bims-cesirm 2026-03-22 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2026–03–22
eighteen papers selected by
Tigist Tamir, University of North Carolina

Metabolic Tracing Reveals IL-2 Driven Glutaminolysis and De Novo Pyrimidine Synthesis in Human Natural Killer Cells.
Therapeutic targeting of tricarboxylic acid cycle and oxidative phosphorylation: a critical analysis of metabolic interventions in cancer treatment.
Discovery of chirally dependent protein modifications by D- and L-2-hydroxyglutarates.
Tracer-assisted shotgun lipidomics (TASL): A quantitative workflow integrating stable-isotope tracing with global lipidome profiling.
Dual-encoder contrastive learning accelerates enzyme discovery.
Extracellular matrix signals promote actin-dependent mitochondrial elongation and activity.
Cooperativity in E. coli aspartate transcarbamoylase is tuned by allosteric breathing.
Radiation-induced autophagy regulates fibroblast mitochondrial metabolism and crosstalk with triple-negative breast cancer cells.
Formation of a reducing microenvironment and regulation of protein supersulfidation by gut microbial supersulfides.
Downregulation of TDP43 by atovaquone inhibits oxidative phosphorylation and enhances sensitivity of triple-negative breast cancer to EGFR-TKIs.
Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.
Alanine catabolism as a targetable vulnerability for MYC-driven liver cancer.
Comprehensive single-cell metabolic profiling identifies targets to sensitize triple-negative breast cancer to chemo-immunotherapy.
PAK5-Mediated Suppression of β-Hydroxybutyrate Production Promotes Breast Cancer Metastasis and Can Be Overcome with Ketogenic Diet.
Mitochondrial control of glycerolipid synthesis by a PEP shuttle.
Mutually exclusive alternative pre-mRNA splicing promotes adaptive metabolic stress signaling by JNK.
Natural Glycoside OSW-1 Targets Glycolytic Enzyme Enolase 1 to Reprogram Tumor Metabolism via Glycolytic Blockade.
Study on the Mechanism of Post-Chemotherapy Metastasis in Breast Cancer Based on Metabolomics and Development of TCM Metabolic Regulators.

J Biol Chem. 2026 Mar 12. pii: S0021-9258(26)00237-1. [Epub ahead of print] 111367

Metabolic Tracing Reveals IL-2 Driven Glutaminolysis and De Novo Pyrimidine Synthesis in Human Natural Killer Cells.

Karen Slattery, Gearóid Conlon, Ethan Collins, Derek P Nolan, Clair M Gardiner, Geraldine M O'Connor.

Natural Killer (NK) cells are innate lymphocytes that are key to intrinsic cancer immunosurveillance and an important target for cancer immunotherapy. Understanding fundamental human NK cell metabolism provides opportunities for optimising NK cell therapies. Little is known about how glutamine, an important cell nutrient and carbon source, is utilised by human NK cells. To address this, we performed U13C-glutamine tracing experiments by Liquid Chromatography Mass Spectrometry (LCMS) and Gas Chromatography Mass Spectrometry (GCMS) analysis of human NK cells stimulated with IL-2 for 18 hours to provide a global overview of glutamine usage by these cells. Our results show that glutamine is taken up by resting NK cells and that this increases further upon IL-2 stimulation. Metabolite labelling analysis identified that IL-2 results in greater conversion of glutamine to glutamate, allowing for anaplerotic flux into the TCA cycle. The fate of the glutamine-derived carbons diverged at oxaloacetate (OAA) allowing both bioenergetic and biosynthetic outcomes - some carbons continued around the TCA cycle while others were exported, converted to aspartate and subsequently used for pyrimidine synthesis. Nucleotide synthesis by IL-2 activated NK cells was found to be essential for expression of the activation marker CD69. The data indicate that glutamine is a key nutrient taken up by human NK cells, and that IL-2 drives glutaminolysis. Subsequent glutamate is used to support the TCA cycle, generating energy and providing intermediates for de novo pyrimidine synthesis.

DOI: https://doi.org/10.1016/j.jbc.2026.111367
Biochem Pharmacol. 2026 Mar 12. pii: S0006-2952(26)00221-2. [Epub ahead of print] 117888

Therapeutic targeting of tricarboxylic acid cycle and oxidative phosphorylation: a critical analysis of metabolic interventions in cancer treatment.

