. At the molecular level, antioxidant defenses are increased in relapsed tumors and during treatment. These data suggest that metabolic adaptations occurring during treatment-induced regression may favor the survival of drug-tolerant persister (DTP) cells, which persist during the subsequent minimal residual disease and are responsible for cancer relapse. Finally, the combined treatment of arsenic trioxide (ROS inducer) and buthionine sulfoximine (glutathione synthesis inhibitor) is able to completely prevent relapse in PDAC xenografts. In conclusion, redox metabolism is a vulnerability of pancreatic DTP cancer cells that can be targeted to prevent relapse.

DOI: https://doi.org/10.1038/s41389-025-00591-0
Cell Death Dis. 2025 Dec 10.

Identification and targeting oxidative phosphorylation/glycolysis to overcome anti-CSF-1R therapy resistance in glioblastoma.

Cheng Miao, Zehua Ding, Jiaxing Wu, Qi An, Ya Shu, Haifeng Jiang, Panpan Gao, Ruoqiao Chen, Xiao Qian Chen.

The standard care of glioblastomas (GBM) confers limited survival benefit for patients due to the rapid tumor recurrence. Targeting tumor-associated macrophages/microglia via colony-stimulating factor 1 receptor (CSF-1R) inhibition is potentially effective in suppressing GBM recurrence. However, clinical trials of CSF-1R inhibitors failed to achieve their goal due to GBM resistance to anti-CSF-1R therapy. Here, we identified and verified key resistance mechanisms of anti-CSF-1R therapy by translatome profiling-combined analyses. To solve above problem, we have established a highly stable and refractory mouse G422TN-GBM model, in which temozolomide (TMZ) is the most effective monotherapy but can only slightly extend animal survival. To identify effective resistance mechanism of anti-CSF1R therapy in GBM, we first apply the Translating ribosome affinity purification (TRAP) RNA-sequencing techniques in GBM tissues, which have previously used in neuroscience. TRAP-seq identified oxidative phosphorylation/glycolysis as anti-CSF1R therapy resistance mechanism, and it's combined with Cancer Therapeutics Response Portal (CTRP) identified piperlongumine (PL) or vorinostat (SAHA) as targeting drugs. PL or SAHA enhanced PLX3397 efficacy by reversing oxidative phosphorylation/glycolysis dysregulation in vitro and in vivo. The triple combination of PLX3397, TMZ, and PL/SAHA significantly improved survival in G422TN-GBM mice. In conclusion, targeting oxidative phosphorylation/glycolysis by PL or SAHA prominently improves therapeutic efficacy of PLX3397 + TMZ in GBM, which deserves priority for clinical trials. Our study also reveals that translatome profiling is efficient for uncovering drug-resistant targets.

DOI: https://doi.org/10.1038/s41419-025-08288-3
Redox Biol. 2025 Dec 08. pii: S2213-2317(25)00481-1. [Epub ahead of print]89 103968

YAP/TEAD-activated TAG synthesis and peroxidation in lipid droplets confer ROS resistance in cancer stem cells.

Jiun-Han Lin, Tien-Wei Hsu, Wei-Chung Cheng, Chen-Chi Liu, Anna Fen-Yau Li, Mien-Chie Hung, Han-Shui Hsu, Shih-Chieh Hung.

   BACKGROUND: Cancer stem cells (CSCs) exhibit reduced levels of reactive oxygen species (ROS) despite increased oxidative phosphorylation, through mechanisms that remain poorly understood. Understanding these mechanisms could lead to new strategies for identifying and eradicating CSCs.
METHODS: We combined lipidomic profiling, RNA-sequencing (RNA-seq), and TAGsig analysis to identify key lipids and genes involved in CSC-mediated resistance to ROS. These findings were further validated through a series of in vitro and in vivo experiments.
RESULTS: We show that triacylglycerol (TAG), the main lipid in lung CSCs, localizes to peri-mitochondrial lipid droplets (LDs) and acts as a ROS scavenger. TAG undergoes peroxidation in these droplets upon exposure to H2O2, tBH, hypoxia, and FeCl2, whereas in non-CSCs, oxidation occurs in mitochondria. RNA-seq analysis revealed upregulation of TAG synthesis enzymes (ACSL1/4, LPIN2, DGAT1/2, PNPLA3) in CSCs compared to non-CSCs. Inhibition and knockdown of DGAT1/2, which block TAG synthesis, led to reduced LDs and diminished sphere formation, radioresistance, and tumor initiation in vivo. Additionally, a six-gene TAG synthesis signature effectively predicted prognosis and survival in lung cancer patients. CSCs upregulated the Y357YAP/TEAD pathway to activate transcription of TAG synthesis genes, enhancing resistance to ROS.
CONCLUSION: We demonstrate that TAG in peri-mitochondrial LDs functions as a ROS scavenger, enabling CSCs to survive in hyperoxidative environments. Targeting the signaling pathways involved in TAG synthesis presents a potential strategy for eradicating CSCs.

