bims-medica 2026-04-05 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–04–05
29 papers selected by
Brett Chrest, Wake Forest University

Targeting systemic and tumor metabolic balances with ketogenic diets enhance efficacy of therapy in FLT3-ITD acute myeloid leukemia.
Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.
Exercise training induces mitochondrial biogenesis, while high-fat diet increases the ability of mitochondria to use long and short-chain fatty acids.
Flip the fuel, and the heat is on! Carnitine synthesis as a physiological mediator of fuel adaptation.
Effects of culture media glucose concentration on LHCN-M2 skeletal muscle cell viability, differentiation and metabolic phenotype: a proof-of-concept study.
Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.
Sexual dimorphism shapes renal metabolic adaptation to a ketogenic diet.
Suppression of de novo lipogenesis and dietary PUFA supplementation inhibit prostate cancer progression.
Dynamic UFMylation governs cellular fitness by coordinating multi-organelle proteostasis.
Protein lactylation: a metabolic signal driving cancer therapy resistance.
The inositol pyrophosphate 5-InsP7 regulates mitochondrial polyphosphate synthesis and bioenergetic function.
Inhibition of mitochondrial RNA polymerase sensitizes cancer cells to radiation by inhibiting mitochondrial respiration.
Mitochondrial protein translation is a heightened dependence and therapeutic vulnerability of chemo-refractory triple negative breast cancer.
Lactate Facilitates the Survival and Invasion of Pancreatic Cancer Cells Under Glucose Deprivation.
NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions.
Treatment of TP53-mutated myelodysplastic syndrome and acute myeloid leukemia with lowintensity metronomic decitabine and venetoclax.
Cell-Type-Dependent Metabolic Compensation Preserves Photoreceptor Survival Through Pyruvate Kinase Isoform Balance.
Acid Ceramidase Inhibition Disrupts Ceramide Homeostasis and Induces Mitochondrial Apoptosis in IDH1-Mutant Oligodendroglioma.
Structural basis for pH-responsive amino acid transport via SLC7A4.
Anatomic Predilection of Isocitrate Dehydrogenase-Mutant Gliomas: A Multi-Institutional Spatial Analysis.
Antitumor natural products targeting mitochondrial NADH: ubiquinone oxidoreductase (complex I): a review.
ALDH1L2 regulates reactive oxygen species and acinar-to-ductal metaplasia in the pancreas.
Dual targeting of GPX4 and TXNRD1 triggers eradication of AML cells through induction of apoptosis and ferroptosis.
Pharmacological blockade of rho kinase enhances venetoclax responses in translational models of acute myeloid leukemia.
Requirement for oxidation of neuronal ketone bodies in aging and neurodegeneration.
MLL3/4 methyltransferases regulate the differentiation of pluripotent stem cells via cellular respiration.
Mitochondrial respiration in human peripheral blood mononuclear cells: methodology and influence of permeabilization and storage.
PSAT1 Promotes NSCLC Progression via the De Novo Serine Synthesis Pathway and Represents a Therapeutic Vulnerability.
The scientific legacy of Martin Karplus from the perspective of his collaborators.

Cell Rep. 2026 Mar 28. pii: S2211-1247(26)00263-9. [Epub ahead of print]45(4): 117185

Targeting systemic and tumor metabolic balances with ketogenic diets enhance efficacy of therapy in FLT3-ITD acute myeloid leukemia.

Léa Goupille, Alexandre Boudet, Laura Lauture, Ambrine Sahal, Guillaume Gautier-Renard, Emeline Chu-Van, Anvi Laetitia Nguyen, Céline Chollet, Coralie Alcazar, Isabelle Bernard, François Vergez, Véronique de Mas, Christian Récher, Tony Kaoma, Paolo Gallipoli, Vilma Dembitz, Irene Basili, Flavia Bernardi, Olivier Ayrault, Carine Joffre, Florence Castelli, Benoit Colsch, Nathalie Bourgès-Abella, Fanny Granat, Jean-Emmanuel Sarry.

  FMS-like tyrosine kinase 3 (FLT3) mutations in acute myeloid leukemia (AML) are associated with adverse prognosis. FLT3 inhibitors (FLT3i) improve therapeutic response; however, diverse resistance mechanisms, such as adaptations in lipid metabolism, have been identified. We hypothesized that a lipid-rich ketogenic diet (KD) might alter both host and tumoral lipid metabolism, enhancing responses to FLT3i. In FLT3-mutated AML mouse models, 3 weeks of lard- or plant-based KD improved the efficacy of FLT3i by 2-fold reduction of engraftment and tumor burden. KD increased ketone bodies and lipid accumulation in plasma, liver, and AML cells and also induced a polyunsaturated fatty acid:monounsaturated fatty acid (PUFA:MUFA) imbalance. KD impacted pentoses, hexoses, and amino acid metabolism, enhancing sugar phosphates and vitamins in the host. Mechanistically, KD rewired anabolism toward fatty acid oxidation and glycine-utilizing pathways, modulated the expression of FLT3 signaling pathways and lipid biosynthesis, and promoted tumor cell differentiation. In conclusion, this study shows that KD reduces FLT3i resistance, offering a promising therapeutic solution.

Keywords:  CP: cancer; CP: metabolism; FLT3-ITD mutations; acute myeloid leukemia; ketogenic diet; metabolism; therapy resistance

DOI:  https://doi.org/10.1016/j.celrep.2026.117185
iScience. 2026 Apr 17. 29(4): 115184

Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.

Edziu Franczak, McLane M Montgomery, Zoe S Terwilliger, Raphael T Aruleba, Polina Krassovskaia, Ilya N Boykov, James T Hagen, Emely A Pacheco, Brett R Chrest, Tonya N Zeczycki, Kayla J Vandiver, P Darrell Neufer, Joseph M McClung, Kelsey H Fisher-Wellman.

  Oxidative phosphorylation (OxPhos) relies on coordinated synthesis of nuclear- and mitochondrial-encoded protein subunits comprising mitochondrial respiratory complexes. Despite a causal link between accumulated mtDNA mutations and age-related diseases, the impact of mtDNA mutation burden on cellular bioenergetics across major organ systems remains only partially resolved. Herein, we leveraged a comprehensive mitochondrial phenotyping platform to assess the phenotypic consequences of heightened mtDNA mutation burden across 8 murine tissues using the polymerase γ (PolG) mutator mouse, incapable of mtDNA proofreading. Despite reductions in OxPhos protein expression, maximal mitochondrial respiratory capacity remained largely intact in PolG Mut mice. Further analysis revealed partial functional deficits in NADH-linked respiration exhibited in brown adipose, colon, kidney, lung, and bone marrow-derived mononuclear cells. In contrast, respiration routed from CII-CIII-CIV was largely preserved across all tissues. Together, these findings suggest that NADH oxidation at respiratory complex I (CI) is the primary functional consequence of heightened mtDNA mutational load.

Keywords:  Biochemistry; Genomics; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.115184
J Physiol. 2026 Apr 03.

Exercise training induces mitochondrial biogenesis, while high-fat diet increases the ability of mitochondria to use long and short-chain fatty acids.

Jessica L Dowling, Rachel M Handy, Nicole M Notaro, Sara M Frangos, David J Dyck, Graham P Holloway.