Yawei Han, Yuhao Wei, Yuanting Xie, Mengzhu Zheng.

  Metabolic reprogramming is a hallmark of cancer cells, characterized by distinct alterations in cellular metabolism that emerge during malignant transformation. Enhanced activities of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in tumor cells support their elevated biosynthetic demands for essential biomolecules, including nucleotides, amino acids, and fatty acids. These cancer-specific metabolic reprogramming not only generates mutant targets that are directly druggable, but also induces targets associated with synthetic lethality effects. In this review, we systematically elucidate the molecular dysregulation mechanism of the TCA cycle and the key enzyme OXPHOS, integrate the preclinical and clinical data of existing dysregulated enzyme inhibitors, and also propose a therapeutic approach using metabolic synthetic lethality as a strategy to overcome the toxicity and acquired resistance of targeted therapies in order to achieve selective potentiation of cancer cells on top of conventional targeted therapies. Furthermore, we critically analyze the structural optimization of key inhibitors, providing medicinal chemistry insights into their design, optimization, and mechanisms of action, which are essential for developing next-generation therapeutics with improved efficacy and selectivity. Through comprehensive analysis of altered tumor metabolism, we aim to provide novel insights and perspectives for drug design and target selection in cancer therapeutics.

Keywords:  Cell metabolic; Metabolic synthetic lethality; OXPHOS; TCA cycle

DOI:  https://doi.org/10.1016/j.bcp.2026.117888
Nat Chem. 2026 Mar 17.

Discovery of chirally dependent protein modifications by D- and L-2-hydroxyglutarates.

Zheng Zhang, Yi-Kai Liu, Zhuojun Luo, Meng-Ju Wu, Claudia N Evans, Zihan Qu, Fanglei Xue, Zijian Wang, Lia Stanciu, Zhong-Yin Zhang, Elizabeth I Parkinson, Nabeel Bardeesy, W Andy Tao.

Mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are common in multiple types of human cancer and cause accumulation of the oncometabolite D-2-hydroxyglutarate (D2HG) instead of α-ketoglutarate, driving cancers like gliomas and acute myeloid leukaemia by blocking cell differentiation and promoting tumour growth. Here we discovered protein O-2-hydroxyglutarylation by D2HG using chemical proteomics and further revealed distinct chiral preferences for D2HG and L-2-hydroxyglutarate (L2HG) modifications. D2HG modifications are upregulated in IDH-mutant cells or upon D2HG treatment, while L2HG modifications increase under hypoxic conditions or following L2HG treatment. Notably, two kinases MRCKA and SLK are modified by D2HG and L2HG, respectively, and confirmed by synthetic peptide standards. Phosphoproteomics revealed reduced phosphorylation of MRCKA and SLK substrates, suggesting crosstalk between D/L-2HG modification and kinase activity. These findings highlight distinctive roles of D/L-2HG modifications in cancer progression and suggest potential avenues for therapeutic targeting of oncometabolite-induced post-translational modifications.

DOI: https://doi.org/10.1038/s41557-026-02093-x
Anal Chim Acta. 2026 May 22. pii: S0003-2670(26)00267-9. [Epub ahead of print]1400 345317

Tracer-assisted shotgun lipidomics (TASL): A quantitative workflow integrating stable-isotope tracing with global lipidome profiling.

Hashmatullah Nasimi, Lya K K Holland, Knut K B Clemmensen, Jan Stenvang, Marja Jäättelä, Kenji Maeda, Mesut Bilgin.

