bims-meract 2026-03-15 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–03–15
nineteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

PKC-iota drives EGFR-TKI resistance in EGFR-mutated NSCLC by phosphorylating FASN to reprogram lipid metabolism.
Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-Like Pancreatic Cancer.
Mitochondrial metabolic vulnerabilities in high-grade serous ovarian cancer.
Exploiting Metabolic Dependencies for Therapeutic Targeting of Brain Cancers.
Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.
IDO1 regulating ROS rhythm reveals glycogenolysis/PPP as a cancer treatment target.
Tumor metabolic plasticity in therapy resistance: from the Warburg effect to mitochondrial hijacking.
DGAT1 Inhibition Induces Ferroptosis and Enhances Cancer Immunotherapy Efficacy.
Declined RTN3 stabilizes DHCR7 to induce cholesterol-dependent tumor progression and MEK inhibitors insensitivity in thyroid cancer.
Targeting the NSUN2-DHODH axis reverses ferroptosis resistance and oxaliplatin resistance in colorectal cancer.
Phase Separation of NFIB Suppresses SLC3A2-Mediated Ferroptosis in Castration-Resistant Prostate Cancer.
The "serine code" of metabolic reprogramming: multidimensional roles of the serine synthesis pathway in tumors and novel breakthroughs for targeted therapy.
β-catenin mutation reprograms ketone body metabolism to drive hepatocellular carcinoma metastasis and resistance to ketogenic therapy via transcriptional activation of OXCT1.
Phase separation of DDHD2 remodels lipid metabolism to dictate treatment sensitivity in luminal breast cancer.
Riboflavin metabolism shapes FSP1-driven ferroptosis resistance.
Metabolic vulnerability in fusion-driven ependymoma.
Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness.
A rise in double-strand breaks sensitizes tumors to oxidative metabolism inhibitors.
OSBPL3-driven sterol metabolic reprogramming promotes oncogenic signaling and therapeutic resistance in pancreatic cancer.

Transl Lung Cancer Res. 2026 Feb 28. 15(2): 25

PKC-iota drives EGFR-TKI resistance in EGFR-mutated NSCLC by phosphorylating FASN to reprogram lipid metabolism.

Lin Ma, Yingwen Han, Lunran Xu, Qingyuan Sun, Siyue Song, Huizhen Yang, Xinran Chen, Wenhui Xie, Yumei Chen, Liu Liu.

   Background: Non-small cell lung cancer (NSCLC) remains a significant challenge to global public health issues. However, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance inevitably occurs in treating EGFR-mutant NSCLC, and the underlying metabolic mechanisms remain unclear. The objective of our study is to explore the regulatory mechanisms of the atypical protein kinase C-iota (PKC-iota) in reprogramming lipid metabolism and whether this regulation contributes to the EGFR-TKI resistance in EGFR-mutant NSCLC.
Methods: We use mass spectrometry (MS), co-immunoprecipitation, proximity ligation assays and molecular docking to investigate the interaction of PKC-iota and fatty acid synthase (FASN). Subsequently, Western blot assay, MS, lipid staining, membrane fluidity assay, and membrane proteins assay were performed to investigate how PKC-iota regulated the lipid metabolism by FASN. We established four types of transiently transfected H1975 and PC9 cell lines. These models were then employed in a series of assays-including Cell Counting Kit-8 (CCK-8), flow cytometry, cell counting, and colony formation-to evaluate changes in cell proliferation and EGFR-TKIs sensitivity. Four types of stably transfected H1975 cell lines were inoculated into female BALB/c nude mice, then the tumorigenicity and osimertinib sensitivity of the cell groups were analyzed. Finally, we collected 45 tumor samples of EGFR-mutated NSCLC patients to examine the clinical significance of the PKC-iota/FASN axis.
Results: We observed that PKC-iota physically interacted with FASN and stabilized the FASN protein by phosphorylating it and inhibiting its ubiquitin-proteasome degradation at the post-transcriptional level. PKC-iota enhanced short/medium-chain and unsaturated fatty acid synthesis via FASN, and the PKC-iota/FASN axis increased membrane fluidity to inhibit lipid raft-mediated EGFR endocytosis and degradation while upregulating EGFR membrane localization and promoting EGFR overactivation in NSCLC. The increased tumor growth and EGFR-TKI resistance induced by the PKC-iota/FASN axis were observed both in vivo and in vitro. Clinically, we showed that high co-expression of PKC-iota and FASN correlated with poor EGFR-TKI response in EGFR-mutated NSCLC.
Conclusions: Our study elucidates a mechanism of EGFR-TKI resistance mediated by the PKC-iota/FASN axis through reprogramming lipid metabolism in EGFR-mutated NSCLC, which provides a novel therapeutic target for overcoming EGFR-TKI resistance and improving the prognosis of EGFR-mutated NSCLC patients.

Keywords:  Protein kinase C-iota (PKC-iota); epidermal growth factor receptor tyrosine kinase inhibitor resistance (EGFR-TKI resistance); fatty acid synthase (FASN); fatty acid synthesis; non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.21037/tlcr-2025-aw-1260
Cancer Res. 2026 Mar 12.

Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-Like Pancreatic Cancer.

Chun-Hao Pan, Yinghuan Lyu, Monisankar Ghosh, Md Afjalus Siraj, Robert Tseng, Nina V Chaika, John D Haley, Bahman Khalvatifahlylani, David A Tuveson, Hardik D Patel, Muaz Faruque, Girish H Rajacharya, Katie L Donnelly, Cindy V Leiton, Carlos Mejia Arbelaez, Haoting Chen, Sumedha Chowdhury, Shayan Sarkar, Lyanne Delgado Coka, Lucia Roa-Peña, Michael Horowitz, Natalia Marchenko, Pankaj K Singh, Kenneth R Shroyer, Luisa F Escobar-Hoyos.

The basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) is highly lethal and therapy resistant. A better understanding of the underlying molecular mechanisms driving this aggressive tumor subtype is necessary for the development of effective therapies. Notably, upregulation of keratin 17 (K17) in cancer is associated with poor patient outcome and the basal-like PDAC subtype. Here, we identified a critical dependency of basal-like PDACs on de novo pyrimidine biosynthesis, driven by intra-mitochondrial K17. Mechanistically, K17 translocated into the mitochondrial intermembrane space via a mitochondrial localization sequence (MLS) recognized by the translocase of the outer mitochondrial membrane 20 (TOM20). In the mitochondria, K17 bound to and stabilized dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of de novo pyrimidine biosynthesis, by preventing its ubiquitination-mediated degradation. Blocking the entry of K17 into the mitochondria sensitized cancer cells to gemcitabine, a pyrimidine analog and standard chemotherapeutic agent. In animal studies, pharmacologic inhibition of DHODH combined with gemcitabine treatment decreased tumor growth and doubled survival in mice bearing K17⁺ but not K17⁻ PDAC. These findings define a mitochondrial role for K17 in driving pyrimidine biosynthesis and uncover a metabolic vulnerability in K17⁺ basal-like PDACs that can be therapeutically targeted.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4534
Biochim Biophys Acta Rev Cancer. 2026 Mar 07. pii: S0304-419X(26)00042-9. [Epub ahead of print] 189570

Mitochondrial metabolic vulnerabilities in high-grade serous ovarian cancer.

Anjali Prasad, Scott H Kaufmann, Arun Kanakkanthara.

  High-grade serous ovarian cancer (HGSOC) is often programmed to rely heavily on mitochondrial metabolism, an adaptation that is linked to disease progression as well as resistance to standard treatments and immunotherapies. As such, mitochondrial metabolism has emerged as a promising therapeutic vulnerability to overcome resistance and selectively eliminate HGSOC cells. Several agents targeting mitochondrial metabolism are currently in or advancing toward clinical trials for various cancers. Additionally, multiple FDA-approved drugs have been repurposed to target this metabolism, and recent studies demonstrate their potential use in HGSOC therapy. This review describes the molecular mechanisms underlying mitochondrial metabolic rewiring in HGSOC and outlines the role of this rewiring in disease progression, immune evasion, and treatment resistance. In addition, we discuss current challenges and potential strategies to exploit this metabolic remodeling for more effective treatment of HGSOC.

Keywords:  Fatty acid β-oxidation; High-grade serous ovarian cancer; Mitochondrial metabolism; Oxidative phosphorylation; TCA cycle; Tumor metabolic reprogramming

DOI:  https://doi.org/10.1016/j.bbcan.2026.189570
Cancer Lett. 2026 Mar 11. pii: S0304-3835(26)00189-8. [Epub ahead of print] 218426

Exploiting Metabolic Dependencies for Therapeutic Targeting of Brain Cancers.

Emma Martell, Helgi Kuzmychova, Akaljot Grewal, Ujala Chawla, Charul Jain, Christopher M Anderson, Tanveer Sharif.

  Metabolic reprogramming is a defining hallmark of cancer, and brain tumors are no exception. The brain's extraordinary energy demands, metabolic compartmentalization, and protection by the blood-brain barrier create a unique microenvironment that profoundly shapes tumor metabolism. Many brain tumors exhibit enhanced glucose uptake and fermentative glycolysis, a phenomenon classically described as the Warburg effect. However, accumulating evidence over the past two decades reveals that brain tumors rely on a far broader and more dynamic metabolic repertoire. Beyond glycolysis, metabolic processes such as the pentose phosphate pathway, serine biosynthesis, tricarboxylic acid cycle, oxidative phosphorylation, glutaminolysis, lipid metabolism, and purine and pyrimidine biosynthesis, all contribute to sustaining tumor growth, stemness, epigenetic identity, and therapeutic resistance. These metabolic adaptations differ markedly across tumor types and developmental contexts, from glioblastoma and diffuse astrocytoma to oligodendroglioma, ependymoma, pediatric high-grade glioma, medulloblastoma, and other embryonal tumors. In this review, we provide an overview of the current understanding of the major metabolic hallmarks of brain cancer, emphasizing mechanisms that support tumor identity, proliferation, and survival. We further highlight emerging metabolic vulnerabilities and discuss progress in developing therapies that target these pathways. Together, these insights illuminate how metabolism underpins the remarkable adaptability of brain tumors and suggest new avenues for precision treatment.