  Short-chain fatty acids (SCFAs), derived from peroxisomal metabolism and the gut microbiota, have been proposed as key substrates to support mitochondrial oxidative phosphorylation (OXPHOS) in extrahepatic tissues such as skeletal muscle. However, the extent to which mitochondria can oxidize SCFAs (acetate, propionate and butyrate) and the ability of exercise training and a high-fat diet (HFD) to modulate this process remains unclear. Here, we show that SCFA-supported respiration in skeletal muscle is relatively limited (18 ± 6 nmol min-1 mg-1), accounting for only ∼7% of maximal carbohydrate (pyruvate: 252 ± 41 nmol min-1 mg-1) and ∼14% of LCFA (palmitoylcarnitine)-linked respiration. Despite this low capacity, the intrinsic mitochondrial ability to oxidize palmitoylcarnitine, acetate and butyrate increased (P < 0.05: +50%) following HFD consumption, suggesting HFD rewires mitochondria to optimize lipid oxidation. By contrast, exercise training prevented these HFD-induced intrinsic mitochondrial responses. Although intrinsic changes are biologically relevant, skeletal muscle adaptation to metabolic stress also involves mitochondrial biogenesis and an expansion of the mitochondrial proteome. Proteomic analysis and citrate synthase activity revealed that, although HFD independently did not alter mitochondrial protein abundance, exercise training increased mitochondrial proteins, a response amplified in the presence of a HFD. Consequently, although exercise did not directly enhance mitochondrial SCFA-supported respiration, the combined effect of HFD and exercise predicted a greater overall capacity for SCFA oxidation because of increased mitochondrial abundance. Collectively, although SCFAs contribute minimally to mitochondrial respiration in skeletal muscle, combined HFD and exercise synergistically enhance overall OXPHOS capacity across diverse substrates, including SCFAs, primarily through increased mitochondrial protein abundance rather than intrinsic mitochondrial remodelling. KEY POINTS: Peroxisome and gut derived short-chain fatty acids (SCFA) have been proposed as an alternative metabolic fuel source to support skeletal muscle oxidative phosphorylation. The capacity and adaptability of mitochondrial SCFA oxidation remains unknown. SCFA-supported mitochondrial respiration is limited (<15%) compared to carbohydrate (pyruvate) and long-chain fatty acid linked substrates. High-fat feeding increased the intrinsic capacity of mitochondria to utilize palmitoylcarnitine, acetate and butyrate- effects prevented by 4 weeks of exercise training. Combined high-fat diet and exercise training increased skeletal muscle mitochondrial protein content in an additive manner, increasing oxidative capacity and ability to utilize both long- and SCFAs as a fuel source.

Keywords:  exercise; high‐fat diet; mitochondria; short‐chain fatty acids; skeletal muscle

DOI:  https://doi.org/10.1113/JP289545
Trends Endocrinol Metab. 2026 Apr 02. pii: S1043-2760(26)00068-8. [Epub ahead of print]

Flip the fuel, and the heat is on! Carnitine synthesis as a physiological mediator of fuel adaptation.

Nicolai R Hathiramani, Alexandra E Jerrett, Jessica B Spinelli.

  To what extent does de novo carnitine synthesis in tissues dictate their fuel preference? Recently, Auger et al. identified Solute Carrier 25A45 (SLC25A45) as a mitochondrial trimethyllysine importer for carnitine biosynthesis. SLC25A45 enables certain tissues to constitutively utilize fatty acids as fuel and, upon bioenergetic crisis, mediates a fuel switch that restores homeostasis.

Keywords:  GLP-1RA; TML transporter; carnitine biosynthesis; cold adaptation; fuel switching; mitochondria

DOI:  https://doi.org/10.1016/j.tem.2026.03.007
J Muscle Res Cell Motil. 2026 Mar 30. pii: 11. [Epub ahead of print]47(2):

Effects of culture media glucose concentration on LHCN-M2 skeletal muscle cell viability, differentiation and metabolic phenotype: a proof-of-concept study.

Ryan Brett, Leanne Hodson, Derek Renshaw, Mark C Turner.

  In vitro skeletal muscle culture models provide important insight into the cellular mechanisms which underpin skeletal muscle physiology and metabolism in health and disease. The establishment of a model that can be cultured in physiological concentrations of glucose is an important factor in its translatability to more complex models and systems. Using the human skeletal muscle cell line, LHCN-M2 myoblasts, we aimed to determine the effects of different concentrations of glucose in culture media on cell viability, proliferation, ATP production and differentiation. LHCN-M2 myoblasts were cultured in NORM (1 g· L- 1) or HIGH (3.8 g· L- 1) glucose growth media, and cell viability, ATP production, and proliferation were measured. Immunofluorescence microscopy was used to determine LHCN-M2 differentiation into multinucleated myotubes with increasing concentrations of human serum (0.5%, 1% and 2% v/v). There were no differences in the viability, proliferation or basal ATP production rates of LHCN-M2 cells grown in NORM compared to HIGH glucose (P > 0.05). Morphological analysis revealed that myotube area was greater when differentiated in 2% compared to 0.5% human serum (P = 0.02), but myotube number and fusion index were unaffected (P > 0.05). These findings demonstrate that LHCN-M2 cells are capable of proliferating and differentiating into multinucleated myotubes under normal glucose concentrations in the culture media. Further work is required to determine the implications of media glucose concentration on the wider metabolic function and phenotype of LHCN-M2 myoblasts cells and myotubes.

Keywords:  Cell health; Cell lines; Human skeletal muscle; Metabolism; Mitochondrial function; Physiologically relevant; Proliferation

DOI:  https://doi.org/10.1007/s10974-026-09729-y
Am J Hum Genet. 2026 Mar 30. pii: S0002-9297(26)00113-8. [Epub ahead of print]

Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.

Natalie B Tan, Matthias Gautschi, Michael Raum, Daniella H Hock, Robert Kopajtich, Jia Wang, Xiao Qian, Tanavi Sharma, Timothy E Green, Jean-Marc Nuoffer, Katrina M Bell, Katarzyna Pospieszny, Tegan Stait, Chloe Pike, Michelle Cao, Susan M White, David R Thorburn, Theresa Brunet, Matias Wagner, Wolfgang Müller-Felber, Leopold Zeng, Thomas Klopstock, André Schaller, Jing Liu, David A Stroud, Holger Prokisch.

  NDUFA5 encodes a structural subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) located in the peripheral arm of the enzyme complex. Complex I is the largest enzyme of the mitochondrial respiratory chain and is essential for oxidative phosphorylation. There are many well-characterized conditions associated with nuclear-encoded mitochondrial complex I dysfunction, including Leigh syndrome, leukoencephalopathy, lethal infantile mitochondrial disease, hypertrophic cardiomyopathy, and exercise intolerance. The vast majority of these nuclear-encoded mitochondrial complex I deficiencies are autosomal-recessive conditions. To date, variants in NDUFA5 have not been associated with mitochondriopathy in humans. We identified a cohort of four individuals from three unrelated families with bi-allelic variants in NDUFA5. All individuals present with variable multisystem disease in the setting of a mitochondrial complex I deficiency, biochemically proven via an array of respiratory chain enzymology, blue native PAGE, and mass-spectrometry-based proteomics in peripheral blood mononuclear cells, lymphoblastoid cell lines, fibroblasts, and skeletal muscle. Transcriptomics and RT-PCR demonstrated aberrant mRNA expression in all affected individuals. Finally, we generated zebrafish ndufa5 F0 mutants that exhibited defects of morphological development, locomotor deficits, and abnormal brain activity. Our data demonstrate that bi-allelic variants in NDUFA5 cause a mitochondrial complex I deficiency, characterized by a variable multisystem phenotype that encompasses severe congenital heart defects, hematological abnormalities, and neurological involvement consistent with Leigh syndrome.

Keywords:  CI deficiency; NDUFA5; complex I deficiency; mitochondrial disease; mitochondriopathy

DOI:  https://doi.org/10.1016/j.ajhg.2026.03.003
Cell Rep. 2026 Mar 28. pii: S2211-1247(26)00268-8. [Epub ahead of print]45(4): 117190

Sexual dimorphism shapes renal metabolic adaptation to a ketogenic diet.