   BACKGROUND: Shotgun lipidomics provides a quantitative, steady-state overview of global lipidomes, but offers limited insight into metabolic dynamics. Tracer lipidomics yields time-resolved quantitative information on specific biosynthetic pathways, but labeling can perturb lipidomes, making labeled time-course samples unsuitable for steady-state comparisons. Here, we introduce Tracer-Assisted Shotgun Lipidomics (TASL), a strategy that integrates stable-isotope tracing with shotgun lipidomics in a single workflow, enabling time-resolved analysis while retaining labeled samples as inputs for steady-state lipidome profiling. This is achieved through a minimally perturbing strategy where cells are pre-equilibrated in an unlabeled precursor before switching to the isotopically labeled precursor at the same concentration.
RESULTS: As a proof of concept, TASL was applied to HCT116 colorectal cancer cells and three drug-resistant variants, sampled over 24 h following the switch from unlabeled l-serine to l-serine-(13C315N) to label de novo synthesized sphingolipids. Leveraging the enhanced statistical power of this design, global steady-state analysis revealed accumulation of dihydrosphingolipid species lacking the canonical 4,5-trans double bond in their long-chain base as the most prominent alteration shared across drug-resistant cell lines. Time-resolved analysis of the de novo sphingolipid biosynthesis pathway subsequently identified a pronounced bottleneck at dihydroceramide desaturation, diverting flux toward dihydrosphingomyelin despite an otherwise intact pathway.
SIGNIFICANCE: Together, TASL provides a generalizable and minimally perturbing framework for integrating global steady-state lipidomics with time-resolved pathway analysis, and can be readily extended to other tracers, pathways, and biological systems to study metabolic rewiring at the lipidome scale.

Keywords:  Cancer; Drug resistance; Lipid metabolism; Mass spectrometry; Sphingolipids; Tracer-assisted shotgun lipidomics; l-serine-((13)C(3)(15)N) labeling

DOI:  https://doi.org/10.1016/j.aca.2026.345317
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2520070123

Dual-encoder contrastive learning accelerates enzyme discovery.

Jason W Rocks, Dat P Truong, Dmitrij Rappoport, Samuel Maddrell-Mander, Daniel A Martin-Alarcon, Toni M Lee, Steven Crossan, Joshua E Goldford.

  The ability to engineer enzymes for desired reactions is a cornerstone of modern biotechnology, yet identifying suitable starting proteins remains a critical bottleneck. Although contrastive learning offers a compelling computational approach for enzyme discovery, these models have yet to be implemented at scale or proven effective in real-world experimental settings. Here, we present Horizyn-1, a computationally efficient deep learning framework that enables large-scale reaction-to-enzyme recommendation validated through comprehensive experimental testing. Leveraging a combination of reaction fingerprints and protein language models, we trained Horizyn-1 on millions of reaction-enzyme pairs to achieve state-of-the-art performance, recovering an enzyme with correct activity within the top 100 hits for over 75% of test reactions. We experimentally validate Horizyn-1 across three enzyme discovery scenarios: identifying enzymes for orphan reactions, predicting enzyme promiscuity for both characterized and uncharacterized enzymes, and discovering enzymes for nonnatural biochemical reactions including lysine-driven transaminations that enable efficient synthesis of noncanonical amino acids. On underrepresented reaction classes, we find that fine-tuning with fewer than 10 additional reactions can dramatically improve performance. Furthermore, a logarithmic scaling of model performance with training dataset size suggests continued improvement with larger and more diverse reaction datasets. Horizyn-1 addresses the critical bottleneck of sourcing initial enzymes for optimization campaigns, enabling efficient and scalable in silico screening for enzymes with desired activities and promising to accelerate future efforts in biocatalysis and metabolic engineering.

Keywords:  AI; deep learning; enzyme discovery; enzymology

DOI:  https://doi.org/10.1073/pnas.2520070123
iScience. 2026 Mar 20. 29(3): 115171

Extracellular matrix signals promote actin-dependent mitochondrial elongation and activity.

Priya Gatti, Pritha Mukherjee, Priyanka Dey Talukdar, Wesley Freppel, Anahita Kasmaie, Joseph Kanou, Laurent Chatel-Chaix, Urmi Chatterji, Marc Germain.

  Mitochondria are crucial metabolic organelles regulated by both intracellular and extracellular cues. The extracellular matrix (ECM) is a key component of the cellular environment that controls cellular behavior and metabolic activity. Here, we determined how ECM signaling regulates mitochondrial structure and activity. To distinguish mitochondrial regulation from general ECM-regulated survival cues, we used mammospheres derived from breast cancer cells because of their ability to grow in suspension culture in the absence of ECM. Using this system, we demonstrate that the association of mammospheres with the ECM results in dramatic mitochondrial elongation, along with enhanced mitochondrial respiration and ATP production. This remodeling occurs independently of DRP1 activity but relies on integrin signaling and actin polymerization. Therefore, our findings demonstrate that ECM-driven actin polymerization plays a crucial role in remodeling mitochondrial networks to promote OXPHOS, which represents a vital step for migrating cells to enhance cellular adhesion and facilitate cell growth.

