bims-medica 2025-10-26 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–10–26
thirteen papers selected by
Brett Chrest, Wake Forest University

Stable isotope tracing in human plasma-like medium reveals metabolic and immune modulation of the glioblastoma microenvironment.
The combination of venetoclax with dimethyl fumarate synergistically induces apoptosis in AML cells by disrupting mitochondrial integrity through ROS accumulation.
Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells.
The Metabolic Transition Between Fasting and Feeding Alters Aging-Associated Metabolites, Lowers BCAAs, and Stimulates FGF21 Production in Humans.
HDAC inhibition triggers release of RNA polymerase II from promoter-proximal pausing in healthy blood progenitors and primary acute myeloid leukemia myeloblasts.
Metabolic reprogramming in diabetes and other endocrine and metabolic disorders: exploring the Warburg effect, ketones, and SGLT2 inhibitors.
Organellar pH as an emerging vulnerability to exploit in cancer.
Oral intake of deuterated choline at clinical dose for metabolic imaging of brain tumors.
Pancreas meets brain: β-hydroxybutyrate as a novel "β-cellular" metabolism therapy.
Reply to Comment by Quistorff: ATP is not consumed solely by hydrolytic reactions.
Longitudinal serum metabolomics predicts therapeutic outcome in acute myeloid leukemia.
Metabolic Flux Analysis Uncovers Substrate-Specific Reprogramming and ATP Deficit in CORT-Induced Depressive-like Astrocytes.
Recent progress in the development of small molecule pyruvate kinase M2 inhibitors: 2020-2025.

Neuro Oncol. 2025 Oct 25. pii: noaf248. [Epub ahead of print]

Stable isotope tracing in human plasma-like medium reveals metabolic and immune modulation of the glioblastoma microenvironment.

Milan R Savani, Mohamad El Shami, Kenji Miki, Lauren C Gattie, Bailey C Smith, William H Hicks, Jacob O Weiss, Skyler S Oken, Lavanya N Katta, Tracey Shipman, Maged T Ghoche, Lauren G Zacharias, Misty S Martin-Sandoval, Eric Y Montgomery, Yi Xiao, Diana D Shi, Jeremy N Rich, Timothy E Richardson, Pascal O Zinn, Bradley C Lega, Thomas P Mathews, Ralph J DeBerardinis, Kalil G Abdullah, Samuel K McBrayer.

   BACKGROUND: In vivo stable isotope tracing is useful for natively surveying glioma metabolism but can be difficult to implement. Stable isotope tracing is tractable using in vitro glioma models, but most models lack nutrient conditions and cell populations relevant to human gliomas. This limits our ability to study glioma metabolism in the presence of an intact tumor microenvironment (TME) and immune-metabolic crosstalk.
METHODS: We optimized an in vitro stable isotope tracing approach for human glioma explants and glioma stem-like cell (GSC) lines that integrates human plasma-like medium (HPLM). We performed 15N2-glutamine tracing in GSC monocultures and human IDH-wildtype glioblastoma explants and developed an analytical framework to evaluate microenvironment-dependent metabolic features that distinguish them. We also conducted spatial transcriptomics to assess transcriptional correlates to metabolic activities.
RESULTS: HPLM culture preserved glioma explant viability and stemness while unmasking metabolic and immune programs suppressed by conventional culture conditions. Stable isotope tracing in HPLM revealed TME-dependent and TME-independent features of tumor metabolism. Tissue explants recapitulated tumor cell-intrinsic metabolic activities, such as synthesis of immunomodulatory purines. Unlike GSC monocultures, tissue explants captured tumor cell-extrinsic activities associated with stromal cell metabolism, as exemplified by astrocytic GDP-mannose production in heterocellular explants. Finally, glioma explants displayed tumor subtype-specific metabolic reprogramming, including robust pyrimidine degradation in mesenchymal cells.
CONCLUSIONS: We present a tractable approach to assess glioma metabolism in vitro under physiologic nutrient levels and in the presence of an intact TME. This platform opens new avenues to interrogate glioma metabolism and its interplay with the immune microenvironment.

