bims-medica 2026-02-22 papers

Issue of 2026–02–22
fourteen papers selected by
Brett Chrest, Wake Forest University

Nat Metab. 2026 Feb 17.

Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.

Andrea Curtabbi, Sara Natalia Jaroszewicz, Rocío Sanz-Cortés, Rebeca Acín-Pérez, Dimitrios Prymidis, Maksym Cherevatenko, Raquel Martínez-de-Mena, María Jesús Esteban-Amo, Miguel A de la Fuente, Christian Frezza, José Antonio Enríquez.

Dihydroorotate dehydrogenase is a rate-limiting enzyme of de novo pyrimidine synthesis. In most eukaryotes, this enzyme is bound to the inner mitochondrial membrane, where it couples orotate synthesis to ubiquinone reduction. As ubiquinone must be regenerated by respiratory complex III, pyrimidine biosynthesis and cellular respiration are tightly coupled. Consequently, inhibition of respiration suppresses DNA synthesis and cell proliferation. Here we show that expression of the Saccharomyces cerevisiae URA1 gene (ScURA) in mammalian cells uncouples pyrimidine biosynthesis from mitochondrial electron transport. ScURA forms a homodimer in the cytosol that uses fumarate as an electron acceptor instead of ubiquinone, enabling respiration-independent pyrimidine biosynthesis. Cells expressing ScURA are resistant to drugs that inhibit complex III and the mitochondrial ribosome. Additionally, ScURA enables growth of mitochondrial-DNA-lacking ρ0 cells in uridine-deficient medium and ameliorates the phenotype of cellular models of mitochondrial diseases. Overall, this genetic tool uncovers the contribution of pyrimidine biosynthesis to the phenotypes arising from electron transport chain defects.

DOI: https://doi.org/10.1038/s42255-026-01454-7

Front Aging Neurosci. 2026 ;18 1689139

Changes in the brain [NAD+]/[NADH] and [NADPH]/[NADP+] with aging and anti-aging dietary restriction.

Leah E Jamerson, Tara D Bradshaw, Patrick C Bradshaw.

Changes in brain [NADPH]/[NADP+] and [NAD+]/[NADH] may contribute to aging. Anti-aging dietary restriction (DR) and intermittent fasting (IF) alter redox states that may contribute to their longevity effects. Pyruvate/lactate and acetoacetate/beta-hydroxybutyrate are indicators of the cytoplasmic and mitochondrial [NAD+]/[NADH], respectively, while the malate/pyruvate and isocitrate/alpha-ketoglutarate are indicators of the cytoplasmic [NADPH]/[NADP+]. Using these metabolite-pair ratios as redox indicators, the C57BL/6J mouse brain showed opposite redox changes with aging to the C57BL/6N mouse brain and human brain in the cytoplasmic [NAD+]/[NADH] and [NADPH]/[NADP+]. Fasting caused universal reductive shifts in the brain cytoplasmic [NAD+]/[NADH] and [NADPH]/[NADP+] and mitochondrial [NAD+]/[NADH]. The reductive shift in the cytoplasmic [NAD+]/[NADH] with fasting was opposite to that occurring with anti-aging ketone ester supplementation or ketogenic diet, which have been shown to cause an oxidative shift of the cytoplasmic [NAD+]/[NADH], but a reductive shift of the cerebral cortical cytoplasmic [NADPH]/[NADP+]. Several pathways that influence redox metabolism and aging are discussed, including fatty acid and cholesterol synthesis, the citric acid cycle, fatty acid beta-oxidation, glutaminolysis, the malate-aspartate shuttle, the glycerol-3-phosphate shuttle, the citrate-pyruvate shuttle, and the citrate-alpha-ketoglutarate shuttle. Brain proteome, brain single-cell RNA-Seq, and brain-region-specific bulk RNA-Seq data sets of aging and DR were examined, focusing on the pathways listed above to determine how they might contribute to the redox changes. Intermittent fasting has been shown to induce cyclic metabolic switching that contributes to neuroprotection and other health benefits resulting in delayed aging, while cyclic reductive redox shifts, especially in mitochondria, may be a driver of the beneficial effects.

Keywords: NAD+; NADPH; aging; astrocyte; brain; dietary restriction; fasting; redox

DOI: https://doi.org/10.3389/fnagi.2026.1689139

BioMed (Basel). 2026 Mar;pii: 7. [Epub ahead of print]6(1):

Fueling the Fire: How Glutamine Metabolism Sustains Leukemia Growth and Resistance.