Keywords:  Biological sciences; Cell biology; Integrative aspects of cell biology; Organizational aspects of cell biology; Specialized functions of cells

DOI:  https://doi.org/10.1016/j.isci.2026.115171
Nat Commun. 2026 Mar 20.

Cooperativity in E. coli aspartate transcarbamoylase is tuned by allosteric breathing.

Robert C Miller, Michael G Patterson, Neti Bhatt, Xiaokun Pei, Nozomi Ando.

Aspartate transcarbamoylase (ATCase) from Escherichia coli catalyzes a key step in pyrimidine nucleotide biosynthesis and has long served as a model for allosteric regulation. Despite decades of study, how nucleotide binding at distant regulatory sites controls cooperativity between active sites remained unresolved. Here we show that ATCase does not simply interconvert between two conformations, as traditionally depicted, but instead samples a continuum of conformations that tune enzyme cooperativity. Using complementary cryo-electron microscopy, small-angle X-ray scattering, and crystallography under conditions that ensure full assembly of the allosteric sites, we show that ATCase behaves like a flexible balloon whose global "breathing" motions directly regulate activity: compression enforces high cooperativity, inhibiting the enzyme, whereas expansion relieves this cooperativity and activates the enzyme. We further show that all four ribonucleoside triphosphates act in symmetric pairs to tune this motion, with the pyrimidines CTP and UTP compressing the enzyme to limit further pyrimidine production, and the purines ATP and GTP expanding it to balance pyrimidine and purine pools. Together, these findings uncover a dynamic breathing mechanism for long-range allosteric communication in ATCase.

DOI: https://doi.org/10.1038/s41467-026-70909-y
Cell Rep. 2026 Mar 13. pii: S2211-1247(26)00174-9. [Epub ahead of print]45(3): 117096

Radiation-induced autophagy regulates fibroblast mitochondrial metabolism and crosstalk with triple-negative breast cancer cells.

Kevin C Corn, Shannon E Martello, Vinay K Menon, Lucy S Britto, Kara M Simmons, Youssef K Mohamed, Yoanna I Ivanova, Abtin A Ghelmansaraei, Sara A Weidenbach, Tian Zhu, Evan S Krystofiak, Jamey D Young, Vivian Gama, Marjan Rafat.

  Patients with triple-negative breast cancer (TNBC) experience high recurrence rates despite current interventions, which include radiation therapy (RT). Tumor cells thought to be involved in recurrence may survive in part due to their interactions with irradiated fibroblasts following treatment. How fibroblasts metabolically respond to RT and influence the behavior of TNBC cells is poorly understood. In this study, we demonstrate that irradiated fibroblasts undergo dynamic mitochondrial changes that are regulated by autophagy, resulting in a metabolic profile characterized by high levels of mitochondrial respiration and fatty acid oxidation. These metabolic adaptations lead to a secretory profile that induces an aggressive phenotype in TNBC cells that is mitigated when fibroblast autophagy is blocked. Our work reveals a burgeoning link between post-RT metabolic adaptations in fibroblasts and crosstalk with TNBC cells that promotes a microenvironment conducive to recurrence.

Keywords:  CP: cancer; CP: metabolism; autophagy; fatty acid oxidation; fibroblasts; lipid metabolism; mitochondrial elongation; mitochondrial fusion; mitochondrial respiration; radiation therapy; recurrence; triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.celrep.2026.117096
Redox Biol. 2026 Mar 11. pii: S2213-2317(26)00121-7. [Epub ahead of print]92 104123

Formation of a reducing microenvironment and regulation of protein supersulfidation by gut microbial supersulfides.

Jun Uchiyama, Yoshimi Shimizu, Takamitsu Unoki, Shingo Kasamatsu, Tomoaki Ida, Hideshi Ihara, Yun-Gi Kim, Koji Hase, Yuri Miura, Tomohiko Maehama, Maiko Kusano, Keitaro Umezawa, Masahiro Akiyama.