Keywords:  Glioma; metabolism; organoids; preclinical models; stable isotope tracing

DOI:  https://doi.org/10.1093/neuonc/noaf248
Cell Death Dis. 2025 Oct 21. 16(1): 750

The combination of venetoclax with dimethyl fumarate synergistically induces apoptosis in AML cells by disrupting mitochondrial integrity through ROS accumulation.

Shin-Ichiro Kawaguchi, Kazuya Sato, Junko Izawa, Norihito Takayama, Hiroko Hayakawa, Kaoru Tominaga, Hitoshi Endo, Tom Kouki, Nobuhiko Ohno, Yoshinobu Kanda.

Leukemia cells are consistently subjected to higher oxidative stress than normal cells. To mitigate reactive oxygen species (ROS) overload, which can trigger various forms of cell death, leukemia cells employ a robust antioxidant defense system and maintain redox homeostasis. Recent evidence suggests that dimethyl fumarate (DMF), a derivative of fumarate, inactivates the antioxidant glutathione (GSH), thereby inducing oxidative stress and metabolic dysfunction, eventually leading to cell death in cancer cells. In this study, we observed that DMF decreases the GSH/oxidated GSH ratio and increases intracellular ROS levels, the extent of which is closely correlated with cell death, in acute myeloid leukemia (AML) cell lines. DMF reduced the mitochondrial membrane potential and oxidative phosphorylation (OXPHOS), effects that were almost fully restored by the antioxidant N-acetylcysteine, suggesting that these responses are ROS-dependent. Electron microscopy and inhibition assays revealed that apoptosis, rather than necroptosis or ferroptosis, is the predominant form of cell death of AML cells following DMF treatment. Notably, the combination of DMF and the BCL-2 selective BH3-mimetic venetoclax induced marked cell death in AML cells, including venetoclax-refractory　BCL-2 low expressing U937 and acquired venetoclax-resistant MOLM-14 cells. This combination also caused greater mitochondrial depolarization and a more profound reduction in OXPHOS activity than either agent alone. Collectively, our findings indicate that DMF exerts potent anti-leukemia activity in AML cells and sensitizes cells to venetoclax treatment by synergistically disrupting mitochondrial integrity through ROS accumulation.

DOI: https://doi.org/10.1038/s41419-025-08040-x
Sci Rep. 2025 Oct 23. 15(1): 37028

Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells.

Martina Spada, Cristina Piras, Vera Piera Leoni, Mattia Casula, Gabriella Simbula, Antonio Noto, Katia Lilliu, Karolina Krystyna Kopeć, Gabriele Serreli, Federica Murgia, Federica Etzi, Tinuccia Dettori, Luigi Atzori, Paola Caria.

  Colorectal cancer (CRC) cells are 'addicted' to glutamine to satisfy energy and biosynthetic needs. Inhibiting glutamine metabolism enzymes, like glutaminase, is a potential cancer therapy strategy. Although the GLS inhibitor CB-839 is being evaluated in clinical trials, a comprehensive assessment of its antitumor activity in CRC cells is crucial. The present study aimed to evaluate the impact of CB-839 treatment on different CRC cell lines in terms of survival and proliferation. Furthermore, metabolic adaptations resulting from CB-839 treatment, particularly in energetic pathways, were investigated. Three CRC cell lines (HCT116, HT29, and SW480) were treated with different CB-839 concentrations. Cytotoxicity was assessed via MTT assay, proliferation capacity by flow cytometry, and ATP production rates by Seahorse XF analysis. Moreover, metabolomic profile was explored with untargeted GC-MS and 1H-NMR, and targeted analysis of the Krebs cycle was conducted using GC-MS/MS. HT29 cells exhibited the highest sensitivity to CB-839. Subsequent experiments focused on HT29 and SW480 cells. CB-839 treatment altered cell cycle progression and increased glycolytic ATP production in HT29 cells. Metabolomic analysis revealed changes in Krebs cycle and glutaminolysis in both cell lines, along with alterations in amino acids, sugars, antioxidants, and organic acid levels. This study highlighted glutamine's key role in CRC cells and provided a foundation for elucidating the mechanisms of response and resistance to CB-839.