Keywords:  Cancer metabolism; brain tumors; epigenetics; metabolic therapy; tumor signaling

DOI:  https://doi.org/10.1016/j.canlet.2026.218426
Mol Biomed. 2026 Mar 10. pii: 25. [Epub ahead of print]7(1):

Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.

Mingkang Yu, Di Yang, Xiuli Chen, Yuling Yang, Bingqiang Zhang, Xinxin Jiang, Lijie Xing, Yuxuan Yang, Yani Sun, Ning Li.

  Metabolic reprogramming is a hallmark of cancer, including hepatocellular carcinoma (HCC). Cancer cells exhibit enhanced glucose and glutamine uptake, increased glycolysis, pentose phosphate pathway activity, de novo lipogenesis, and altered amino acid metabolism. However, the metabolic crosstalk underlying cancer progression and the strategic directions for drug development remain insufficiently synthesized. This review systematically summarizes the functional mechanisms of key signaling regulators involved in cancer metabolic reprogramming, including mammalian target of rapamycin complex 1 (mTORC1), myelocytomatosis viral oncogene homolog (c-Myc), hypoxia-inducible factor-1α (HIF-1α), activating transcription factor 4 (ATF4), nuclear factor erythroid 2-related factor 2 (NRF2), and sterol regulatory element-binding protein 1 (SREBP1). Notably, we highlight the interconnections among metabolic pathways in cancer cells and the signaling hubs that orchestrate metabolic crosstalk, which together constitute an integrated network of metabolic pathways and their regulatory signals. Metabolic targets and metabolism-directed therapeutic agents with substantial developmental potential are comprehensively summarized, providing up-to-date insights and concrete directions for metabolism-targeted cancer therapy. Encouragingly, agents such as the fatty acid synthase inhibitor TVB-2640 and the glutaminase inhibitor CB-839 have already entered clinical trials. We recognize that adverse effects on normal tissues and drug resistance driven by metabolic plasticity represent major challenges for metabolism-targeted therapies. Accordingly, we systematically summarize innovative strategies that offer new therapeutic possibilities, including targeting multiple metabolic pathways through combination therapy to enhance efficacy, combining metabolic inhibitors to overcome resistance to conventional anticancer agents, leveraging metabolic reprogramming for early cancer detection, and exploring emerging approaches such as immunometabolism and metabolomics.

Keywords:  Glutamine; Glycolysis; Hepatocellular carcinoma; Lipogenesis; Metabolic reprogramming; Metabolism-targeted therapy

DOI:  https://doi.org/10.1186/s43556-026-00427-2
Nat Chem Biol. 2026 Mar 13.

IDO1 regulating ROS rhythm reveals glycogenolysis/PPP as a cancer treatment target.

Nannan Zhou, Zheng Ling, Xiankai Cao, Chaoqi Zhang, Dianheng Wang, Chaoying Zhang, Lu Zhang, Dingfei Yan, Jie Chen, Yabo Zhou, Li Zhou, Zhenfeng Wang, Jingwei Ma, Ke Tang, Huafeng Zhang, Jiadi Lv, Bo Huang.

Reactive oxygen species (ROS) dynamics exhibits rhythmic oscillations in cancer cells but how this rhythm influences tumorigenesis and therapeutic responses remains unclear. Here we found coexistence of ROS rhythmicity and rhythm loss in tumor samples. Under low-ROS conditions, indoleamine 2,3-dioxygenase 1 (IDO1), an immune-checkpoint molecule, binds to KEAP1 for proteasomal degradation in the nucleus. In contrast, elevated ROS levels drive IDO1 translocation into the cytosol, where it binds mitochondria-released heme to form an active holoenzyme. This holoenzyme catalyzes tryptophan to kynurenine that allosterically activates glucose-6-phosphate dehydrogenase, enhancing NADPH production and promoting ROS clearance. However, in hypoxic tumor microenvironments, ROS rhythmicity is lost. Compensating for this, hypoxic tumor cells mobilize the sulfenylated aryl hydrocarbon receptor (AhR)-mediated glycogenolysis pathway to manage disordered ROS accumulation, maintaining elevated ROS levels that favor tumor growth. Dual inhibition of IDO1 and AhR significantly prolongs survival of NSG mice, highlighting enforced disruption of ROS rhythm as a common therapeutic strategy.

DOI: https://doi.org/10.1038/s41589-026-02161-w
Theranostics. 2026 ;16(9): 4865-4882

Tumor metabolic plasticity in therapy resistance: from the Warburg effect to mitochondrial hijacking.

Yen-Dun Tony Tzeng, Emmanuel Naveen Raj, Shih-Hsuan Cheng, Su-Boon Yong, Shih-Chieh Lin, Ren-Wang Peng, Chia-Jung Li.