  Supersulfides, sulfur species containing catenated sulfur atoms, are potent reducing agents produced by diverse organisms. Although their intracellular functions are increasingly recognized, the ecological and physiological importance of gut microbial supersulfides remains poorly understood. In this study, we explored two complementary aspects of gut microbiota-derived supersulfide. First, by assessing the reducing activity, we found that bacterial supersulfides contribute to the enhancement of the extracellular reducing capacity. In particular, Dorea longicatena and Enterocloster bolteae exhibit strong cystine-dependent supersulfide production, which is associated with protection against oxidative stress. Second, beyond their ecological roles, supersulfides influence protein supersulfidation, which is a reversible post-translational modification. Supersulfidated proteins have been detected across multiple commensal taxa with species-specific profiles. This modification is redox-sensitive and modulated by extracellular supersulfides. Members of the Lactobacillaceae family are particularly susceptible to exogenous supersulfides. Supersulfidation involves proteins linked to core microbial processes, including bile acid metabolism, suggesting their potential role in tuning bacterial functions. Together, these findings suggest that microbial supersulfides act as dual regulators: (i) contributing to a protective reducing milieu and (ii) modulating bacterial protein function through supersulfidation. By highlighting post-translational control in gut bacteria and their sensitivity to the local redox environment, this work broadens the current models of microbial redox biology and provides a basis for linking bacterial sulfur metabolism with gut ecosystem stability and host-microbe interactions.

Keywords:  Gut microbiota; Oxidative stress; Redox; Supersulfidation; Supersulfides

DOI:  https://doi.org/10.1016/j.redox.2026.104123
Free Radic Biol Med. 2026 Mar 18. pii: S0891-5849(26)00238-8. [Epub ahead of print]

Downregulation of TDP43 by atovaquone inhibits oxidative phosphorylation and enhances sensitivity of triple-negative breast cancer to EGFR-TKIs.

Liang Lin, Hao Ke, Mengxin Chen, Yi Zhang, Shiting Fu, Fan Yu, Jianbin Su, Xing Yang, Yingqi Guo, Qianzhe Ding, Yuhan Zhang, Limin Zhao.

  Epidermal growth factor receptor (EGFR) is overexpressed in most triple-negative breast cancer (TNBC) patients with poor prognosis; however, the therapeutic benefit of EGFR inhibitors (EGFRi) in breast cancer remains limited. In this study, we found poor response to EGFRi in TNBC was related to oxidative phosphorylation (OXPHOS) and breast cancer stem cells (BCSCs), and demonstrated that TDP43 (TAR DNA-binding protein 43) expression is positively correlated with non-response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). TDP43 knockdown significantly enhances EGFR-TKI sensitivity and decreases EGFR-TKI resistance. Mechanistically, TDP43, a DNA/RNA-binding protein predominantly localized to the nucleus, translocates to mitochondria upon EGFR-TKI stimulation. The increased mitochondrial localization promotes OXPHOS, thereby enriching BCSCs and contributing to EGFR-TKI resistance. Inhibiting TDP43 expression or using our newly identified TDP43 inhibitor, atovaquone, suppresses OXPHOS and reduces EGFR-TKI resistance. Overall, our research identified TDP43 as a key regulator of EGFR-TKI sensitivity and resistance, and offers new therapeutic targets and promising application perspectives in TNBC.

Keywords:  Atovaquone; Breast cancer stem cells; EGFR inhibitor resistance; Oxidative phosphorylation; TDP43; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.047
FEBS J. 2026 Mar 19.

Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.

Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.

  The stress-inducible protein Sestrin2 (SESN2) has recently emerged as an orchestrator of mitochondrial signaling. The regulation of mitochondria-related pathways, such as aerobic respiration, is thought to be mediated by SESN2, but the underlying mechanisms are not fully understood. Here, we characterized mitochondria in Sesn2-knockdown myoblasts under physiological conditions using oxygen consumption rate measurements, fluorescence microscopy, and protein content analysis. We discovered that SESN2 is essential for sustaining oxidative phosphorylation and maintaining the mitochondrial network organization. SESN2 loss diminished ATP production, decreased the levels of nuclear- and mitochondrial-encoded complex IV subunits, and increased superoxide generation. Moreover, the assessment of mitochondrial distribution in Sesn2-knockdown cells revealed a more fragmented network. This was associated with an increased ratio of short to long optic atrophy 1 (OPA1) forms. Remarkably, disruption of mitochondrial signaling suppressed cellular proliferation and altered both cell and nuclear morphology. In summary, our findings suggest that SESN2 plays an important role in maintaining cellular homeostasis, partly through its impact on mitochondrial function.