Giovannino Silvestri.

Glutamine metabolism has emerged as one of the most critical bioenergetic and biosynthetic programs sustaining leukemic cell growth, survival, stemness and therapeutic resistance. In both acute and chronic leukemias, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), malignant cells display a strong dependency on extracellular glutamine to support mitochondrial respiration, anabolic biosynthesis and redox homeostasis. This dependency is reinforced by oncogenic signaling networks, post-transcriptional metabolic regulation and microenvironmental adaptation within the bone marrow niche. Therapeutic strategies targeting glutamine utilization, including glutaminase inhibition, transporter blockade and enzymatic glutamine depletion, have demonstrated robust antileukemic activity in preclinical models, and early clinical efforts have begun to explore glutamine-directed interventions in myeloid neoplasms. However, metabolic plasticity, microenvironment-derived nutrient buffering and systemic toxicity remain significant limitations to clinical translation. This review provides a detailed synthesis of the biochemical framework of glutamine metabolism in leukemia, the molecular mechanisms enforcing glutamine addiction, the downstream functional consequences on proliferation, redox balance and leukemic stem cell biology, the current landscape of therapeutic strategies and emerging directions aimed at overcoming resistance and improving clinical efficacy.

Keywords: FLT3-ITD; IGF2BP2; SLC1A5; acute myeloid leukemia (AML); cancer metabolism; glutaminase inhibition; glutamine addiction; glutamine metabolism; leukemia; leukemic stem cells; metabolic targeting; redox balance; therapeutic resistance

DOI: https://doi.org/10.3390/biomed6010007

Annu Rev Anal Chem (Palo Alto Calif). 2026 Feb 17.

A Stable Isotope Tracing Primer for the Mass Spectrometrist.

Ashley Solmonson, Brandon Faubert, Thomas P Mathews.

Metabolic function plays a key role in our understanding of both biological and pathophysiological processes. Metabolism is a complex combination of intrinsic processes and environmental cues across a heterogeneous mix of cell types. To investigate metabolism, stable isotope tracing is a versatile approach to assess metabolism across scales, including in cultured cells, animal models, and humans. From the first tracing studies over a century ago, the development and utility of these studies have gone hand-in-hand with technological advances in detecting these labeled atoms, particularly with mass spectrometry. In this review, we describe the instrumentation used to measure isotopically labeled metabolites and approaches to analyze and interpret stable isotope tracing data, and discuss current challenges and opportunities for discovery with these methods.

DOI: https://doi.org/10.1146/annurev-anchem-080524-014717

Sci Rep. 2026 Feb 19.

Ketogenic diet sex-dependent effects on rat bone marrow cells during development and β-HB protection in hypoglycemia.

Karolina Truchan, Bartosz Ilnicki, Zuzanna Setkowicz, Anna Maria Osyczka.

The ketogenic diet (KD) is a high-fat, moderate-protein, and low-carbohydrate diet. Initially prescribed for drug-resistant epilepsy, KD has become popular for weight reduction in patients with diabetes and obesity, who are often affected by reduced bone mass. However, KD's impact on bone marrow cells remains largely unexplored. Here, we show the effects of low protein KD on bone marrow cells (BMCs) during pregnancy, lactation, and postnatal development in 30-day-old Wistar rat offspring. KD consumption in female juvenile rat offspring supported BMC osteogenic differentiation and inhibited osteoclast activity, while in male rat BMCs it reduced bone regenerative potential. This was observed despite a strongly reduced body weight in both sexes. The addition of the primary ketone body β-hydroxybutyrate (β-HB) to juvenile and adult rat BMC cultures in a low glucose culture medium effectively promoted extracellular matrix mineralization and proliferation of rat BMCs and reversed the negative impact of low glucose on BMC viability, inflammation, and osteoclast activity. Given the above, we recommend considering the potential sex differences when implementing restrictive diets and their consequences during pregnancy. Our results also highlight the distinct effects of low glucose and β-HB on the osteogenesis of juvenile and adult rat BMCs, which suggests caution in considering short-term KD or fasting for bone-related therapies.