Miranda E Kelly, Lauren A Hoffner, Cuauhtemoc B Ramirez, Alexis L Anica, Joohwan Kim, Gregory Tong, Yeojin Kim, Vyshnavi Mannepalli, Wonsuk Choi, Ki-Hong Jang, Yasmine H Alam, Sunhee Jung, Johnny Le, Miranda L Lopez, Varvara I Rubtsova, Hosung Bae, Yujin Chun, Won-Suk Song, Ian J Tamburini, Victor L Schuster, Hoda Anton-Culver, Wei Ling Lau, Thomas F Martinez, Gina Lee, Cholsoon Jang.

  While kidneys are essential for maintaining systemic metabolic homeostasis and exhibit sexual dimorphism, the effects of sex and environmental factors, such as diet, on renal metabolism remain unclear. Using kidney-specific arteriovenous (AV) metabolomics, in vivo isotope tracing, and transcriptomics, we discover profound sex differences in kidney metabolic reprogramming under ketogenic diet (KD) in C57BL/6J mice. Tissue metabolomics shows the accumulation of aldosterone and acylcarnitines exclusively in female kidneys under a normal chow (NC) diet, suggesting basal sex differences in sodium and fatty acid metabolism. Under KD, AV metabolomics reveals that only female kidneys activate ketogenesis and gluconeogenesis, supported by transcriptional sex differences in related rate-limiting enzymes and transporters. Given the widespread public and clinical interest in KD for treating epilepsy, metabolic disorders, and cancers, our findings underscore the importance of considering sex differences in kidney metabolism as a fundamental variable when interpreting KD's diverse effects on pathophysiology and therapeutics.

Keywords:  CP: metabolism; aldosterone; arteriovenous; gluconeogenesis; ketogenesis; ketogenic diet; ketone body; kidney; metabolic flux; metabolomics; sex difference

DOI:  https://doi.org/10.1016/j.celrep.2026.117190
bioRxiv. 2026 Mar 27. pii: 2026.03.25.714193. [Epub ahead of print]

Suppression of de novo lipogenesis and dietary PUFA supplementation inhibit prostate cancer progression.

Silvia D Rodrigues, Caroline Fidalgo Ribeiro, Giuseppe N Fanelli, Isadora Ferreira Teixeira, Hubert Pakula, Pier Vitale Nuzzo, Filippo Pederzoli, Fabio Socciarelli, Sara Bleve, Jeanne Jiang, Jonas Dehairs, Guilherme Henrique Tamarindo, Giorgia Zadra, Lisa M Butler, Stephen R Plymate, David W Goodrich, Johannes V Swinnen, David M Nanus, Massimo Loda.

Prostate cancer progression is characterized by dysregulated lipid metabolism, with fatty acid synthase (FASN), the rate-limiting step in de novo lipogenesis (DNL), resulting in significant accumulation of saturated lipids. Here, we investigate whether pharmacologic FASN inhibition creates a metabolic state that increases reliance on exogenous polyunsaturated fatty acids (PUFAs). Inhibition of FASN profoundly alters membrane phospholipid composition, driving compensatory incorporation of PUFAs into membrane phospholipids, thus increasing susceptibility to lipid peroxidation and oxidative damage. Combined FASN inhibition and PUFA exposure increased reactive oxygen species, induced mitochondrial hyperpolarization, and enhanced lipid peroxidation in both hormone-sensitive and castration-resistant prostate cancer models. Marked inhibition of human and murine prostate cancer organoids is achieved ex vivo . In genetically engineered, DNL-reliant Hi-Myc mice, a diet enriched in PUFAs significantly inhibited invasive carcinoma compared to a saturated fat-enriched diet. Environmental PUFAs modulate and enhance the therapeutic efficacy of FASN-targeted strategies. These findings set the stage for pharmacologic and dietary intervention in prostate cancer patients.

DOI: https://doi.org/10.64898/2026.03.25.714193
bioRxiv. 2026 Mar 28. pii: 2026.03.27.714830. [Epub ahead of print]

Dynamic UFMylation governs cellular fitness by coordinating multi-organelle proteostasis.

Guy B Kunzmann, William E Leiter, Sophie E Durn, Amy M Weeks, Jason R Cantor.

Ubiquitin-fold modifier 1 (UFM1) is a ubiquitin-like protein (UBL) covalently attached to substrates through a dedicated enzymatic cascade (UFMylation) and removed by specific proteases. Despite a key role in endoplasmic reticulum (ER)-ribosome homeostasis, the basis by which this UBL supports cell fitness remains elusive, as the essentiality of UFMylation machinery varies widely across hundreds of cancer lines. Here, we trace a conditional dependence on the UFMylation pathway to the availability of alanine, an amino acid provided by human plasma-like medium but absent from most conventional synthetic media. We show that by facilitating the clearance of stalled ribosomes at the ER, dynamic UFMylation maintains cellular levels of glutamic-pyruvic transaminase 2 (GPT2), the primary enzyme responsible for de novo alanine synthesis in most human cancer lines. This buffering preserves the alanine pools required to sustain protein synthesis under alanine-restricted conditions. Beyond GPT2, UFM1 deficiency leads to widespread proteomic remodeling that spans diverse processes, including mitochondrial translation. Our results reveal that despite primarily targeting ER-localized ribosomes, the UFMylation system orchestrates a multi-organelle proteostasis network whose client composition and contributions to cell fitness are shaped by intrinsic factors and nutrient conditions.

DOI: https://doi.org/10.64898/2026.03.27.714830
Cell Death Discov. 2026 Mar 31.

Protein lactylation: a metabolic signal driving cancer therapy resistance.

Silvia D'amico, Sara Giovannini, Gerry Melino, Angelo Peschiaroli, Francesca Bernassola.

Unlike normal cells, which primarily rely on oxidative phosphorylation, cancer cells reprogram their metabolism by preferentially utilizing glycolysis even in the presence of oxygen to generate ATP. As a result, cancer cells and the tumor microenvironment typically accumulate high levels of lactate. Although initially considered a mere byproduct of glucose metabolism, lactate has recently emerged as an important metabolic intermediate involved in many intracellular pathways and protein modifications. Lysine lactylation is indeed a newly identified, metabolism-linked post-translational modification in which lactate is covalently bound to specific lysine residues. This review provides an overview of the current understanding of how lysine lactylation mechanistically contributes to therapeutic resistance in tumor cells. Remarkably, protein lactylation is emerging as a promising druggable approach for overcoming therapy resistance. Hence, here, we also highlight new strategies that target lactylation with pharmacological inhibitors to counteract drug resistance in cancer.

DOI: https://doi.org/10.1038/s41420-026-03050-w
J Biol Chem. 2026 Mar 31. pii: S0021-9258(26)00283-8. [Epub ahead of print] 111413

The inositol pyrophosphate 5-InsP7 regulates mitochondrial polyphosphate synthesis and bioenergetic function.

Jayashree S Ladke, Azmi Khan, Anshit Singh, Henning J Jessen, Ullas Kolthur-Seetharam, Manish Jaiswal, Rashna Bhandari.

  Inorganic polyphosphate (polyP) is a linear polymer of phosphate residues linked by phosphoanhydride bonds. PolyP remains poorly understood in mammals due to its low abundance and lack of information on its metabolism. We developed a DAPI fluorescence-based assay to quantify the low levels of polyP present in mammalian cell lines and tissues, detecting an enrichment of polyP in the mitochondria compared with the nucleus and post-mitochondrial fraction. Mitochondrial polyP synthesis was found to depend on active FoF1 ATP synthase and an intact proton gradient across the inner mitochondrial membrane. Additionally, orthophosphate (Pi) is essential for mitochondrial polyP production, and ATP enhances Pi-driven polyP synthesis in isolated mitochondria. We discovered that the inositol pyrophosphate 5-InsP7, synthesized by IP6K1, regulates mitochondrial polyP levels. Mice and cells deficient in IP6K1 showed a significant reduction in mitochondrial polyP synthesis compared with wild type controls. Cells lacking IP6K1 also showed impaired mitochondrial respiration. The expression of active IP6K1, but not its catalytically inactive form, restored mitochondrial polyP synthesis in IP6K1 deficient cells, but mitochondrial respiration was rescued by expression of either active or inactive IP6K1. These data show that IP6K1 regulates mitochondrial function and polyP production both through the synthesis of 5-InsP7 and via a catalytic activity-independent mechanism. Our findings uncover a link between 5-InsP7, an energy sensor, and polyP, an energy store, in the regulation of mammalian mitochondrial homeostasis.