Keywords:  SESN2; mitochondria; mitochondrial dynamics; mitophagy; oxidative phosphorylation

DOI:  https://doi.org/10.1111/febs.70497
Cell Rep. 2026 Mar 17. pii: S2211-1247(26)00185-3. [Epub ahead of print]45(4): 117107

Alanine catabolism as a targetable vulnerability for MYC-driven liver cancer.

Tonatiuh Montoya, Joyce V Lee, Longhui Qiu, Abigail Krall, Nedas Matulionis, Yurim Seo, Brian N Finck, Robin K Kelley, Heather Christofk, Andrei Goga.

  Liver cancer is a leading cause of cancer-related death due to the shortage of effective therapies, and MYC overexpression defines an aggressive and difficult-to-treat subset of patients. Given MYC's ability to reprogram cancer metabolism and the liver's role in coordinating systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited liver tumorigenesis. In vivo isotope tracing identified alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle and biosynthesis. Finally, treating a MYC-driven liver tumor model with L-cycloserine diminished the frequency of mouse tumor formation and attenuated the growth of established human liver tumors. Thus, we identify a targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.

Keywords:  CP: cancer; CP: metabolism; GPT2; MYC; alanine metabolism; liver cancer

DOI:  https://doi.org/10.1016/j.celrep.2026.117107
Cell Rep Med. 2026 Mar 17. pii: S2666-3791(26)00076-5. [Epub ahead of print]7(3): 102659

Comprehensive single-cell metabolic profiling identifies targets to sensitize triple-negative breast cancer to chemo-immunotherapy.

Ying Xu, Xin-Yi Liu, Hang Zhang, Li Chen, Han Wang, Zhi-Ming Shao, Yi Xiao, Yi-Zhou Jiang.

  The treatment of triple-negative breast cancer (TNBC) poses significant challenges, necessitating innovative approaches to identify therapeutic targets. This study presents a cohort of patients with early-stage TNBC receiving neoadjuvant chemotherapy or chemo-immunotherapy, leveraging single-cell RNA sequencing and metabolic analysis to elucidate the impact of metabolic reprogramming on treatment response. Our findings reveal metabolic heterogeneity at levels of metabolic genes, pathways, and fluxes. Cell-type-specific metabolic traits show stronger associations with therapeutic response compared with bulk metabolic features and the proportion of major cell types. We identify a dynamic collaboration between tumor cells and myeloid cells driven by differential glucose utilization and lactate production, which facilitates tumor progression. Monocarboxylate transporter 1 (MCT1) inhibitors disrupt their interaction, enhancing the efficacy of anti-PD-1 and antibody-drug conjugate (ADC) treatments in TNBC mouse models. Overall, our study delineates the single-cell metabolic landscape of TNBC and positions MCT1 as a promising target.

Keywords:  flux; metabolism; precision immunotherapy; single-cell RNA sequencing; triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.xcrm.2026.102659
Cancer Res. 2026 Mar 16. 86(6): 1435-1450

PAK5-Mediated Suppression of β-Hydroxybutyrate Production Promotes Breast Cancer Metastasis and Can Be Overcome with Ketogenic Diet.

Yao Xing, Yuen Tan, Bingtao Hu, Hongyan Zhang, Yanshu Li, Jinyu Zuo, Yidu Liu, Fuyi Han, Shu-Lan Sun, Xu Wang, Yang Li, Feng Li.