  The clinical efficacy of targeted cancer therapies is persistently undermined by the emergence of acquired resistance. While secondary genetic mutations are well-characterized, increasing evidence implicates non-genetic metabolic reprogramming as a primary driver of survival during the initial phase of treatment. This review elucidates the concept of "Metabolic Shapeshifters"-specifically, drug-tolerant persister cells (DTPs) that dynamically adapt their bioenergetic machinery to evade therapeutic stress. We examine the plasticity between the classical Warburg Effect and the Reverse Warburg Effect, describing how DTPs shift from a glucose-addicted proliferative state to a quiescent phenotype strictly reliant on mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid oxidation. Crucially, we highlight a paradigm shift from intracellular reprogramming to intercellular "organelle parasitism." Recent breakthroughs demonstrate that DTPs actively hijack functional mitochondria from infiltrating immune cells and the stromal network via tunneling nanotubes (TNTs). This predatory behavior not only restores the tumor's respiratory capacity but also induces metabolic exhaustion in T cells, thereby orchestrating immune evasion. Finally, we delineate emerging therapeutic strategies designed to dismantle this metabolic fortress. By targeting the "Achilles' heel" of mitochondrial dependency, disrupting the physical infrastructure of organelle hijacking, and revitalizing immunometabolism, we propose a multi-pronged framework to eradicate DTPs and prevent clinical relapse.

Keywords:  drug-tolerant persisters (DTPs); immunometabolism; mitochondrial hijacking; oxidative phosphorylation; reverse Warburg effect; tumor metabolism

DOI:  https://doi.org/10.7150/thno.131708
Cancer Res. 2026 Mar 11.

DGAT1 Inhibition Induces Ferroptosis and Enhances Cancer Immunotherapy Efficacy.

Dong Pan, Meng Jiao, Yanyan Zhu, Mengjie Hu, Fang Li, Jinming Yu, Chuan-Yuan Li.

Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has emerged as a promising mechanism in cancer therapy. However, the lack of clinically viable ferroptosis inducers has precluded its therapeutic evaluation in patients. Here, we demonstrated that inhibition of diacylglycerol O-acyltransferase 1 (DGAT1) induces a ferroptosis-like phenotype in cancer cells and enhances the efficacy of immune checkpoint blockade (ICB) therapy. In human cancer cohorts, low DGAT1 expression correlated with improved prognosis and elevated ferroptosis-associated gene signatures. In murine models, both genetic knockout and pharmacological inhibition of DGAT1 enhanced ICB therapy efficacy by promoting increased infiltration of cytotoxic T lymphocytes (CTLs). Mechanistically, DGAT1 inhibition reduced lipid droplet (LD) accumulation, triggering elevated lipid peroxidation, mitochondrial dysfunction, and reactive oxygen species (ROS) production. These events culminated in glutathione peroxidase 4 (GPX4) depletion and ferroptosis. Given the availability of clinical-stage DGAT1 inhibitors, these findings provide a strong rationale for repurposing these agents as ferroptosis inducers to improve responses to cancer immunotherapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0840
Cell Death Dis. 2026 Mar 11.

Declined RTN3 stabilizes DHCR7 to induce cholesterol-dependent tumor progression and MEK inhibitors insensitivity in thyroid cancer.

Anwen Ren, Nan Feng, Tinglin Yang, Zimei Tang, Huan Liu, Yi Li, Qingyi Hu, Zihan Xi, Jiaqing Zhu, Jun Zhou, Jie Ming, Nan Liu, Tao Huang, Ming Xu.

Mechanism underlying thyroid cancer progression and treatment resistance remains an unsolved problem in clinical practice. Endoplasmic reticulum (ER) proteins modulate cell biosynthesis and mediate tumor progression, among which Reticulon 3 (RTN3) is verified to play important roles in cancers. However, its effect in thyroid cancer has not been clarified. Meanwhile, cholesterol is found to contribute to proliferation and drug resistance in many tumors. As ER is the primary site of cholesterol synthesis, we aimed to study how RTN3 regulates cholesterol concentration and influences tumor progression and sensitivity to MEK inhibitors in thyroid cancer. This study found that RTN3 is low-expressed in thyroid cancer, and is related to poor prognosis and insensitivity to MEK inhibitors. It binds to a cholesterol synthesis enzyme DHCR7 and promotes its ubiquitination. Downregulation of RTN3 lead to stabilization of DHCR7 and elevate cholesterol concentration, activating EGFR/ERK pathway and contributes to progression of thyroid cancer, which can be rescued by HMG-CoA reductase inhibitor Simvastatin. We identified RTN3 as a tumor suppressor and a biomarker of sensitivity to MEK inhibitors and verified the role of cholesterol in drug resistance. The combination of statins provides a novel therapeutic method in patients resistant to MEK inhibitors.

DOI: https://doi.org/10.1038/s41419-026-08538-y
Front Pharmacol. 2026 ;17 1739981

Targeting the NSUN2-DHODH axis reverses ferroptosis resistance and oxaliplatin resistance in colorectal cancer.