Keywords: Bone marrow cells; Ketogenic diet; Osteogenesis; Pregnancy; Sex-dependent differences

DOI: https://doi.org/10.1038/s41598-026-40169-3

Exp Hematol. 2026 Feb 13. pii: S0301-472X(26)00034-2. [Epub ahead of print] 105401

Heme Synthesis Inhibition Induces the Intrinsic Apoptosis Pathway in Leukemia with OSGIN1 Upregulation.

Yan Yan, Hiroki Kato, Sayaka Sano, Eijiro Furukawa, Satoshi Ichikawa, Koichi Onodera, Yasushi Onishi, Noriko Fukuhara, Hisayuki Yokoyama, Tohru Fujiwara, Hideo Harigae.

Acute myeloid leukemia (AML) is one of the hematological malignancies with a poor outcome. AML has a unique metabolic status, and identifying its metabolic vulnerabilities is warranted. Recent genome-wide screenings suggest that heme synthesis might be such a vulnerability. Heme is required not only for hemoglobin synthesis but also for the proper function of hemoproteins. Cytochromes are such hemoproteins and are necessary for mitochondrial respiration. Therefore, heme synthesis inhibition can diminish AML by altering mitochondrial status and function. However, still little is known about the importance of heme synthesis in leukemia cells. To reveal the roles of heme synthesis in leukemia, we treated human leukemia cell lines with heme synthesis inhibitors, succinylacetone (SA) or N-methyl Protoporphyrin IX (NMPP). Heme synthesis inhibition induced cell growth inhibition and cell death in a concentration-dependent manner. Therefore, heme synthesis is required for leukemia cell proliferation and survival. Increased pro-apoptotic factors (cleaved caspase 3 and cleaved PARP) and decreased anti-apoptotic factor (XIAP) were observed following heme synthesis inhibition. Cytochrome c and Smac were released into the cytoplasm by heme synthesis inhibition, suggesting that heme synthesis inhibition led to mitochondrial outer membrane permeabilization and activation of the intrinsic pathway of apoptosis. Comprehensive transcriptomic analysis revealed that heme synthesis inhibition induced OSGIN1 expression, leading to the release of cytochrome c and Smac from mitochondria into the cytoplasm. Therefore, heme synthesis inhibition induced leukemia apoptosis by activating the intrinsic apoptosis pathway.

Keywords: OSGIN1; heme; intrinsic apoptosis pathway; leukemia

DOI: https://doi.org/10.1016/j.exphem.2026.105401

FEBS J. 2026 Feb 18.

The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes.

Michaela Veliova, Caroline M Ferreira, Katrina P Montales, Francisco Villalobos, Alexandra J Brownstein, Rebeca Acín-Pérez, Gabrielly S Ferreira, Anthony E Jones, Linsey Stiles, Ajit S Divakaruni, Marc Liesa, Orian S Shirihai, Marcus F Oliveira.

Brown adipose tissue (BAT) plays a central role in thermogenesis by coupling fatty acid oxidation to heat production. Efficient BAT thermogenic activity requires enhanced glycolytic flux, which in turn depends on continuous regeneration of cytosolic NAD+ to sustain glyceraldehyde-3-phosphate dehydrogenase activity. This regeneration is mediated by three main pathways: lactate dehydrogenase, the glycerol-3-phosphate shuttle (GPSh), and the malate-aspartate shuttle (MASh). We previously showed that inhibition of the mitochondrial pyruvate carrier increases energy expenditure in brown adipocytes via MASh activation. However, the specific contribution of MASh to BAT energy metabolism remains poorly defined. Here, we show that MASh is functional and directly regulates lipid metabolism in BAT. Enzymatic activities of cytosolic and mitochondrial malate dehydrogenases and glutamic-oxaloacetic transaminases in BAT were comparable to those in the liver. Using a reconstituted system of isolated BAT mitochondria and cytosolic MASh enzymes, we demonstrated that extra-mitochondrial NADH is efficiently reoxidized in a glutamate-dependent manner via MASh. Genetic silencing of the mitochondrial carriers critical to MASh, namely the oxoglutarate carrier (Ogc) and aspartate-glutamate carrier (Aralar1), had no apparent effects on respiratory rates. However, silencing either Ogc or Aralar1 led to the accumulation of small lipid droplets and impaired norepinephrine-induced lipolysis. Taken together, our data indicate a novel role of MASh in regulating BAT lipid homeostasis with potential implications to body energy expenditure and thermogenesis.