The ketogenic diet (KD) is an emerging metabolic approach for enhancing the efficacy of cancer therapy, and the KD is characterized by increased production of ketone bodies, including β-hydroxybutyrate (β-HB). Clarifying the direct effects of β-HB on cancer cells is critical for optimizing the therapeutic potential of KD. In this study, we show that β-HB levels were markedly decreased in tumor tissues and serum from patients with breast cancer, particularly in metastatic patients. Additionally, β-HB supplementation demonstrated potent antitumor effects in breast cancer models in vitro and in vivo. P21-activated kinase 5 (PAK5) inhibited β-HB synthesis by interacting with 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2), a key enzyme in ketone generation, and inducing phosphorylation at Ser138 and Ser311. PAK5-mediated HMGCS2 Ser138 phosphorylation recruited the E3 ubiquitin ligase BMI1, thereby facilitating HMGCS2 degradation, and phosphorylation at Ser311 reduced the enzymatic activity of HMGCS2 by inhibiting SIRT3-dependent deacetylation. Collectively, phosphorylation at these two sites coordinately suppressed the generation of intracellular β-HB. Elevated PAK5 in breast cancer stimulated lymph node metastasis, whereas the expression of HMGCS2, particularly its nonphosphorylatable mutants, inhibited PAK5-driven breast tumor growth and metastasis. Consistently, KD or β-HB treatment could reverse breast cancer progression induced by PAK5. Low HMGCS2 expression and β-HB synthesis were associated with lymph node metastasis and poor clinical outcomes in patients, and PAK5 protein levels positively correlated with HMGCS2 phosphorylation at Ser311 residue in breast cancer tissues. Together, these findings demonstrated that the PAK5-HMGCS2 pathway drives breast cancer metastasis and can be circumvented using a KD.
SIGNIFICANCE: PAK5-mediated phosphorylation of HMGCS2 promotes breast cancer growth and metastasis by inhibiting β-hydroxybutyrate production, revealing the role of PAK5 in ketone metabolism and highlighting a potential therapeutic target for breast cancer metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2174
Cell. 2026 Mar 17. pii: S0092-8674(26)00224-2. [Epub ahead of print]

Mitochondrial control of glycerolipid synthesis by a PEP shuttle.

Tadashi Yamamuro, Daisuke Katoh, Guilherme Martins Silva, Hiroshi Nishida, Satoshi Oikawa, Yusuke Higuchi, Dandan Wang, Masanori Fujimoto, Naofumi Yoshida, Mark Li, Jihoon Shin, Zezhou Zhao, Jin-Seon Yook, Lijun Sun, Shingo Kajimura.

  Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains a higher-energy phosphate bond than ATP and has diverse biological functions. However, how mitochondria-generated PEP is delivered to the cytosol and fulfills cell-specific requirements remains elusive. Here, we show that SLC25A35 regulates mitochondrial PEP efflux and glyceroneogenesis in lipogenic cells that utilize the pyruvate-to-PEP bypass. Reconstitution and structural studies demonstrated PEP transport by SLC25A35 in a pH gradient-dependent manner. Loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, thereby reducing glycerolipid synthesis. Significantly, hepatic inhibition of SLC25A35 in obese mice alleviated steatosis and improved systemic glucose homeostasis. Together, these results suggest that mitochondria facilitate glycerolipid synthesis by providing PEP via SLC25A35, offering lipogenic mitochondria as a target to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and type 2 diabetes.

Keywords:  bioenergetics; diabetes; glyceroneogenesis; hepatic steatosis; mitochondria; obesity

DOI:  https://doi.org/10.1016/j.cell.2026.02.017
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2527162123

Mutually exclusive alternative pre-mRNA splicing promotes adaptive metabolic stress signaling by JNK.

Alexandra Lee, Autumn Gentzler, Declan Fitzpatrick, Sithara Raju Ponny, Ozkan Aydemir, Myoung Sook Han, Caroline A Lewis, Guangping Gao, Roger J Davis.

  The JUN NH2-terminal kinase (JNK) signal transduction pathway is activated during the hepatic metabolic stress response. The JNK1 and JNK2 pre-mRNAs expressed by hepatocytes exhibit mutually exclusive inclusion of exons 7a or 7b that encode a segment of the substrate binding site that is required for selective protein phosphorylation. We established mice with conditional inclusion of exons 7a or 7b to test the function of these JNK spliceoforms. We report that the JNK27b spliceoform plays a key role in the hepatic metabolic stress response. This function of JNK27b is mediated by coordinated mechanisms that independently regulate circadian gene expression and phosphorylation of Retinoid X Receptor α (RXRα) on Ser265. This analysis identifies an important role for JNK27b in the hepatic adaptive response to metabolic stress.