Keywords:  ATP synthase; cell metabolism; inorganic polyphosphate; inositol phosphate; inositol pyrophosphates; mitochondria; mitochondrial membrane potential; mitochondrial respiration

DOI:  https://doi.org/10.1016/j.jbc.2026.111413
J Radiat Res. 2026 Apr 01. pii: rrag021. [Epub ahead of print]

Inhibition of mitochondrial RNA polymerase sensitizes cancer cells to radiation by inhibiting mitochondrial respiration.

Sachiko Tsunoda, Yukina Osawa, Noriko Hosoya.

  Radiotherapy is a cornerstone of cancer treatment, but its efficacy is limited by tumor radioresistance and toxicity to normal cells. Thus, radiosensitizing agents that selectively target cancer-specific pathways are needed. Mitochondria contain their own deoxyribonucleic acid (DNA) that encodes proteins essential for oxidative phosphorylation (OXPHOS), the primary energy source for cell growth and survival. Recently, IMT1, a specific inhibitor of mitochondrial transcription targeting mitochondrial RNA polymerase (POLRMT), was developed and shown to suppress tumor growth in several cancers overexpressing POLRMT. However, the effect of combining IMT1 with radiation remains uncharacterized. Here, we show that IMT1 enhances radiosensitivity in cancer cells by inhibiting mitochondrial respiration. We inhibited POLRMT by administrating sublethal dose of IMT1 in OXPHOS-dependent cancer cell lines HeLa, A549, MDA-MB-468, HCT116, A431 and AN3CA, and observed increased radiosensitivity. While radiation alone upregulated mitochondrial respiration, IMT1 abolished this capacity when combined with radiation, showing very low oxygen consumption rates in all respiratory states. IMT1 enhanced radiation-induced apoptosis, but did not affect DNA damage repair and cell cycle regulation. Supplementation with galactose rescued hyper-radiosensitivity induced by IMT1. These findings support the mechanistic link between impaired mitochondrial respiration and radiosensitization induced by POLRMT inhibition. The radiosensitizing effect of IMT1 was not observed in normal cell lines RPE1 and HME1 and the glycolysis-dominant cancer cell line HT1080, suggesting that OXPHOS-dominant cancers would profit most from POLRMT inhibition. Thus, this study presents a novel therapeutic strategy that may improve the efficacy of radiotherapy in OXPHOS-dependent cancer cells while minimizing damage to normal cells.

Keywords:  IMT1; mitochondrial RNA polymerase; mitochondrial respiration; mitochondrial transcription; radiosensitization

DOI:  https://doi.org/10.1093/jrr/rrag021
bioRxiv. 2026 Mar 26. pii: 2026.03.23.712647. [Epub ahead of print]

Mitochondrial protein translation is a heightened dependence and therapeutic vulnerability of chemo-refractory triple negative breast cancer.

Mariah J Berner, Steven W Wall, Mokryun L Baek, Audra Lane, Allison S Greer, Karen Wang, Lacey E Dobrolecki, Ivy Strope, Qian Zhu, Bing Zhang, Jonathan T Lei, Michael T Lewis, Gloria V Echeverria.

Triple negative breast cancer (TNBC) patients harboring residual cancer burden following completion of conventional neoadjuvant chemo-immunotherapy regimens have poor relapse-free and overall survival rates despite recent advances in immunotherapies and antibody drug conjugates. We and others have demonstrated the requirement of mitochondrial function for survival of chemo-refractory TNBC, as well as its pervasive association with chemoresistance in human and patient-derived xenograft (PDX) cohorts. We sought to gain new mechanistic insights into the mitochondrial vulnerability of TNBC. Analyses of human and PDX mass spectrometry proteomics datasets revealed that mitochondrial protein translation-related signatures were among the top significantly associated with chemoresistance. Those signatures encompassed many core mitoribosome components as well as the mitoribosome accessory protein, Oxidase (Cytochrome C) Assembly 1-Like (OXA1L), which was consistently enriched in chemoresistant versus chemosensitive TNBCs across datasets. OXA1L, while not yet characterized in cancer, has been reported to be crucial for the termination of translation of the 13 mtDNA-encoded electron transport chain (ETC) proteins and for the insertion of those proteins, as well as nDNA-encoded ETC proteins, into the inner mitochondrial membrane. Together, those functions are crucial for the proper formation and function of the ETC. Therefore, we hypothesized that mitochondrial translation supported by OXA1L supports mitochondrial dependence and chemoresistance in TNBC. Knockdown (KD) of OXA1L in human TNBC cells reduced ETC protein levels, mitochondrial 'respirasome' supercomplex levels, ATP production, and oxidative phosphorylation (oxphos). Of note, OXA1L was required for the characteristic oxphos elevation induced by carboplatin (CRB), and KD significantly enhanced CRB sensitivity. To explore the translational potential of targeting the mitoribosome in TNBC, we leveraged the bacterial ancestry of mitochondria to repurpose the FDA-approved antibiotic tigecycline (TIG) as a chemo-sensitizing drug based on its mitoribosome inhibitory function. Direct measurement of mitochondrial nascent peptide levels revealed that, while CRB elevated mitochondrial translation, TIG potently diminished mitochondrial translation as monotherapy and when combined with CRB or docetaxel (DTX). Further, TIG abolished CRB-induced oxphos, decreased oxphos in combination with DTX, and significantly improved sensitivity to chemotherapies in human TNBC cell lines, PDX-derived spheroids, and in an in vivo PDX trial. These findings identify OXA1L-dependent mitochondrial translation and ETC formation as critical determinants of mitochondrial function that support TNBC chemoresistance, justifying further exploration of the clinical potential of repurposed antibiotics for TNBC.
DISCLOSURES: GVE is co-founder, Chief Scientific Officer, and an equity stakeholder of Nemea Therapeutics. G.V.E. formerly received sponsored research funding from Chimerix Inc. G.V.E. receives experimental compounds from the Lead Discovery Center of Germany and from Jazz Pharmaceuticals. MLB is a co-inventor at Nemea Therapeutics. MTL is a founder and limited partner in StemMed Ltd. and a manager in StemMed Holdings, its general partner. He is a founder and equity stakeholder in Tvardi Therapeutics Inc. Some PDX models, including BCM-4272 and BCM-7649, are exclusively licensed to StemMed Ltd., resulting in royalty income to MTL when used for commercial purposes. LED is a compensated employee of StemMed Ltd. Some PDX models, none of which are included in this study, are exclusively licensed to StemMed Ltd., resulting in royalty income to LED. All other authors have nothing to disclose.

DOI: https://doi.org/10.64898/2026.03.23.712647
FASEB J. 2026 Apr 15. 40(7): e71726

Lactate Facilitates the Survival and Invasion of Pancreatic Cancer Cells Under Glucose Deprivation.

Fan Wang, Ping Hu, Shengbo Han, Ya Zhang, Yang Li, Wenfeng Zhuo, Yong Zhao, Yan Huang, Guozheng Lv, Hongda Wang, Gang Zhao.