Keywords: energy; heat; metabolism; obesity; redox; thermogenesis

DOI: https://doi.org/10.1111/febs.70461

Nat Metab. 2026 Feb 16.

A genetically encoded bifunctional enzyme mitigates redox imbalance and lipotoxicity.

Xingxiu Pan, Subrata Munan, Austin L Zuckerman, Andrew Pon, Niklas B Thompson, Rasangi M Perera, Nirajan Shrestha, Sara Violante, Justin R Cross, Russell P Goodman, Hardik Shah, Valentin Cracan.

Dihydroxyacetone phosphate (DHAP), glycerol-3-phosphate (Gro3P) and reduced/oxidized nicotinamide adenine dinucleotide (NADH/NAD⁺) are key metabolites of the Gro3P shuttle, which transfers reducing equivalents between the cytosol and mitochondria. Targeted activation of Gro3P biosynthesis has recently emerged as a promising strategy to alleviate reductive stress. However, because Gro3P constitutes the backbone of triglycerides, its accumulation can promote extensive lipogenesis. Here we show that a genetically encoded tool based on a di-domain glycerol-3-phosphate dehydrogenase from the alga Chlamydomonas reinhardtii (CrGPDH) effectively operates both the alternative Gro3P shunt, which regenerates NAD⁺ while converting DHAP to Gro3P, and the glycerol shunt, which converts Gro3P to glycerol and inorganic phosphate, across transformed and primary mammalian cell cultures as well as mouse liver. CrGPDH expression supported proliferation of cancer cells under respiratory chain inhibition or hypoxia, as well as patient-derived fibroblasts with mitochondrial dysfunction. Moreover, CrGPDH decreased triglyceride levels in kidney cancer cell lines and reversed ethanol-induced triglyceride accumulation in mouse liver. Thus, CrGPDH represents a promising xenotopic tool to alleviate redox imbalance and associated impaired lipogenesis in conditions ranging from primary mitochondrial diseases to steatosis.

DOI: https://doi.org/10.1038/s42255-025-01450-3

Cochrane Database Syst Rev. 2026 Feb 16. 2 CD015610

Intermittent fasting for adults with overweight or obesity.

Luis I Garegnani, Gisela Oltra, Diego Ivaldi, Mariana Andrea Burgos, Paola J Andrenacci, Sabrina Rico, Melinda Boyd, Diane Radler, Camila Micaela Escobar Liquitay, Eva Madrid.