Keywords:  Cancer stem cells (CSCs); Lipid droplet; Reactive oxygen species (ROS); Triacylglycerol; YAP/TEAD

DOI:  https://doi.org/10.1016/j.redox.2025.103968
Nat Genet. 2025 Dec;57(12): 2942

Targeting ferroptosis in cancer.

Safia Danovi.

DOI: https://doi.org/10.1038/s41588-025-02456-z
Cancer Lett. 2025 Dec 09. pii: S0304-3835(25)00776-1. [Epub ahead of print] 218204

High-fat diet induced ECM remodeling attenuates chemosensitivity in prostate cancer via activating Piezo1-dependent mitochondria-ER contacts.

Yupeng Guan, Fei Cao, Yusheng Luo, Jun Li, Peng Wu, Junfu Zhang, Wenhan Qiu, Shaohong Lai, Hanqi Lei, Jun Pang.

  High-fat diet (HFD) and obesity are established risk factors for therqpy resistance in prostate cancer (PCa), but the underlying mechanisms remain incompletely understood. Here, we demonstrate that a HFD promote chemoresistance by remodeling the tumor microenvironment (TME) and activating extracellular matrix (ECM)-dependent mitochondria-endoplasmic reticulum contacts (MERCs). Through integration of clinical data with multi-omics and biomechanical analyses, we show that lipid-overloaded tumor cells secrete TGF-β1 to indirectly drive the activation of cancer-associated fibroblasts (CAFs). This triggers pathological ECM stiffening and collagen deposition. These biomechanical alterations are sensed by the mechanosensor Piezo1, which transduces pro-malignant signals that foster chemoresistance. Pharmacological inhibition of Piezo1 blocks its channel activity, disrupts intracellular ion homeostasis and consequently induces MERCs dissociation.. MERCs disassembly, in return, destabilizes the IP3R-GRP75-VDAC complex, leading to metabolic reprogramming characterized by mitochondrial dysfunction, endoplasmic reticulum stress, and redox imbalance. Crucially, dual targeting of lipid metabolism (with statins) and mechanotransduction (with GsMTx4) resensitizes PCa to chemotherapy by normalizing ECM architecture and restoring MERCs integrity. Our work defines the "mechanometabolic niche" as a targetable signaling hub where coordinated lipid metabolism and TME biomechanics converge to dictate therapeutic response and unveils a novel co-targeting strategy for advanced PCa.

Keywords:  chemoresistance; high-fat diet; matrix stiffness; mitochondria-endoplasmic reticulum contacts; piezo1

DOI:  https://doi.org/10.1016/j.canlet.2025.218204
J Biol Chem. 2025 Dec 05. pii: S0021-9258(25)02856-X. [Epub ahead of print] 111004

The microbial metabolite I3A inhibits ferroptosis and the effectiveness of redox-based cancer therapy.

Zixuan Guo, Lei Cui, Ruhui Yao, Yanxun Lin, Zining Wang, Huan Jin, Hui Guo, Chunyuan Xie, Lin Li, Peng Huang, Xiaojun Xia.

  Ferroptosis, a lipid peroxidation-driven form of regulated cell death, has emerged as a promising target for cancer therapy. However, the endogenous metabolic checkpoints restraining ferroptosis remain poorly defined. Here, we identify the tryptophan-derived indole metabolite indole-3-aldehyde (I3A), as a potent suppressor of ferroptosis. Mechanistically, I3A activates the aryl hydrocarbon receptor (AHR) to suppress JNK/c-JUN signaling under oxidative stress. This inhibition of c-JUN limits autophagic flux by downregulating LC3B expression, thereby stabilizing nuclear GPX4. As a result, I3A not only prevents ferroptosis-associated lipid peroxidation but also mitigates oxidative DNA damage. In mouse models of melanoma and colorectal cancer, I3A administration significantly reduced the antitumor efficacy of the ferroptosis inducer RSL3, accompanied by reduced lipid peroxidation and preserved GPX4 levels. Furthermore, gut colonization with Lactobacillus reuteri increased I3A concentration and conferred ferroptosis resistance in vivo. Together, these findings identify a host-microbe metabolic axis in which microbial I3A suppresses cancer cell ferroptosis through AHR-JNK signaling, which may have critical implications for redox-based cancer therapies.