Keywords:  JNK; alternative pre-mRNA splicing; circadian rhythm; metabolic stress

DOI:  https://doi.org/10.1073/pnas.2527162123
ACS Chem Biol. 2026 Mar 19.

Natural Glycoside OSW-1 Targets Glycolytic Enzyme Enolase 1 to Reprogram Tumor Metabolism via Glycolytic Blockade.

Yan Xia, Mingyu Xia, Zihao Dai, Pan Fang, Pengfei Fang, Jing Wang, Dapeng Zhu, Cheng Luo, Heng Xu, Biao Yu.

OSW-1, a steroidal disaccharide isolated from the bulbs of Ornithogalum saundersiae, has been extensively studied for its extremely potent cytotoxicity against the National Cancer Institute's 60 cancer cell lines with an average IC50 of 0.78 nM, while exhibiting selectivity toward normal cells. Although OSBP and ORP4L have been identified as its binding targets, their known functions appear insufficient to account for the compound's exceptional potency, suggesting the involvement of additional mechanisms and targets. Therefore, elucidating novel target proteins associated with its activity is essential for the further development of this molecule. Here, we disclose that OSW-1 can block the glycolytic pathway and trigger compensatory mitochondrial oxidative phosphorylation. This previously uncharacterized mechanism is relevant to the key rate-limiting enzyme, enolase 1 (ENO1), which shows subnanomolar affinity with OSW-1. Our study repurposes OSW-1 to be a small-molecule probe to investigate the function of ENO1 and a promising candidate for metabolism-targeted anticancer therapy.

DOI: https://doi.org/10.1021/acschembio.6c00022
Anticancer Agents Med Chem. 2026 Mar 12.

Study on the Mechanism of Post-Chemotherapy Metastasis in Breast Cancer Based on Metabolomics and Development of TCM Metabolic Regulators.

Zhe Yu, Weiqi Wang, Junjie Tao, Ye Qiu, Mengyuan Wang, Zhidong Qiu, Wanfang Zhu.

   INTRODUCTION: Breast cancer (BC) is a leading global malignancy in women. Although central to treatment, chemotherapy may paradoxically promote metastasis. The role of metabolic changes in chemotherapy- induced metastasis remains unclear. This study aims to investigate the association between metabolic alterations and BC metastasis after CMF (cyclophosphamide (CCP), methotrexate (MTX), and 5-fluorouracil (5-FU)) chemotherapy.
METHODS: A murine BC model treated with CMF was used. Metabolomic profiling identified altered pathways. Metastasis was assessed via tumor growth, hematoxylin and eosin (H&E), and immunohistochemistry (IHC). Phospholipid metabolism was inhibited with idelalisib combined with CMF. Traditional Chinese medicine (TCM) components were screened. Epicatechin (EC) was identified as a modulator of phospholipid metabolism and tested in CMF.
RESULTS: Metabolomic analysis revealed a marked upregulation of phospholipid metabolism in CMF-treated BC mice, which was linked to enhanced metastasis. Intervening with idelalisib in combination with CMF abolished these protumorigenic effects. Among the screened TCM components, EC was identified as a modulator of phospholipid metabolism. Similarly, the combination of EC and CMF maintained chemotherapy's antitumor efficacy while substantially reducing metastatic spread.
DISCUSSION: Our findings reveal that CMF chemotherapy induces phospholipid metabolic reprogramming, which drives BC metastasis. Targeting this pathway-either through pharmacological inhibitors (idelalisib) or natural compounds (EC)-can mitigate chemotherapy-induced metastasis without compromising tumor suppression. This suggests that metabolic modulation could be a viable strategy to enhance chemotherapy efficacy.
CONCLUSION: Upregulated phospholipid metabolism is a critical mechanism behind chemotherapy-induced BC metastasis. Combining CMF with phospholipid-targeting agents (idelalisib or EC) offers a promising therapeutic approach to optimize chemotherapy outcomes. These results provide a theoretical foundation for developing novel combination therapies in BC treatment.

Keywords:  Breast cancer; epicatechin.; metabolomics; phospholipid metabolism; tumor metastasis

DOI:  https://doi.org/10.2174/0118715206433354251202101936