  Lactate has been considered as a tumor-promoting metabolite, however, its functional roles in pancreatic cancer (PC) have not yet been fully elucidated. Here, we explored the roles of lactate on the proliferation and invasion of PC cells under glucose deprivation. We found that lactate enhanced PC cells' proliferation and invasion under glucose deprivation, but not in normal conditions. The Cancer Genome Atlas (TCGA) Pancreatic Adenocarcinoma (PAAD) dataset showed that monocarboxylic acid transporter 1 (MCT1), a lactate transporter, was overexpressed and correlated with poor prognosis in PC patients. Additionally, knockdown or inhibition of MCT1 distinctively attenuated lactate-induced proliferation and invasion of PC cells under glucose deprivation by suppressing their tricarboxylic acid (TCA) cycle. Importantly, the MCT1 inhibitor AZD3965 synergistically enhanced the anticancer effects of the glycolysis inhibitor 2-DG. Taken together, our results demonstrate that MCT1-mediated lactate influx sustains PC proliferation under glucose starvation, and combined inhibition of MCT1 and glycolysis could be leveraged for treatment of PC.

Keywords:  MCT1; TCA; lactate; metastasis; proliferation

DOI:  https://doi.org/10.1096/fj.202503162RR
Nat Metab. 2026 Apr 01.

NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions.

Megan D Radyk, Barbara S Nelson, Mariana Tannus Ruckert, Christopher J Halbrook, Mengrou Shan, Jonathan M Alektiar, Brooke L Lavoie, Lucie Salvatore, Wei Yan, Matthew D Perricone, Kathryn Buscher, Alexander Wood, Hanna S Hong, Peter Sajjakulnukit, Li Zhang, Gabriel Corfas, Filip Bednar, Timothy L Frankel, Marina Pasca di Magliano, Justin A Colacino, Yatrik M Shah, Howard C Crawford, Costas A Lyssiotis.

Acinar-to-ductal metaplasia (ADM) is a reversible cell state that facilitates pancreas repair following injury. Oncogenic KRAS mutations can progress ADM to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). However, the metabolic alterations in these precancerous lesions are understudied. Here, we identify global changes in central carbon metabolism genes and metabolites during ADM formation. In particular, NRF2-target genes are significantly induced in ADM. Among these, we focus on genes encoding NADPH-producing enzymes glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1), which participate in the regulation of oxidative stress. In mouse models of pancreatic tumourigenesis, G6PD deficiency or Me1 loss increases reactive oxygen species and lipid peroxidation, which is accompanied by accelerated formation of ADM and PanIN lesions. Notably, Me1 loss, but not G6PD deficiency, promotes faster PDAC progression. We demonstrate that oxidative stress is required for ADM, as pharmacological antioxidant treatment attenuates ADM progression in vivo and ex vivo. Conversely, depleting the antioxidant glutathione promotes precancerous lesions in primary human acinar cells and in mice. Together, our findings shed light on metabolic reprogramming in the precancerous pancreas.

DOI: https://doi.org/10.1038/s42255-026-01496-x
Haematologica. 2026 Apr 02.

Treatment of TP53-mutated myelodysplastic syndrome and acute myeloid leukemia with lowintensity metronomic decitabine and venetoclax.

Mendel Goldfinger, Ioannis Mantzaris, Aditi Shastri, Bradley Rockwell, Yogen Saunthararajah, Shanye Yin, David Levitz, Kira Gritsman, Alejandro R Sica, Noah Kornblum, Lauren C Shapiro, Ridhi Gupta, Stephen Peeke, Nishi Shah, Kith Pradhan, Anne Munoz, Aradhika Dhawan, Jhannine Alyssa Verceles, Karen Fehn, Monica Comas, Lamisha Shah, Yang Shi, Brian A Jonas, Dennis L Cooper, Marina Konopleva, Eric J Feldman, Amit Verma.

Venetoclax (Ven) in combination with hypomethylating agents (HMA) (azacitidine or decitabine) is the standard of care for elderly or unfit patients with acute myeloid leukemia (AML) and is being explored in high-risk myelodysplastic syndrome (HR-MDS). However, currently approved dosing of HMA/Ven is associated with prolonged cytopenias, without a clear improvement in survival for TP53-mutated myeloid malignancies. In order to reduce hospitalizations during COVID, a once-weekly, metronomic schedule of decitabine (0.2 mg/Kg) and venetoclax (400 mg) was developed for patients with MDS and AML. Based on encouraging results, a phase 2 trial was performed. In the current study, we analyzed response rates and survival for all patients with TP53-mutated disease treated on the metronomic schedule. In total, 40 patients with TP53-mutated MDS and AML (26 in a prospective trial and 14 in the retrospective cohort) were included; 26 had HR-MDS and 14 had AML. The median age was 76.5 years, 70% had complex cytogenetics and 82% had bi-allelic TP53 mutations. The ORR for AML (CR+Cri) was 70% and 57% (CR+mCR) for MDS. With a median follow-up of 12.9 months, the median OS for the entire cohort was 11.3 months (11.6 months for AML, 9.9 months for MDS), and median OS in the 31 patients with bi-allelic mutated TP53 was 10.4 months. Transfusion independence was achieved in 58%. Neutropenic fever occurred in 15%, there were no therapy-related fatalities, and the 100-day mortality was 7.5%. A non-cytotoxic metronomic dosing schedule of decitabine/Ven has a low toxicity profile in TP53-mutated myeloid malignancies.

DOI: https://doi.org/10.3324/haematol.2026.300534
FASEB J. 2026 Apr 15. 40(7): e71730

Cell-Type-Dependent Metabolic Compensation Preserves Photoreceptor Survival Through Pyruvate Kinase Isoform Balance.

Ammaji Rajala, Larissa J Trevino, Tyler M Black, Raju V S Rajala.

  Photoreceptors depend on aerobic glycolysis to meet the high biosynthetic demand required for continuous outer segment renewal. Disruption of this metabolic program is increasingly recognized as a contributor to retinal degeneration; however, the coordinated roles of key glycolytic enzymes across retinal cell types remain incompletely understood. Pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA) are central regulators of aerobic glycolysis; however, the mechanisms by which their interplay supports retinal homeostasis remain unclear. Here, we investigated the effects of selectively deleting LDHA alone or in combination with PKM2 in retinal neurons. Rod-specific deletion of LDHA, as well as combined deletion of LDHA and PKM2 in rods, led to progressive photoreceptor degeneration, accompanied by structural disorganization and functional impairment. Loss of LDHA reduced PKM2 expression and induced compensatory upregulation of PKM1; however, PKM1 levels did not reach those of PKM2, correlating with increased susceptibility to degeneration. In contrast, deletion of both LDHA and PKM2 throughout the retina led to robust PKM1 induction to levels comparable to those of PKM2 and was associated with preservation of retinal structure and function. Translating ribosome affinity purification demonstrated that LDHA, LDHB, PKM1, and PKM2 are expressed across multiple retinal cell types, and metabolic analyses revealed that non-rod neurons contribute substantially to retinal lactate production. We propose a PKM isoform balance threshold model in which retinal outcome depends on the level of PKM1 compensation following PKM2 loss. When PKM1 reaches levels comparable to PKM2, retinal structure and function are preserved; insufficient compensation results in degeneration. These findings highlight cell-type-dependent metabolic compensation and pyruvate kinase isoform balance as key determinants of retinal integrity and photoreceptor survival.

Keywords:  LDHA; PKM1; PKM2; neurodegeneration; photoreceptors; retinal metabolism

DOI:  https://doi.org/10.1096/fj.202505064R
Res Sq. 2026 Mar 25. pii: rs.3.rs-9077389. [Epub ahead of print]

Acid Ceramidase Inhibition Disrupts Ceramide Homeostasis and Induces Mitochondrial Apoptosis in IDH1-Mutant Oligodendroglioma.