Keywords:  CB-839; Colorectal cancer; Energetic metabolism; Glutaminase-1 inhibition; Glutamine metabolism; Glutaminolysis

DOI:  https://doi.org/10.1038/s41598-025-20528-2
Aging Cell. 2025 Oct 21. e70270

The Metabolic Transition Between Fasting and Feeding Alters Aging-Associated Metabolites, Lowers BCAAs, and Stimulates FGF21 Production in Humans.

Maria Lastra Cagigas, Nancy T Santiappillai, Serena Commissati, Giovanni Fiorito, Andrius Masedunskas, Gayathiri Rajakumar, Isabella de Ciutiis, Alan Goldhamer, Brian K Kennedy, Andrew J Hoy, Luigi Fontana.

  Fasting-based interventions are gaining momentum as strategies to modulate longevity. Conversely, the same metabolic adaptations that once ensured survival during starvation now contribute to the global obesity epidemic. While previous studies have characterized metabolic changes during fasting, few have examined the refeeding phase, and most lack an integrated analysis of key hormonal and metabolic regulators, including insulin, leptin, adiponectin, free T3, FGF21, and the plasma metabolome. To address this gap, we profiled 134 plasma metabolites using mass spectrometry, covering pathways involved in lipid, amino acid, and ketone metabolism, in a cohort of 20 adults (mean age 52.2 ± 11.8 years, 55% women, BMI 28.8 ± 6.4 kg/m2) undergoing medically supervised prolonged fasting (mean duration 9.8 ± 3.1 days), followed by plant-based refeeding (5.3 ± 2.4 days). Fasting reduced metabolic rate, reflected by lower free T3 levels (p < 0.0001), and markedly reprogrammed the plasma metabolome, including shifts in seven aging-associated metabolites (glucose, 3-hydroxybutyric acid, glycine, glutamine, alanine, phenylalanine, and tyrosine). Notably, plasma branched-chain amino acid (BCAA) levels remained stable during fasting, suggesting active tissue release to support energy homeostasis alongside ketogenesis. Upon refeeding, 81% of metabolite levels normalized, yet BCAAs declined sharply (valine -45%, leucine -52%, isoleucine -48%; all p < 0.001), consistent with insulin-stimulated tissue uptake. Changes in BCAAs were inversely associated with a fivefold increase in FGF21 levels (243.2-1176 pg/mL, p = 0.0007), which occurred exclusively during refeeding, unlike in rodent models where FGF21 levels rise during fasting. Together, our findings identify refeeding as a critical window for modulating aging-related metabolites and highlight the importance of post-fast refeeding dynamics.

Keywords:  BCAA; FGF21; fasting; ketogenesis; refeeding

DOI:  https://doi.org/10.1111/acel.70270
Mol Cancer Ther. 2025 Oct 22.

HDAC inhibition triggers release of RNA polymerase II from promoter-proximal pausing in healthy blood progenitors and primary acute myeloid leukemia myeloblasts.

Yanzi Xing, Alexander Pfab, George Hunt, Kajsa Ax, Sören Lehmann, Johanna Ungerstedt, Mattias Mannervik.

Histone deacetylase (HDAC) inhibitors have been considered as anti-leukemic agents, but have shown poor efficacy in clinical trials. Here, we investigated the immediate transcriptional response to the HDAC inhibitor SAHA (Vorinostat) in healthy CD34+ blood stem/progenitor cells and primary acute myeloid leukemia (AML) patient myeloblasts, carrying TET2 and NPM1 mutations. We found that although healthy CD34+ and AML cells differed substantially at the transcriptional level, they responded very similarly to 10 min SAHA-treatment. HDAC inhibition led to a global increase in histone acetylation, however only 150-250 genes were up-regulated. These were involved in oxidative stress, metabolism, chromatin regulation, cell-cycle control and cell death, and the vast majority were up-regulated in both healthy and AML cells. Up-regulated genes were more highly acetylated compared to average expressed genes, and had higher levels of promoter-proximal paused RNA polymerase II (Pol II) before treatment. Upon HDAC inhibition, up-regulated genes increased BRD4 occupancy the most and released paused Pol II into transcription elongation. Our results suggest that the immediate effect of HDAC inhibition is to trigger release of paused Poll II into elongation. We speculate that the similar transcriptional response in healthy and leukemic cells may contribute to the poor efficacy of HDAC inhibitors in patients with hematological malignancies.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0150
Rev Endocr Metab Disord. 2025 Oct 23.