RATIONALE: Weight loss remains the primary strategy for reducing health risks and societal consequences associated with overweight and obesity. The most common dietary interventions are calorie-restricted diets, including various permutations of energy restriction, macronutrients, foods, and dietary intake patterns, which achieve initial but often unsustained weight loss. Intermittent fasting involves eating patterns during which individuals take little or no energy for extended time periods, alternated with periods of normal food intake. The mechanism for weight loss is related to caloric restriction, increased fat metabolism, enhanced insulin sensitivity, and improved glucose metabolism. Intermittent fasting has been publicised in blogs and news articles but studies show inconsistent effects on health, highlighting the uncertainty faced by physicians and people with overweight or obesity when considering intermittent fasting as a feasible approach for sustained weight loss.
OBJECTIVES: To evaluate the benefits and harms of intermittent fasting versus regular dietary advice, no intervention or waiting list for adults with overweight or obesity.
SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), and two trials registers up to 5 November 2024, as well as reference checking, citation searching and contact with study authors to identify additional studies.
ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) and cluster-RCTs that compared intermittent fasting (including time-restricted feeding, periodic fasting, alternate-day fasting, and modified alternate-day fasting) with regular dietary advice, no intervention or waiting list in men and women with overweight or obesity, with or without associated comorbid conditions. The minimum duration of the intervention was four weeks, and the minimum duration of follow-up was six months. We excluded cross-over and quasi-RCTs.
OUTCOMES: Our outcomes were weight loss, quality of life, participant satisfaction, diabetes status, and adverse events. We considered outcomes measured up to and including 12 months after randomisation as short-term, and longer than 12 months as long-term.
RISK OF BIAS: We used the Cochrane risk of bias tool (RoB 2) and the RoB2 extension for cluster-RCTs.
SYNTHESIS METHODS: We synthesised results for each outcome using meta-analysis where possible, using random-effects models to calculate risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and mean differences (MD) or standardised mean differences (SMD) for continuous outcomes. Where this was not possible due to the nature of the data, we would have synthesised results using narrative synthesis, including the summary of effect estimates. We used GRADE to assess the certainty of evidence for each outcome.
INCLUDED STUDIES: We included 22 studies with 1995 participants. All studies were conducted in an outpatient setting in North America, Australia, China, Denmark, Germany, Norway, and Brazil and were published between 2016 and 2024.
SYNTHESIS OF RESULTS: Compared to regular dietary advice, intermittent fasting may result in little to no difference in percentage from baseline weight loss (MD -0.33, 95% CI -0.92 to 0.26; 21 studies, 1430 participants; low-certainty evidence due to risk of bias). Intermittent fasting may have little to no effect on achieving a 5% reduction in body weight, but the evidence is very uncertain (RR 0.98, 95% CI 0.82 to 1.18; 4 studies, 472 participants; very low-certainty evidence due to risk of bias and imprecision). Intermittent fasting may result in little to no difference in quality of life (SMD 0.11, 95% CI -0.27 to 0.49; 3 studies, 106 participants; low-certainty evidence due to risk of bias and imprecision). Intermittent fasting may have little to no effect on adverse events but the evidence is very uncertain (RR 1.45, 95% CI 0.64 to 3.28; 7 studies, 619 participants; very low-certainty evidence due to risk of bias, inconsistency and imprecision). Compared to no intervention or waiting list, intermittent fasting likely results in little to no difference in percentage weight loss from baseline (MD -3.42, 95% CI -4.95 to -1.90; 6 studies, 427 participants; moderate-certainty evidence due to risk of bias). Intermittent fasting may result in little to no difference in quality of life, but the evidence is very uncertain (MD 3.49, 95% CI -49.35 to 56.33, 1 study, 60 participants; very low-certainty evidence due to extreme concerns about imprecision). Intermittent fasting may result in little to no difference in adverse events, but the evidence is very uncertain (RR 1.84, 95% CI 0.88 to 3.85; 2 studies, 189 participants; very low-certainty evidence due to risk of bias and imprecision). None of the included studies reported participant satisfaction, diabetes status or overall measure of comorbidity.
AUTHORS' CONCLUSIONS: Compared to regular dietary advice, intermittent fasting may result in little to no difference in weight loss or quality of life. Intermittent fasting may result in little to no difference in adverse events, but the evidence is very uncertain. These approaches did not differ in achieving weight loss, producing no clinically meaningful changes in most of the outcomes considered in this review. Compared to no intervention or waiting list, intermittent fasting likely results in little to no difference in weight loss and may result in little to no difference in quality of life or adverse events, but the evidence is very uncertain. Physicians and patients may need to evaluate willingness and readiness to implement intermittent fasting as a treatment strategy, based on individual practicality and sustainability. The included studies focused on short-term effects of the intervention (up to 12 months), limiting the applicability of the evidence in this review to inform decision-making for longer durations. It would be beneficial for future studies to extend follow-up periods beyond 12 months to build a stronger evidence base for the long-term effects. Further research is needed to address the effect of intermittent fasting on several outcomes, including participant satisfaction, diabetes status and overall measures of comorbidities. These studies must consider different populations where obesity and overweight have different burdens, like those from low- and middle-income countries and high-income countries, men or women separately, and different body mass index categories.
FUNDING: This Cochrane review had no dedicated funding.
REGISTRATION: Protocol (2023): doi.org/10.1002/14651858.CD015610.

DOI: https://doi.org/10.1002/14651858.CD015610.pub2

Leukemia. 2026 Feb 17.

A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with a poor prognosis. Venetoclax (Ven), a BCL2 inhibitor, has shown promising results but often leads to relapse due to mitochondrial dysregulation, particularly due to upregulation of the anti-apoptotic protein MCL1. Overexpression of the transcription factor STAT3 has been linked to poor survival in AML patients. Overexpression of STAT3 in a transgenic murine model induces a myeloid malignancy with a short latency period and inflammatory upregulation. The current study identifies STAT3 upregulation as a key mechanism of Ven resistance. A clinically relevant STAT3 degrader effectively reduces both total and phosphorylated STAT3, corrects mitochondrial structural and functional dysregulation, and induces apoptosis in Ven-resistant AML cell lines. KT-333 significantly decreases STAT3 and MCL1 protein levels and improves survival in Ven-resistant (Ven-Res) AML murine models. In summary, STAT3 hyperactivation is leukemogenic, is further potentiated in Ven-resistance and can be clinically targeted with a novel and specific STAT3 degrader. Pictorial representation depicting upregulation of STAT3 and MCL1 in venetoclax resistant myeloid malignancies such as MDS and AML causing mitochondrial structural abnormalities and dysfunction. By using specific STAT3 degrader, STAT3 inhibition, and thereby indirect downregulation of MCL1 can be a promising therapeutic intervention to target drug resistant clones in MDS and AML.