Mioara Larion, Helena Muley, Faris Zaibaq, Meili Zhang, Dionne Davis, Michael Kruhlak, Samarth Mathur, Adrian Lita, Hua Song, Wei Zhang, Zalman Wong, Taylor Harmon, Lumin Zhang, Chen Cam-El Makranz, Aiguo Li, George Karadimov, Fengchao Lang, Christel Herold-Mende, Chunzhang Yang, Tyrone Dowdy.

Oligodendroglioma is genetically defined by mutations in isocitrate dehydrogenase 1 or 2 (IDH1/IDH2) and 1p/19q codeletion. We previously showed that in IDH1-mutant oligodendroglioma, the oncometabolite D-2-hydroxyglutarate biases the sphingosine-1-phosphate-to-ceramide rheostat toward ceramides. Taking advantage of this intrinsic metabolic vulnerability, we investigated whether further elevating ceramide levels through inhibition of acid ceramidase could exacerbate this imbalance and promote apoptotic cell death. Analysis of patient datasets demonstrated that acid ceramidase is expressed at higher levels in both low- and high-grade gliomas compared with normal tissue. Pharmacologic inhibition of acid ceramidase with SABRAC preferentially reduced viability in human IDH1-mutant oligodendroglioma cell lines. In these sensitive models, acid ceramidase inhibition markedly increased ceramide levels and induced coordinated sphingolipid remodeling. Subcellular imaging using a fluorescent ceramide analogue demonstrated increased ceramide localization to lysosomes and mitochondria following acid ceramidase inhibition. This was accompanied by cytochrome c redistribution, executioner caspase activation, and caspase-dependent apoptotic cell death, consistent with engagement of intrinsic mitochondrial apoptosis. Transcriptomic and biochemical analyses further revealed activation of endoplasmic reticulum stress and unfolded protein response signaling, including PERK- and IRE1α-associated programs, suggesting coordinated multi-organelle stress responses under sustained ceramide elevation. These mechanistic effects translated into a survival benefit in oligodendroglioma xenograft-bearing mice. Together, these findings suggest that IDH1-mutant oligodendroglioma harbors a pre-existing heightened sensitivity to ceramide stress and identify acid ceramidase as a therapeutically actionable target in this disease.

DOI: https://doi.org/10.21203/rs.3.rs-9077389/v1
Nat Commun. 2026 Mar 28.

Structural basis for pH-responsive amino acid transport via SLC7A4.

Dimitrios Kolokouris, Anuja Bothra, Takafumi Kato, Yi C Zeng, Simon Lichtinger, Joanne L Parker, Philip C Biggin, Simon Newstead.

The transport of amino acids across cell membranes is essential for metabolism, neuronal signalling, and immune system function. The amino acid polyamine organocation (APC) superfamily controls amino acid transport via mechanisms including amino acid exchange, facilitative diffusion, and sodium- or proton-coupled transport. Although many mammalian APC members functioning as exchangers and sodium-coupled systems have been identified, the mechanisms underlying pH-regulated amino acid transport in mammalian cells remain unclear. Here, we show that the plasma membrane amino acid transporter SLC7A4 is regulated by low extracellular pH and functions as a leucine transporter in human cells. Using Cryo-EM structures of the plant homologue, CAT4, from Arabidopsis thaliana in outward-open apo and L-ornithine-bound states, as well as transport assays and molecular dynamics simulations based on homology models of the human transporter, we identify residues responsible for amino acid selectivity that supports an allosteric mechanism linking ligand recognition to pH regulation. This mechanism is consistent with an evolutionary link to proton-coupled prokaryotic homologues. Overall, our findings provide a structural and functional basis for pH-gated leucine transport by the human SLC7A4 transporter and provides a framework for understanding amino acid selectivity within the wider SLC7 family.

DOI: https://doi.org/10.1038/s41467-026-70956-5
Neurosurgery. 2026 Apr 03.

Anatomic Predilection of Isocitrate Dehydrogenase-Mutant Gliomas: A Multi-Institutional Spatial Analysis.

Minjun Park, Hannah Weiss, Edward S Harake, Camila Fang, Alex Springer, Nicolas K Goff, John E Markert, David Reinecke, Nader Maarouf, Dieter H Heiland, Alex M Miller, Todd Hollon, John G Golfinos, Daniel A Orringer.

   BACKGROUND AND OBJECTIVES: Interactions between cancer cells and their microenvironment are central to tumor formation. Regional microenvironmental variability in the brain may offer insights into essential factors in tumorigenesis. Surprisingly, a granular assessment of regional patterns of gliomagenesis has not been undertaken in the molecular era. The aim of this study was to quantitatively establish the anatomic distribution of the major molecular subtypes of adult diffuse glioma.
METHODS: We retrospectively analyzed 204 isocitrate dehydrogenase (IDH)-mutant and 200 IDH-wildtype gliomas. Reproducibility was assessed in an external cohort (190 IDH-mutant, 227 IDH-wildtype), and microarray expressions from Allen Human Brain Atlas were used to compare transcriptomic profiles between IDH-mutant hotspots and coldspots.
RESULTS: A total of 50.5% (103/204) of IDH-mutant tumors arose with the superior and middle frontal gyri, indicating a 3.1-fold regional enrichment relative to the volume of these gyri (P < .001). Totally, 9.5% (19/200) of IDH-wildtype tumors arose in the superior temporal gyrus with a 2.1-fold enrichment (P = .01). IDH-mutant and wildtype tumors were enriched by 4 and 4.5-fold, respectively, in the insula (both P < .001). Overall, 23.3% (24/103) of astrocytomas occurred disproportionately higher in the insula compared with oligodendrogliomas (P < .001). Transcriptomic analysis comparing the lobar hotspot (frontal lobe) to the coldspot (occipital lobe) revealed frontal enrichment of cholesterol (normalized enrichment score = 1.78) and fatty acid (normalized enrichment score = 1.94) metabolism pathways, paralleling the observed regional enrichment of IDH-mutant gliomas.
CONCLUSION: This study identifies molecular subtype-specific glioma hotspots and may suggest that regional metabolic differences may underlie the brain's variable vulnerability to gliomagenesis. These findings provide a framework for investigating additional microenvironmental factors that drive human glioma formation.

Keywords:  Astrocytoma; Gliomagenesis; IDH-mutant; Oligodendroglioma; Superior frontal gyrus

DOI:  https://doi.org/10.1227/neu.0000000000004019
Front Pharmacol. 2026 ;17 1799383

Antitumor natural products targeting mitochondrial NADH: ubiquinone oxidoreductase (complex I): a review.

Jiaqi Gou, Lingdang Chen, Yuting Xu, Binbin Liao, Yuanmin Shen, Juntao Tai, Jianying Zhang, Aixue Zuo.

  Mitochondrial complex I (NADH:ubiquinone oxidoreductase) is a critical hub for bioenergetics and redox signaling. Beyond its canonical role in oxidative phosphorylation and ATP synthesis, complex I regulates the intracellular NADH/NAD+ balance and reactive oxygen species (ROS) production, both of which are vital for tumor survival. Consequently, targeting complex I has emerged as a promising therapeutic strategy. Increasing evidence shows that diverse natural products-ranging from alkaloids to annonaceous acetogenins-exert potent antitumor effects by inhibiting complex I. These compounds disrupt mitochondrial function, inducing metabolic stress and cancer cell death. However, a systematic overview linking their chemical structures to specific binding modes and antitumor mechanisms is currently lacking. In this review, we summarize recent advances in natural products targeting mitochondrial complex I. We categorize these agents based on their structural characteristics and discuss their distinct mechanisms, such as acting as "deep tunnel blockers" versus "shallow pocket binders." This work aims to provide a theoretical foundation for the rational development of novel complex I-targeted antitumor drugs.