Metabolic reprogramming in diabetes and other endocrine and metabolic disorders: exploring the Warburg effect, ketones, and SGLT2 inhibitors.

Pedro Carrera-Bastos, Marcel H A Muskiet, Fernando Mata-Ordoñez, Leo Pruimboom, Alejandro Lucia, Raul M Luque, Frits A J Muskiet.

  The "Warburg effect", a metabolic adaptation observed in dividing cells, involves a shift from mitochondrial oxidative phosphorylation to cytoplasmic glucose metabolism. This metabolic process is characterized by increased cellular uptake of glucose and glutamine, elevated intracellular pH and sodium levels, enhanced protection against oxidative stress, altered autophagy, and increased lactate production. Initially identified by Otto Warburg in cancer cells, the Warburg effect is now recognized as a common feature of all dividing cells, prioritizing biomass production for cell proliferation over energy generation for specialized cellular functions. Indeed, the Warburg effect is emerging as an important feature not only in cancer but also in a range of metabolic, endocrine, and neurological chronic disorders, including type 2 diabetes, heart and kidney failure, therapy-refractory epilepsy, Alzheimer's and Parkinson's diseases, chronic fatigue syndrome, and post-viral syndromes. The prevailing notion that "dysfunctional mitochondria" are the primary cause of the "energy deficit" observed in these conditions may be misleading. Instead, this "energy deficit" can result from cells reprogramming their metabolism to support cell division. Additionally, in these disorders, senescent cells are abundant, exhibiting a Warburg-like metabolism with cell cycle arrest and enhanced anabolic activity. This review explores the multifaceted role of the Warburg effect in type 2 diabetes and other metabolic and endocrine chronic disorders and examines the therapeutic potential of different interventions such as intermittent fasting, ketogenic diets, ketone supplements, and sodium/glucose co-transporter 2 inhibitors. Through a comprehensive analysis of existing literature, we aim to shed light on the mechanisms underlying these interventions and their potential impact on disease progression and patient outcomes.

Keywords:  Diabetes; Heart failure; Ketones; Senescent cells; Sodium/glucose cotransporter; Warburg effect

DOI:  https://doi.org/10.1007/s11154-025-09996-z
Trends Cancer. 2025 Oct 23. pii: S2405-8033(25)00234-1. [Epub ahead of print]

Organellar pH as an emerging vulnerability to exploit in cancer.

Cheska Marie Galapate, Cosimo Commisso.

  Cancer cells undergo metabolic reprogramming to sustain their energy demands, and favor glycolysis despite the presence of functional mitochondria. This metabolic shift leads to the rapid production of lactate and protons. If not managed, this accumulation of acidic byproducts would lower the intracellular pH (pHi). To counteract this, cancer cells employ diverse mechanisms to extrude excess protons through membrane transporters, and also sequester them within acidic organelles. Consequently, an alkaline pHi provides cancer cells with a survival advantage by promoting their proliferation, migration, and resistance to cell death. Given the role of organellar acidification in sustaining this altered pH balance, targeting this process represents a potential therapeutic vulnerability in cancer. We explore the mechanisms by which cancer cells maintain pH homeostasis, with a particular focus on organellar pH and its impact on tumor progression. In addition, we assess inhibitors of the key transporters involved in organellar acidification and discuss their therapeutic potential in cancer.

Keywords:  cancer metabolism; organelle acidification; pH homeostasis

DOI:  https://doi.org/10.1016/j.trecan.2025.09.006
Npj Imaging. 2025 Oct 24. 3(1): 54

Oral intake of deuterated choline at clinical dose for metabolic imaging of brain tumors.

Victor E Osoliniec, Monique A Thomas, Robin A de Graaf, Henk M De Feyter.