Keywords:  AHR; DNA damage; Ferroptosis; Indole-3-aldehyde; JNK/JUN; Lactobacillus reuteri; tumor therapy

DOI:  https://doi.org/10.1016/j.jbc.2025.111004
JCI Insight. 2025 Dec 09. pii: e191465. [Epub ahead of print]

Enhanced lipid metabolism serves as a metabolic vulnerability to polyunsaturated fatty acids in glioblastoma.

Shiva Kant, Yi Zhao, Pravin Kesarwani, Kumari Alka, Jacob F Oyeniyi, Ghulam Mohammad, Nadia Ashrafi, Stewart F Graham, C Ryan Miller, Prakash Chinnaiyan.

  Enhanced lipid metabolism, which involves the active import, storage, and utilization of fatty acids from the tumor microenvironment, plays a contributory role in malignant glioma transformation; thereby, serving as an important gain of function. In this work, through studies initially designed to understand and reconcile possible mechanisms underlying the anti-tumor activity of a high-fat ketogenic diet, we discovered that this phenotype of enhanced lipid metabolism observed in glioblastoma may also serve as a metabolic vulnerability to diet modification. Specifically, exogenous polyunsaturated fatty acids (PUFA) demonstrate the unique ability of short-circuiting lipid homeostasis in glioblastoma cells. This leads to lipolysis-mediated lipid droplet breakdown, an accumulation of intracellular free fatty acids, and lipid peroxidation-mediated cytotoxicity, which was potentiated when combined with radiation therapy. Leveraging this data, we formulated a PUFA-rich modified diet that does not require carbohydrate restriction, which would likely improve long-term adherence when compared to a ketogenic diet. The modified PUFA-rich diet demonstrated both anti-tumor activity and potent synergy when combined with radiation therapy in mouse glioblastoma models. Collectively, this work offers both a mechanistic understanding and a potentially translatable approach of targeting this metabolic phenotype in glioblastoma through diet modification and/or nutritional supplementation that may be readily integrated into clinical practice.

Keywords:  Brain cancer; Metabolism; Metabolomics; Neuroscience; Oncology; Radiation therapy

DOI:  https://doi.org/10.1172/jci.insight.191465
Cell Death Dis. 2025 Dec 10.

Chloroquine Overcomes Chemotherapy Resistance and Suppresses Cancer Metastasis by Eradicating Dormant Cancer Cells.

Marina A Mikeladze, Liubov S Kuznetcova, Elena Y Komarova, Margarita A Galcheva, Vladimir F Lazarev, Lev A Khamaev, Maria A Konanova, Yana A Gladova, Anna B Danilova, Boris A Margulis, Bashar A Alhasan, Irina V Guzhova.

Cancer cell resistance and tumor relapse remain major challenges in cancer treatment. Chloroquine, an FDA-approved antimalarial drug currently undergoing clinical trials for various cancers, has emerged as a promising candidate for combination therapy with conventional anticancer agents. In this study, we demonstrate that in patients-derived osteosarcoma cells who had undergone multiple chemotherapy treatments, as well as in murine colorectal cancer cells, administration of standard chemotherapeutic agents induces autophagy, which likely serves as a cytoprotective mechanism promoting therapy resistance in at least of part of tumor population. Incorporating chloroquine into the treatment regimen effectively suppressed autophagy, significantly enhancing osteosarcoma cell death in both 2D and 3D models while simultaneously reducing cell proliferation and migration capacity. In an orthotopic in vivo model of colorectal cancer, the combination of chloroquine and oxaliplatin not only impaired tumor growth but also prevented metastatic dissemination and inhibited the formation of metastasis. Notably, comparative analyses of proliferating and dormant tumor cell populations revealed that chloroquine exerts preferential cytotoxicity toward dormant cancer cells. This suggests a dual therapeutic advantage, wherein cytostatic agents primarily eliminate proliferating cells, while chloroquine specifically eradicates dormant cancer cells, which are often implicated in tumor recurrence. Collectively, these findings highlight the potential of autophagy inhibition to enhance the chemotherapy efficacy and suggest chloroquine-based combination therapy as a promising strategy for suppressing tumor growth and metastasis, ultimately improving treatment outcomes in cancer patients.