Keywords:  NADH; antitumor mechanisms; mitochondria; mitochondrial complex I; natural products; ubiquinone oxidoreductase

DOI:  https://doi.org/10.3389/fphar.2026.1799383
Nat Metab. 2026 Apr 01.

ALDH1L2 regulates reactive oxygen species and acinar-to-ductal metaplasia in the pancreas.

Marc Hennequart, Loic Mervant, Julie Stockis, Jack Coomes, Martha M Zarou, Louise Gerard, Virginie Tevel, Valérie Migeot, Steven E Pilley, Younghwan Lee, Paul C Driscoll, Nathalie M Legrave, Christiaan F Labuschagne, Fabio Zani, Alejandro Huerta Uribe, Rute Machado De Morais Ferreira, Eric C Cheung, Ilaria Malanchi, James I MacRae, Oliver D K Maddocks, Timotheus Y F Halim, Karen H Vousden.

Acinar-to-ductal metaplasia (ADM) contributes to pancreatic repair after injury1. However, persistent ADM, combined with KRAS mutation, leads to the development of precancerous pancreatic intraepithelial neoplasia (PanIN) that can progress into pancreatic ductal adenocarcinoma (PDAC)2. While PDAC development is well documented, the metabolic rewiring that occurs during early events such as ADM is poorly understood. Here we show that aldehyde dehydrogenase 1 family member L2 (ALDH1L2), an NADPH-producing mitochondrial enzyme of the one-carbon pathway, limits reactive oxygen species (ROS) and formate production in pancreatic acinar cells. However, ALDH1L2 expression decreases progressively during ADM and is completely absent in pancreatic ductal cells. ALDH1L2 loss elevates ROS and promotes ADM in a model of pancreatitis and accelerates tumour progression in models of pancreatic cancer. We also show that formate increases during PDAC progression in mice and humans. Overall, our findings identify ROS as a driver of ADM and suggest that circulating formate may serve as a biomarker for PDAC progression.

DOI: https://doi.org/10.1038/s42255-026-01456-5
Exp Hematol Oncol. 2026 Mar 31. pii: 38. [Epub ahead of print]15(1):

Dual targeting of GPX4 and TXNRD1 triggers eradication of AML cells through induction of apoptosis and ferroptosis.

Cécile Favreau, Maxence Bourgoin, Coline Savy, Thomas Botton, Sarah Bailly, Florence Granger, Catherine Birck, Marwa Zerhouni, Emeline Kerreneur, Adele Rivault, Alban Vigroux, Jade Dussart-Gautheret, Marie-Laure Arcangeli, Arnaud Poterszman, Thomas Cluzeau, Stephane Rocchi, Arnaud Jacquel, Rachid Benhida, Patrick Auberger, Anthony R Martin, Guillaume Robert.

  Myelodysplastic syndromes (MDS) are hematological disorders associated with bone marrow failure and abnormal hematopoietic cell growth, often progressing to acute myeloid leukemia (AML). Current treatments for AML and high-risk MDS are limited in efficacy, highlighting the need for new therapies. Recent studies show ferroptosis induction, alone or with standard chemotherapy, as a promising strategy for treating MDS/AML cells. Here, we report two novel compounds, HA344 and #231, that target both ferroptosis and apoptosis pathways to effectively eradicate MDS/AML cell lines and patient-derived bone-marrow blasts. RNASeq analysis reveals oxidative stress and apoptosis as key pathways activated by these compounds in different AML cell lines. In cellulo click-chemistry experiments coupled to mass spectrometry analysis identified glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1) as primary targets of both compounds, inhibiting GPX4 and TXNRD1 in the micromolar range. Mass spectrometry analysis confirms that HA344 and #231 covalently bind GPX4; with however a higher affinity for selenium-containing GPX4 (GPX4-Se) than for sulfur-containing GPX4 (GPX4-S). These findings design HA344 and #231 as potential therapeutic options for MDS/AML treatment.

Keywords:  Acute myeloid leukemia; Apoptosis; Covalent inhibitor; Ferroptosis; GPX4; TXNRD1; Targeted therapies

DOI:  https://doi.org/10.1186/s40164-026-00766-4
Haematologica. 2026 Apr 02.

Pharmacological blockade of rho kinase enhances venetoclax responses in translational models of acute myeloid leukemia.

Upendarrao Golla, Riya Bhalodia, Charyguly Annageldiyev, Satyam Patel, Vishnu Sravan Bollu, Su-Fern Tan, Myles C Cabot, David J Feith, Thomas P Loughran, Ross L Levine, Shin Mineishi, Hong Zheng, Kentaro Minagawa, Jeremy Hengst, Giselle L Saulnier Sholler, Dhimant Desai, Sinisa Dovat, Kelsey H Fisher-Wellman, David F Claxton, Arati Sharma.

Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy requiring concomitant targeting of critical cellular survival pathways due to resistance and frequent relapse with monotherapies. Venetoclax (VEN), a BCL-2 inhibitor, is one such promising clinical agent best utilized in combination therapies due to transient responses and acquired resistance. Given the involvement of the Rho/ROCK pathway in VEN activity, we combined Rho-associated coiled-coil-containing protein kinase inhibitors (ROCKi))with VEN to achieve superior antileukemic activity. The ROCKi (Fasudil, DJ4, GSK269962A) synergized with VEN to enhance cytotoxicity in both VEN-sensitive and VEN-resistant cell lines in vitro. Among the three ROCKi, GSK269962A (GSK) was best-tolerated in combination with VEN and effectively inhibited leukemia growth across multiple AML cell line-derived xenograft models in vivo. The GSK+VEN combination exhibited additive to synergistic cytotoxicity in primary AML patient cells ex vivo and enhanced antileukemic activity in a patientderived xenograft model. Additionally, the GSK+VEN combination significantly decreased the clonogenicity of primary AML cells, relatively sparing normal cells. Functional assays demonstrated enhanced apoptosis (Annexin V, caspase-3/7), elevated reactive oxygen species, and mitochondrial depolarization in both VENsensitive and VEN-resistant AML cells following combination treatment. Mechanistically, GSK augmented venetoclax responses by downregulating anti-apoptotic proteins (BCL2, MCL1) and inducing pro-apoptotic mediators (NOXA, MCL1 short isoforms), including in VEN-resistant AML cells. Together, these findings across multiple preclinical AML models demonstrate synergistic antileukemic activity and support combining VEN with ROCKi as a promising therapeutic strategy for AML.

DOI: https://doi.org/10.3324/haematol.2025.289041
bioRxiv. 2026 Mar 27. pii: 2026.03.24.712448. [Epub ahead of print]

Requirement for oxidation of neuronal ketone bodies in aging and neurodegeneration.

Joyce Yang, Mitsunori Nomura, Jonathan X Meng, Thelma Y Garcia, Timothy R Matsuura, Daniel P Kelly, Ken Nakamura, John C Newman.

Glucose is the brain's primary fuel, but the brain can also use alternative energy substrates, especially during development or starvation. Emerging evidence suggests ketone metabolism may help the brain adapt to energy stress in neurodegenerative diseases such as Alzheimer's disease, although its role in constitutive brain function in normal aging is poorly understood. Using iPSC-derived human neurons and adult-inducible, neuron-specific Bdh1 knockout mice, we show that ketone body metabolism is essential for maximum energy production, neuronal function, and mouse survival-even under normal nutritional conditions. Mechanistically, phenotypes of Bdh1 knockout neurons are mitigated by provision of acetoacetate, a downstream energy metabolite. Moreover, loss of neuronal ketone oxidation markedly increases mortality and memory deficits in Alzheimer's disease model mice. These findings identify ketones as critical neuronal fuels, with particular importance during neurodegeneration. While non-energetic activities of ketone bodies are increasingly appreciated, oxidation for energy provision is an essential mechanism for normal function in neurons and mice. Targeting the energetic function of ketones may thus offer new therapeutic strategies for both aging and neurodegenerative diseases such as Alzheimer's.