Junyi Zhang, Junxiao Shen, Tangye Zeng, Chang Gao, Biao Sheng, Junliang Li, Weiqi Zeng, Jieyi Shen, Chong Shen, Jiaojiao Wang, Jianwei Wang.

   Background: Oxaliplatin (OXA) is a standard chemotherapy for advanced colorectal cancer (CRC), yet acquired resistance frequently limits its efficacy. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a promising strategy to overcome chemoresistance. The RNA 5-methylcytosine (m5C) methyltransferase NSUN2 has been implicated in tumor progression, but its role in CRC chemoresistance remains unclear.
Methods: We investigated the functional and mechanistic involvement of NSUN2 in CRC progression and OXA response, focusing on ferroptosis-related pathways. Integrative analyses of bulk, single-cell, and spatial transcriptomic datasets, together with multi-cohort clinical validation, were performed. Functional assays included colony formation, CCK-8 proliferation, migration, invasion, apoptosis, and xenograft experiments. Lipid ROS, malondialdehyde (MDA), and mitochondrial morphology were assessed to evaluate ferroptotic stress.
Results: NSUN2 was upregulated in CRC and associated with poor prognosis. NSUN2 depletion suppressed CRC growth and enhanced sensitivity to OXA. Knockdown of NSUN2 increased lipid ROS accumulation, elevated MDA levels, and induced mitochondrial damage, consistent with enhanced ferroptosis. In vivo, NSUN2 depletion potentiated the antitumor activity of OXA in SW480 xenografts, and combining OXA with the ferroptosis inducer imidazole ketone erastin (IKE) further reduced tumor burden compared with OXA alone, accompanied by increased tumor MDA levels. Mechanistically, NSUN2 stabilized dihydroorotate dehydrogenase (DHODH) mRNA via m5C modification, thereby increasing DHODH expression. Elevated DHODH suppressed ferroptosis independently of GPX4, whereas NSUN2 depletion disrupted this axis, promoting lipid peroxidation and ferroptosis sensitivity. DHODH restoration rescued ferroptosis and reversed the enhanced drug sensitivity induced by NSUN2 knockdown.
Conclusion: These findings identify an NSUN2-DHODH epitranscriptomic axis that promotes CRC progression and OXA resistance by limiting ferroptosis, supporting NSUN2-targeting and ferroptosis-inducing strategies to improve chemotherapy response.

Keywords:  5-methylcytosine; DHODH; NSun2; colorectal cancer; drug resistance; ferroptosis; oxaliplatin

DOI:  https://doi.org/10.3389/fphar.2026.1739981
Adv Sci (Weinh). 2026 Mar 09. e15340

Phase Separation of NFIB Suppresses SLC3A2-Mediated Ferroptosis in Castration-Resistant Prostate Cancer.

Qiunuo Li, Danyang Chen, Yongzhen Xia, Yili Long, Nan Huang, Rongna Li, Mengting Shi, Mairehaba Kadier, Huafeng Luo, Xiaohui Chen, Hao Liu, Guanmin Jiang.

  Castration-resistant prostate cancer (CRPC) is frequently resistant to conventional therapies and lacks effective treatment options. Although CRPC cells exhibit sensitivity to ferroptosis inducers, the mechanisms regulating ferroptosis remain unclear. Here, we identify nuclear factor I/B (NFIB) as a critical suppressor of ferroptosis in CRPC. NFIB is upregulated in CRPC tissues and cell lines, positively correlating with SLC3A2, a critical subunit of System Xc-. NFIB knockout enhances erastin-induced ferroptosis, marked by elevated Fe2 +, MDA, and ROS levels. Mechanistically, NFIB directly activates SLC3A2 transcription and forms nuclear condensates through intrinsically disordered regions at both the N-terminus (1-69) and C-terminus (173-495), with the C-terminal IDR additionally supporting nuclear localization. Moreover, SIRT7-dependent deacetylation of NFIB regulates acetylation at K65 within the N-terminal IDR, thereby tuning condensate dynamics. K65 mutation reduces condensate liquidity and weakens NFIB-driven SLC3A2 transcriptional activation, resulting in enhanced ferroptosis. In vivo, combined NFIB suppression and ferroptosis induction significantly inhibit tumor growth and increase lipid peroxidation in CRPC xenografts. These findings uncover a critical role of NFIB phase separation and acetylation in ferroptosis regulation and suggest NFIB as a promising therapeutic target in CRPC.

Keywords:  NFIB; SLC3A2; castration‐resistant prostate cancer; ferroptosis; liquid–liquid phase separation

DOI:  https://doi.org/10.1002/advs.202515340
Front Immunol. 2026 ;17 1779543

The "serine code" of metabolic reprogramming: multidimensional roles of the serine synthesis pathway in tumors and novel breakthroughs for targeted therapy.

Peng Su, Ying Yang, Hong Zheng.