DOI: https://doi.org/10.1038/s41419-025-08304-6
Nature. 2025 Dec 10.

Fasting boosts breast cancer therapy efficacy via glucocorticoid activation.

Nuno Padrão, Tesa M Severson, Sebastian Gregoricchio, Ana Guijarro, Catrin Lutz, Daniel Taranto, Stefan Hutten, Francesca Ligorio, Angelica Persia, Merel Roest, Joyce Sanders, Ji-Ying Song, Sara Pires-Oliveira, Maria Donaldson Collier, Hugo Horlings, Livia Pisciotta, Filippo de Braud, Claudio Vernieri, Leila Akkari, Jos Jonkers, Alessio Nencioni, Irene Caffa, Wilbert Zwart.

The majority of breast cancers are driven by oestrogen receptor-α (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients1. However, resistance is common and tumours often progress after years of endocrine suppression2. Periodic fasting enhances the efficacy of standard endocrine therapy and delays acquired drug resistance, although the underlying mechanisms remain unclear3. Here we show that fasting induces extensive epigenetic reprogramming in ERα-positive breast cancer xenografts when combined with endocrine therapy, with large-scale activation of glucocorticoid receptor (GR) and progesterone receptor signalling and concomitant reduction in the activity of activator protein-1 (AP-1) family members. GR-driven gene programmes are selectively activated in in vivo models of ERα-positive breast cancer during fasting, and GR knockout hinders the anti-tumour effects of fasting combined with tamoxifen. Exogenous administration of GR ligands recapitulates fasting-enhanced anti-oestrogen action, thus promoting tumour regression. Patients undergoing a cyclic fasting-mimicking diet exhibited increased blood progesterone and cortisol concentrations. Additionally, tumours collected after the fasting-mimicking diet showed an inverse correlation of GR activation with proliferation markers, providing clinical confirmation of our observations in animal models. Our results indicate that GR activation has a pivotal role in the ability of fasting to enhance endocrine therapy activity in breast cancer and suggest that corticosteroid administration should be evaluated as an adjuvant to endocrine therapy in this setting.

DOI: https://doi.org/10.1038/s41586-025-09869-0
Cell Death Differ. 2025 Dec 11.

P4HA3 drives cervical cancer lymphatic metastasis by facilitating ACLY-mediated ferroptosis resistance.

Li Yuan, Hongye Jiang, Meng Xia, Weijia Wen, Haolin Fan, Songlin Liu, Yuandong Liao, Pan Liu, Yan Jia, Xueyuan Zhao, Linna Chen, Caixia Shao, Yan Liao, Dingze Xu, Tianyu Liu, Jie Li, Wei Wang, Chaoyun Pan, Junxiu Liu, Shuzhong Yao, Chunyu Zhang.

The lymph node is the most common site of distant metastasis of cervical cancer (CCa), which elicits dismal prognosis and limited efficiency for treatment. Identification of the factors contributing to CCa lymphatic metastasis is needed to develop effective prevention and treatment strategies. Here, we found upregulation of prolyl 4-hydroxylase subunit alpha 3 (P4HA3), an α-subunit of prolyl hydroxylase, in lymphatic metastatic lesions of cervical cancer, which is strongly associated with poor prognosis. In vitro and in vivo experiments showed that P4HA3 promoted CCa lymphatic metastasis by conferring ATP-citrate lyase (ACLY)-mediated ferroptosis resistance. Mechanistically, P4HA3 stabilizes ACLY protein by competitively inhibiting its interaction with the E3 ubiquitin ligase UBR4, which prevents UBR4-mediated proteasomal degradation of ACLY. ACLY-derived acetyl-CoA enhances H3K27 acetylation (H3K27ac) modification level in the promoter of SLC7A11 gene, ultimately enhancing SLC7A11 transcription and ferroptosis resistance. Collectively, our study provides a mechanistic understanding of the interplay between ferroptosis resistance and lymph node metastasis, providing a possibility to combat lymph node metastasis in cervical cancer.

DOI: https://doi.org/10.1038/s41418-025-01644-y