DOI: https://doi.org/10.64898/2026.03.24.712448
bioRxiv. 2026 Mar 26. pii: 2026.03.24.713976. [Epub ahead of print]

MLL3/4 methyltransferases regulate the differentiation of pluripotent stem cells via cellular respiration.

Suza Mohammad Nur, Yunbo Jia, Muyi Ye, Caylin A Lepak, Issam Ben-Sahra, Kaixiang Cao.

Enhancer-regulating epigenetic modifiers play critical roles in normal physiological processes and human pathogenesis. The major enhancer regulator paralogs MLL3 and MLL4 (MLL3/4) belong to the lysine methyltransferase 2 (KMT2) family, which catalyzes the methylation of lysine 4 on histone H3 (H3K4me). MLL3/4 are required for enhancer activation and are essential for mammalian development and stem cell differentiation. Recent studies have linked MLL3/4 with different metabolic pathways in the context of stem cell self-renewal and cancer cell growth; however, the underlying mechanisms remain elusive. Here, we utilize Seahorse extracellular flux analysis, stable isotope tracing, stem cell biology techniques, and transcriptomic analysis to investigate the functional relationship of MLL3/4, cellular respiration, and stem cell differentiation. Our results indicate that the loss of MLL3/4 impairs glycolytic activity and mitochondrial respiration in murine embryonic stem cells by downregulating the rate-limiting glycolytic enzyme Hexokinase 2 (HK2) and impairing the function of the Alpha-ketoglutarate dehydrogenase (OGDH) complex. Furthermore, simultaneously overexpression of HK2 and OGDH rescues defects in both cellular respiration and differentiation caused by MLL3/4 loss. Taken together, our study reveals a novel mechanism by which epigenetic machineries such as MLL3/4 govern the differentiation of pluripotent stem cells and facilitates the understanding of disease pathogenesis driven by enhancer malfunction.

DOI: https://doi.org/10.64898/2026.03.24.713976
Front Mol Biosci. 2026 ;13 1756657

Mitochondrial respiration in human peripheral blood mononuclear cells: methodology and influence of permeabilization and storage.

Shusuke Sekine, Imen Chamkha, Evelina Elmér, Eleonor Åsander Frostner, Emil Westerlund, Tianshi Liu, Johannes Ehinger, Fredrik Sjövall, Hiroyuki Uchino, Eskil Elmér.

  Human peripheral blood mononuclear cells (PBMCs) can be easily sampled from healthy individuals and patients. Density gradient isolation from human blood or leukocyte concentrates yields a mononuclear cell population of mainly lymphocytes, monocytes, and natural killer (NK) cells. PBMCs are vital circulating cells of the immune system and rely on oxidative phosphorylation (OXPHOS) for their energy production. OXPHOS capacity can be assessed using oxygraphy in intact and permeabilized PBMCs and has been used to investigate disorders of the immune system, but also, similarly to platelets, employed as a bioenergetic biomarker, that is, a "liquid biopsy" of disease conditions unrelated to immune dysregulation. Here, we present some key aspects of mitochondrial respiration in PBMCs isolated from leukocyte concentrates and whole blood using the Oroboros O2k oxygraph. We assessed the limits of sample amount and the impact of storage time and temperature and explored critical aspects of digitonin permeabilization. Furthermore, we provide respiratory rates and internal ratios from healthy controls using simple and comprehensive protocols for intact and permeabilized PBMCs, respectively. We conclude that detailed information on OXPHOS capacity in PBMCs can be reproducibly assessed ex vivo, but that great care must be taken during permeabilization to achieve correct measures of respiratory rates.

Keywords:  Oroboros; digitonin; electron transfer system; lymphocytes; peripheral blood mononuclear cells; permeabilization; respirometry; substrate–uncoupler–inhibitor titration protocol

DOI:  https://doi.org/10.3389/fmolb.2026.1756657
Cancer Med. 2026 Apr;15(4): e71780

PSAT1 Promotes NSCLC Progression via the De Novo Serine Synthesis Pathway and Represents a Therapeutic Vulnerability.

Xijia Zhou, Min Zhao, Yingshu Cao, Xiangyu Zhou, Ke Wang.

   BACKGROUND: Non-small cell lung cancer (NSCLC) is a malignant tumor characterized by high morbidity and mortality, as well as metabolic reprogramming. Enhanced serine synthesis plays a crucial role in the aberrant metabolism of NSCLC. Among the three key enzymes involved in serine synthesis, phosphoserine aminotransferase 1 (PSAT1) requires further investigation to elucidate its regulatory mechanisms in NSCLC.
METHODS: In this study, we employed bioinformatics analysis, immunohistochemistry, CCK-8 assay, colony formation assay, flow cytometry assay, isotope tracing technique, WB analysis, and nude mouse xenograft models to validate the expression and function of PSAT1 in NSCLC.
RESULTS: Our results demonstrated that PSAT1 was significantly upregulated in NSCLC cells and contributed to promoting cell proliferation, inhibiting apoptosis, and attenuating the efficacy of gefitinib treatment. Moreover, knockdown of PSAT1 led to inhibition of the de novo serine synthesis pathway (SSP), elevation of reactive oxygen species (ROS) levels, and activation of the mitochondrial apoptotic pathway. Notably, combined knockdown of PSAT1 with exogenous serine intake inhibition synergistically suppressed NSCLC progression.
CONCLUSION: Collectively, our findings highlight that PSAT1 serves as a biomarker for metabolic reprogramming in NSCLC and exhibits a close association with disease development and treatment.

Keywords:  PSAT1; ROS; apoptosis; de novo serine synthesis pathway; non‐small cell lung cancer

DOI:  https://doi.org/10.1002/cam4.71780
Biophys J. 2026 Apr 01. pii: S0006-3495(26)00234-1. [Epub ahead of print]

The scientific legacy of Martin Karplus from the perspective of his collaborators.

Ioan Andricioaei, Robert B Best, Robert R Birge, Stefan Boresch, Axel Brunger, Bernard R Brooks, Matthias Buck, Rafael Brüschweiler, Amedeo Caflisch, David A Case, Qiang Cui, Annick Dejaegere, Aaron R Dinner, Ron Elber, Jeffrey D Evanseck, Jiali Gao, Hong Guo, Roderick E Hubbard, John Kuriyan, Diane Joseph-McCarthy, Ronald M Levy, Lennart Nilsson, Carla Mattos, Alexander D MacKerell, J Andrew McCammon, Stephen W Michnick, Adrian Mulholland, Markus Meuwly, Richard W Pastor, Nathalie Reuter, Benoît Roux, Andrej Sali, Tamar Schlick, Jeremy C Smith, Roland H Stote, John E Straub, Antoine Taly, Arjan van der Vaart, Shunzhou Wan, Michael A Weiss, Wei Yang, Darrin M York, Yaoqi Zhou.

The work of Martin Karplus, who passed away on Dec 28 2024, was at the forefront of computational chemistry and molecular biophysics for a period of more than sixty years. His career started with a PhD in theoretical chemistry at Caltech with Linus Pauling in 1953 . After performing leading research in molecular quantum chemistry for two decades, in the 1970s he began to incorporate work on biological systems, and his work was instrumental in creating modern computational molecular biophysics. In 2013, he was awarded the Nobel Prize together with Arieh Warshel and Michael Levitt "for the development of multiscale models for complex chemical systems". This article aims at briefly reviewing the main achievements of the research performed in the Karplus lab from the point of view of the people working under his unique mentorship.

DOI: https://doi.org/10.1016/j.bpj.2026.03.050