  As a pivotal contributor to tumor metabolism following glucose and glutamine, serine plays a crucial role in the metabolic network of tumors via its de novo synthesis pathway (SSP). The SSP is aberrantly activated in a variety of malignant tumors and promotes tumor progression through multi-dimensional mechanisms. On the one hand, it provides the material basis and one-carbon units required for the synthesis of nucleotides, proteins and phospholipids to support the rapid proliferation of tumor cells. On the other hand, it maintains cellular redox homeostasis by generating glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH). Furthermore, it regulates the tumor immune microenvironment through metabolic reprogramming, inducing macrophage polarization and modulating T-cell function, thereby shaping an immunosuppressive microenvironment. The activity and stability of key enzymes in the SSP are precisely regulated by transcription factors (such as c-Myc, HIF-1α, and NRF2), epigenetic modifications (including m5C and m6A), and post-translational modifications (such as methylation, ubiquitination, and deacetylation). Meanwhile, the SSP forms an interactive network with tumor signaling pathways including Akt, mTOR, and EGF-ERK, collectively driving metabolic reprogramming. Therapeutic strategies targeting the SSP have emerged as a research hotspot, encompassing dietary intervention, the development of inhibitors targeting key enzymes such as phosphoglycerate dehydrogenase (PHGDH), as well as combination therapies with radiotherapy, chemotherapy and immunotherapy. Notably, these strategies have shown promising potential in reversing drug resistance to BRAF inhibitors, sorafenib, 5-fluorouracil (5-FU) and other agents, providing novel strategies for pan-cancer therapy. Through a systematic and comprehensive analysis of the multi-dimensional functions, heterogeneous regulation and roles in therapeutic resistance of the SSP across cancer types, this review aims to elucidate the conserved principles and cancer-specific characteristics of the SSP as a metabolic hub. Additionally, we discuss the prospects and unique challenges of precise intervention strategies targeting the SSP in overcoming tumor heterogeneity and drug resistance.

Keywords:  metabolic reprogramming; phosphoglycerate dehydrogenase (PHGDH); serine metabolism; serine synthesis pathway (SSP); targeted therapy; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1779543
Cell Death Dis. 2026 Mar 09.

β-catenin mutation reprograms ketone body metabolism to drive hepatocellular carcinoma metastasis and resistance to ketogenic therapy via transcriptional activation of OXCT1.

Huan Li, Liyuan Qian, Yifan Ji, Yuanhao Geng, Yanjun Lu, Laizhu Zhang, Yanchao Xu, Weiwei Zong, Xiang Jiang, Xianwei Zhou, Jingyuan Wen, Donglin Liu, Ye Wang, Yunzheng Li, Binghua Li, Hucheng Ma, Decai Yu.

The ketogenic diet is a controversial approach to cancer therapy. Over 30% of hepatocellular carcinoma (HCC) cases harbor β-catenin activating mutations, among which the S33Y mutation represents a classical hotspot conferring constitutive pathway activation. Our previous metabolic profiling predicted that β-catenin-mutated HCC may exhibit intrinsic resistance to ketogenic therapy. 3-oxoacid CoA-transferase 1 (OXCT1), the key enzyme for ketone body catabolism, is aberrantly expressed in β-catenin-mutated HCC. This study explores how β-cateninS33Y-mutated HCC activates OXCT1 to reprogram ketone body metabolism to drive HCC ketogenic therapy resistance and metastasis. Utilizing subcutaneous tumor models and patient-derived xenograft (PDX) models of HCC, we demonstrated that ketogenic treatment was effective in β-catenin-wild-type HCC, whereas β-cateninS33Y-mutated HCC exhibited ketogenic therapy resistance and increased metastasis. Mechanistically, mutated β-cateninS33Y bound the transcription factor LEF1, which activated OXCT1 to promote ketolysis. An isotope metabolic flux experiment with C13-labeled β-hydroxybutyrate confirmed that β-catenin-activated OXCT1 converts ketone bodies into glutamate. Blocking OXCT1 in β-cateninS33Y-mutated HCC abolished resistance to ketogenic therapy and reduced tumor glutamate levels. Furthermore, OXCT1, activated by mutated β-catenin, enhanced HCC metastasis via the p-STAT3 and epithelial-mesenchymal transition pathways. Inhibition of OXCT1 attenuated its promoting effect on metastasis. Overall, in β-cateninS33Y-mutated HCC, OXCT1 activation leads to metabolic reprogramming of ketone bodies, resulting in resistance to ketogenic therapy and promoting metastasis. Targeting OXCT1 represents a promising strategy for treating β-cateninS33Y-mutated HCC.

DOI: https://doi.org/10.1038/s41419-026-08457-y
Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2503019123

Phase separation of DDHD2 remodels lipid metabolism to dictate treatment sensitivity in luminal breast cancer.

Xiao-Hong Ding, Fenfang Chen, Fan Yang, Gen-Hong Di, Zhi-Ming Shao, Yi Xiao, Yi-Zhou Jiang.