Deuterium metabolic imaging (DMI) is a new imaging approach that provides unique, complementary information to anatomical MRI of brain tumors. Preclinical DMI studies have demonstrated excellent image contrast following intravenous infusion of deuterated choline (2H9-Cho) at a severalfold higher dose than recommended for humans. We investigated DMI performance in rat glioblastoma models after oral administration of a 2H9-Cho dose recommended for humans. DMI, following the three daily oral low doses, resulted in 2H9-Cho concentrations in the tumor and tumor-to-normal-brain image contrast comparable to a single, high intravenous dose. Further, ²H and 2D ¹H-14N HSQC NMR on excised tumor tissue revealed that oral administration led to increased contributions from Cho-derived molecules that were products of tumor metabolism compared to intravenous infusion of 2H9-Cho. These results can advance clinical translation of Cho-DMI as a noninvasive imaging tool for brain tumor characterization by demonstrating the feasibility of an oral intake approach using a clinical dose.

DOI: https://doi.org/10.1038/s44303-025-00113-y
Metabolism. 2025 Oct 16. pii: S0026-0495(25)00288-4. [Epub ahead of print]174 156419

Pancreas meets brain: β-hydroxybutyrate as a novel "β-cellular" metabolism therapy.

Caroline Lopa, Donatella Pietrangelo, Gaetano Santulli, Jessica Gambardella, Speranza Rubattu, Mihaela Stefan-Lifshitz, Crystal Nieves Garcia, Stanislovas S Jankauskas, Angela Lombardi.

  β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once considered a mere metabolic intermediate, BHB is now recognized as a potent signaling molecule that links nutrient status to gene regulation, inflammation, and cellular stress responses. In fact, beyond serving as an energy substrate, BHB functions as a versatile signaling metabolite that integrates environmental cues to epigenetic regulation, gene expression, and cellular physiology. Accumulating evidence highlights its protective and disease-modifying effects, positioning BHB as a promising therapeutic candidate for diverse conditions associated with energy deficits or metabolic imbalances. Nevertheless, the precise mechanisms underlying these benefits remain incompletely defined. This review discusses recently identified molecular pathways regulated by BHB, with a focus on its roles in cellular signaling, inflammation, transcriptional control, and post-translational protein modifications. For the first time, we also explore the translational relevance of BHB in endocrine pancreas biology, drawing mechanistic parallels with the nervous system. Although neurons and β-cells share remarkable functional similarities, the impact of BHB on β-cell survival and function remains unexplored. Clarifying these effects may uncover new strategies to harness ketosis for the treatment of diabetes.

Keywords:  BHB; Ketone bodies; Pancreatic beta cells; Type 1 diabetes; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.metabol.2025.156419
Fluids Barriers CNS. 2025 Oct 23. 22(1): 105

Reply to Comment by Quistorff: ATP is not consumed solely by hydrolytic reactions.

Gerald A Dienel, Martin Lauritzen.

A Comment to our recent paper that described a budget for brain metabolic water production claimed that all ATP produced by oxidation of glucose is consumed by hydrolysis, and that the net calculated production of metabolic water is equal to that obtained by combustion of glucose. However, ATP is synthesized and consumed by enzymatic reactions that do not involve water in the mechanism. Not all ATP consumed is hydrolyzed.

DOI: https://doi.org/10.1186/s12987-025-00711-3
Transl Oncol. 2025 Oct 19. pii: S1936-5233(25)00298-0. [Epub ahead of print]62 102567

Longitudinal serum metabolomics predicts therapeutic outcome in acute myeloid leukemia.

Qing Cai, Wanying Liu, Changjian Yan, Jiazheng Li, Yan Huang, Xiang Li, Qinwen Yang, Xiaoyu Wei, Huilin Yang, Guanbin Zhang, Ting Yang, Yanxin Chen, Jianda Hu.

  Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with approximately 50 % of patients failing to achieve remission during initial treatment and progressing to refractory AML. Metabolomics, a technology directly linked to clinical phenotypes, offers more precise susceptibility biomarkers compared to genomics and epigenetics. Our study compares metabolic samples collected at multiple time points pre- and after-chemotherapy, performs longitudinal integrated analysis to characterize dynamic alterations, and assesses the temporal impacts of therapeutic responses. Four metabolites-pseudouridine, O-phospho-L‑serine, l-aspartate, and 2-deoxy-d-ribose 1-phosphate-were significantly elevated in AML patients, mechanistically linking dysregulated nucleotide biosynthesis and adaptive amino acid metabolic reprogramming to leukemogenic proliferation.Longitudinal sampling during AML treatment revealed temporal metabolic changes, identifying key metabolites and pathways associated with therapeutic responses.By integrating pre- and after-treatment metabolic index with clinical indicators, we developed predictive models for treatment outcomes. The pre-treatment metabolic model (AUC=0.9143, 95 % CI 0.816-1) and the after-treatment metabolic index (AUC=0.9136, 95 % CI 0.83-1) both demonstrated excellent predictive performance for AML therapeutic outcomes. In conclusion, our findings underscore the potential of targeting glycolipid synthesis and amino acid metabolism to improve clinical outcomes. The dynamic metabolic reprogramming landscape serves as a robust indicator of AML treatment efficacy, offering novel directions for precision therapy in AML.