  Luminal breast cancer is characterized by a persistent risk of recurrence and dysregulated lipid metabolism. However, the role of phase separation, a novel mechanism for the spatial compartmentalization of proteins, in lipid remodeling within the context of breast cancer remains largely unexplored. Utilizing the multiomics data from our large breast cancer cohort (n = 773), we revealed that aberrant lipid metabolism negatively impacts the prognosis of patients with luminal breast cancer. Furthermore, we deciphered that the copy number alteration-driven cis-regulation of DDHD domain containing 2 (DDHD2) is correlated with lipid remodeling in luminal breast cancer. Mechanistically, DDHD2 forms biomolecular condensates through phase separation upon AKT1-mediated phosphorylation, which enhances its lipase activity, reduces the abundance of proferroptotic lipids, and consequently decreases ferroptosis susceptibility. Therapeutically, the DDHD2 inhibitor KLH45 remarkably enhances ferroptosis sensitivity to restrict luminal breast cancer progression, and its combination with ferroptosis inducers further improves the efficacy of endocrine therapy. Collectively, our findings reveal a key role of DDHD2 condensates in lipid reprogramming and propose an innovative therapeutic strategy for luminal breast cancer.

Keywords:  DDHD2; ferroptosis; lipid metabolism; luminal breast cancer; phase separation

DOI:  https://doi.org/10.1073/pnas.2503019123
Nat Cell Biol. 2026 Mar 13.

Riboflavin metabolism shapes FSP1-driven ferroptosis resistance.

Vera Skafar, Izadora de Souza, Biplab Ghosh, Ancely Ferreira Dos Santos, Florencio Porto Freitas, Zhiyi Chen, Shibo Sun, Merce Donate Castillo, Palina Nepachalovich, Lars Seufert, Sebastian Bothe, Juliane Tschuck, Apoorva Mathur, Ariane Nunes-Alves, Jannik Buhr, Camilo Aponte-Santamaría, Werner Schmitz, Matthias Mack, Martin Eilers, Ralf Bargou, Milena Chaufan, Mayher Kaur, Mario Palma, Jessalyn M Ubellacker, Ulrich Elling, Hellmut G Augustin, Kamyar Hadian, Svenja Meierjohann, Bettina Proneth, Marcus Conrad, Maria Fedorova, Hamed Alborzinia, José Pedro Friedmann Angeli.

Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. More recently, ferroptosis suppressor protein 1 (FSP1) was identified as a critical ferroptosis inhibitor, acting via the regeneration of membrane-embedded antioxidants. Yet, regulators of FSP1 are largely uncharacterized, and their identification is essential for understanding the mechanisms buffering phospholipid peroxidation and ferroptosis. Here we report a focused CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying riboflavin (vitamin B2) as a modulator of ferroptosis sensitivity. We demonstrate that riboflavin supports FSP1 stability and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. Furthermore, we show that the riboflavin antimetabolite roseoflavin markedly impairs FSP1 function and sensitizes cancer cells to ferroptosis. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway and underscore the therapeutic potential of targeting riboflavin metabolism, with implications for understanding the interaction of nutrients, as well as their contributions to a cell's antioxidant capacity.

DOI: https://doi.org/10.1038/s41556-025-01856-x
Nat Rev Cancer. 2026 Mar 12.

Metabolic vulnerability in fusion-driven ependymoma.

Daniela Senft.

DOI: https://doi.org/10.1038/s41568-026-00920-4
Nat Commun. 2026 Mar 13.

Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness.

Michel Kahi, Abigail Mazzu, Ludovic Batistic, Marc Pujalte-Martin, Victor Tiroille, Anne Vincent, Joseph Murdaca, Loic Trapani, Paraskevi Kousteridou, Oumayma Benaceur, Amine Belaid, Marie Irondelle, Emilie Thomas, Christelle Boscagli, Pierre Bertrand, Heather S Carr, Frédéric Larbret, Emilie Baudelet, Stéphane Audebert, Didier F Pisani, Silvère Baron, Luc Camoin, Mathieu Carlier, Matthieu Durand, Damien Ambrosetti, Yu Chen, Jean-Jacques Diaz, Arnaud Jacquel, Issam Ben-Sahra, Nathalie M Mazure, Pascal Peraldi, Frédéric Bost.

Protein synthesis plays a central role in cancer development and progression. eukaryotic initiation factor 5 A (eIF5A), a translation factor activated by hypusination, is implicated in tumorigenesis, however, its mode of action is still unclear. We find that hypusinated eIF5A (eIF5Ahyp) promotes metastasis and tumor growth in prostate cancer (PCa) by supporting mitochondrial metabolism and translation. eIF5Ahyp controls the subcellular localization of Mitochondrial Ribonuclease P Protein 3 (MRPP3) mRNA encoding a protein essential for mitochondrial tRNA (mt-tRNA) maturation. We show that eIF5Ahyp regulates the nuclear export of MRPP3 mRNA, its expression, thereby promoting mt-tRNA maturation. Our findings establish that MRPP3 enhances mitochondrial metabolism and supports PCa metastasis. Importantly, its expression restores mitochondrial translation and tumor growth inhibited by the downregulation of eIF5Ahyp. Together, we uncover a critical role for eIF5Ahyp in mitochondrial protein synthesis and highlight its broader implications in coordinating the expression of nuclear and mitochondrial genomes, linking hypusination to cancer progression.