Keywords:  Acute myeloid leukemia; Dynamic analysis; Metabolic model; Metabolomics

DOI:  https://doi.org/10.1016/j.tranon.2025.102567
J Proteome Res. 2025 Oct 19.

Metabolic Flux Analysis Uncovers Substrate-Specific Reprogramming and ATP Deficit in CORT-Induced Depressive-like Astrocytes.

Yunhao Zhao, Ting Linghu, Qi Wang, Xuemei Qin, Junsheng Tian.

  Depression is closely associated with brain energy metabolism; however, its metabolic characteristics and the mechanisms underlying energy dysregulation remain poorly understood. In this study, we employed an in vitro depression model using corticosterone (CORT)-induced astrocytes and applied stable isotope-resolved metabolomics (SIRM) to trace the metabolic fate of [U-13C6]-glucose, [U-13C3]-lactate, and [U-13C5]-glutamine. Metabolic flux analysis (MFA) was subsequently used to quantify intracellular fluxes. CORT exposure triggered substrate-specific metabolic reprogramming: glucose and lactate catabolism were impaired, whereas glutamine utilization was upregulated. Despite increased glucose uptake and glycolytic flux, most glucose-derived carbon was shunted toward excessive lactate production rather than entering the tricarboxylic acid (TCA) cycle, resulting in a net lactate efflux. Concurrently, glutaminolysis was enhanced to partially compensate for reduced oxidative metabolism. These findings indicate that while glucose remains the dominant energy substrate, its preferential diversion to aerobic glycolysis markedly diminishes ATP production. Collectively, this work provides novel insights into astrocytic energy dysfunction in depression and highlights potential metabolic targets for therapeutic strategies aimed at restoring cerebral energy homeostasis.

Keywords:  aerobic glycolysis; astrocyte; depression; metabolic flux analysis; stable isotope-resolved metabolomics

DOI:  https://doi.org/10.1021/acs.jproteome.5c00667
Future Med Chem. 2025 Oct 24. 1-34

Recent progress in the development of small molecule pyruvate kinase M2 inhibitors: 2020-2025.

Rudradip Das, Shailendra Sharma, Pranav Kumar Ambast, Amit Shard.

  Pyruvate kinase M2 (PKM2) is a central regulator of glycolysis and anabolic metabolism, playing a pivotal role in cancer cell proliferation. Its multifunctional nature and involvement in various disease pathways make it an attractive therapeutic target, especially in oncology and inflammation. This review summarizes research over the past five years on small molecule PKM2 inhibitors. Activators of PKM2 promote the tetrameric form of PKM2, enhancing oxidative phosphorylation and reversing the Warburg effect. In contrast, inhibitors like micheliolide (MCL) and isoselenazolium compounds disrupt PKM2's non-metabolic roles, inducing tumor cell death. Literature was selected through focused searches on PKM2-targeted therapies in cancer, inflammation, and neurodegeneration, with attention to recent advances in structural biology, computational modeling, and high-throughput screening. PKM2 modulators show promise across a range of diseases beyond cancer, including inflammatory and neurodegenerative conditions. However, challenges in isoform selectivity, toxicity, and clinical translation persist. Although, no PKM2 inhibitors have entered and succeeded in clinical trials, continued research and technological advances are essential to unlock PKM2's full therapeutic potential and guide its development into safe, effective clinical treatments.

Keywords:  Cancer; glycolysis; inhibitors; pyruvate kinase M2; small molecules

DOI:  https://doi.org/10.1080/17568919.2025.2571029