DOI: https://doi.org/10.1038/s41467-026-70566-1
Biomed Pharmacother. 2026 Mar 10. pii: S0753-3322(26)00217-9. [Epub ahead of print]197 119184

A rise in double-strand breaks sensitizes tumors to oxidative metabolism inhibitors.

Ferran Medina-Jover, Agnès Figueras, Núria Gendrau-Sanclemente, Emilio Racionero-Andrés, Meritxell Sociats-Font, Álvaro Lahiguera, Pau Guillén, María Tormo-Fabios, Roderic Espín, Miguel Ángel Pardo-Cea, Andrés Mendez-Lucas, Edurne Berra, Josep Maria Piulats, Álvaro Aytés, Alberto Villanueva, Adrià Bernat-Peguera, Margarita Romeo, Miquel Angel Pujana, José Carlos Perales, Francesc Viñals.

  Double-strand breaks (DSBs) accumulate in tumoral DNA due to deficiencies in homologous recombination (HR) repair, such as mutations in BRCA genes, or following antitumoral treatments. In the present study, we show that DSB accumulation, irrespective of origin, triggers an adaptive shift toward oxidative metabolism. We demonstrate that DSBs downregulate the glycolytic transcription factor HIF-1α. This downregulation reduces PDHK1 expression, thereby activating the pyruvate dehydrogenase complex, a key mitochondrial gatekeeper of cellular metabolism. We establish that the induction of oxidative metabolism represents a therapeutically actionable vulnerability across diverse cancer types, independent of HR proficiency. Targeting this metabolic switch in combination with DSB-inducing chemotherapies synergizes in vivo, resulting in significantly reduced tumor growth. Collectively, our findings reveal a critical feedback loop linking DSBs to cancer cell metabolism that constrains metabolic plasticity and creates a compelling therapeutic opportunity for rational combination strategies.

Keywords:  Cancer metabolism; Chemotherapy; DNA damage; OXPHOS inhibitors

DOI:  https://doi.org/10.1016/j.biopha.2026.119184
Theranostics. 2026 ;16(9): 4745-4767

OSBPL3-driven sterol metabolic reprogramming promotes oncogenic signaling and therapeutic resistance in pancreatic cancer.

Qihui Sun, Xiaojia Li, Qi Zou, Yang Chen, Xiaoqi Zhu, Hailin Jiang, Tingting Jiang, Fang Wei, Keping Xie.

   Background: As a member of the oxysterol-binding protein-like (OSBP) family, which is primarily involved in lipid transport and metabolic regulation, Oxysterol-binding protein-like protein 3 (OSBPL3), has garnered increasing attention due to its abnormal expression and functional roles in various cancers. However, the specific role and molecular mechanisms of OSBPL3 in pancreatic cancer (PDA) remain unclear.
Methods: Single-cell and spatial transcriptomic data analyses combined with functional experiments were utilized to systematically evaluate OSBPL3 expression changes at various stages of PDA. Cell lines with decreased or increased expression of OSBPL3 were generated to analyze its role in cell proliferation, stemness, metastasis and chemoresistance. Single-cell transcriptomic and mass spectrometry data was further integrated with functional validation to explore the regulatory mechanisms through which OSBPL3 modulates PDA malignancy.
Results: OSBPL3 was highly expressed throughout various stages of pancreatic inflammation, precursor lesions, and PDA in both human and mouse pancreatic tissues. Increased OSBPL3 expression significantly enhanced the proliferative capacity and stemness of PDA cells, and promoted their migration, invasion, and metastasis. Moreover, increased OSBPL3 expression impacted on the malignant behaviors of PDA, e.g., reduced PDA cell sensitivity to oxaliplatin, whereas inhibition of NOTCH pathway significantly attenuated the drug resistance and stemness features induced by increased OSBPL3 expression, suggesting that OSBPL3 modulated PDA malignancy via oncogenic pathways such as NOTCH signaling pathway. Furthermore, increased OSBPL3 expression was significantly associated with the enrichment of cholesterol esters and other steroid metabolites, as well as their related pathways. Inhibition of key enzymes involved in cholesterol synthesis resulted in a significant reduction in NOTCH pathway and stemness in PDA in vivo mouse models.
Conclusions: Aberrant expression of OSBPL3 plays a pivotal role in PDA initiation and progression and serves as an independent prognostic factor for poor outcomes in PDA patients. OSBPL3 promotes PDA cell proliferation, stemness, and chemoresistance by mediating lipid metabolic reprogramming and regulating oncogenic pathways such as NOTCH. Therefore, inhibition of OSBPL3 expression or blockade of its signaling represent a potential therapeutic strategy to improve therapeutic efficacy and prognosis in PDA patients.

Keywords:  OSBPL3; Pancreatic cancer; immune microenvironment; therapeutic resistance; tumor stemness

DOI:  https://doi.org/10.7150/thno.113637