DOI: https://doi.org/10.1038/s41375-026-02883-9

Front Cell Dev Biol. 2026 ;14 1712076

Branched-chain amino acid transaminases as promising targets in tumor therapy.

Weiran Zhang, Jie Shen, Xuanyin Ding, Hele Liu, Xu Wang, Dan Feng.

Branched-chain amino acid transaminases (BCATs), including BCAT1 and BCAT2, play pivotal roles in tumorigenesis and therapeutic resistance in various cancers. These enzymes regulate branched-chain amino acid (BCAA) metabolism and influence critical oncogenic pathways such as mTOR, PI3K/AKT, and Wnt/β-catenin signalling. Furthermore, BCATs contribute to metabolic reprogramming, epigenetic modifications, and immune evasion. Collectively, they promote tumor proliferation, invasion, and metastasis, thus making BCATs potential biomarkers and therapeutic targets. Recent studies highlight their aberrant expression in cancers including gastric cancer, pancreatic cancer, non-small cell lung cancer, leukaemia, gliomas, and breast cancer, where they contribute to resistance to chemotherapy, targeted therapy, and endocrine therapy. Strategies targeting BCATs, including enzyme inhibitors, dietary BCAA restriction, and combination therapies, have shown the potential to overcome drug resistance and improve treatment outcomes. This review synthesizes current knowledge on the mechanisms of BCATs in cancer progression and resistance, providing a foundation for future research and clinical applications.

Keywords: biomarker; branched-chain amino acid transaminases; drug resistance; oncogenic pathway; tumor metabolism

DOI: https://doi.org/10.3389/fcell.2026.1712076

Cell Death Differ. 2026 Feb 19.

What does BCL-2 do? From new molecular insights to the clinical implications.

Carlo M Croce, Stephen W G Tait, Ana J Garcia-Sáez, Andreas Villunger, Anthony Letai, Harriet S Walter, Martin J S Dyer, Douglas R Green, Yufang Shi, Gerry Melino.

It took decades from the discovery of BCL-2, initially identified in chromosomal translocations associated with lymphoid malignancies, to understand how BCL-2 and its family members regulate apoptosis, launching a transformative journey in cancer biology often called "the road to ruin". Developing powerful BCL-2 inhibitors for clinical use required decades. Yet, this remains as one of the most successful achievements in a field that started ~40 years ago, as recounted by its pioneers. BCL-2 was later found to inhibit apoptosis by preventing mitochondrial outer membrane permeabilization (MOMP), a breakthrough that clarified its role in cancer pathogenesis. Such effects of BCL-2 on MOMP prevent cytochrome c release and caspase activation, while its family members-anti-apoptotic proteins (e.g. BCL-2, BCL-XL) and pro-apoptotic proteins (e.g. BAX, BAK, BH3-only proteins)-orchestrate a delicate balance in cell death regulation. MicroRNAs like miR-15/16, often deleted in chronic lymphocytic leukaemia (CLL), modulate BCL-2 expression, driving oncogenesis. Mechanistically, BAX/BAK oligomerization forms mitochondrial pores, with sublethal MOMP triggering inflammation via cGAS-STING and NF-κB pathways. Alternative MOMP inducers (e.g. BOK) and mitochondrial dynamics further refine apoptotic control. Clinically, the BCL-2 inhibitor venetoclax has revolutionized CLL and acute myeloid leukemia (AML) treatment, showing efficacy in TP53-mutant CLL and elderly AML patients when combined with CD20 antibodies or hypomethylating agents. However, resistance, driven by BCL-2 mutations (e.g. Gly101Val) or MCL-1 upregulation, poses challenges. Limited success in solid tumors underscores the complexity of BCL-2 family dependencies. Future directions include novel inhibitors targeting MCL-1 or BCL-XL, BH3 profiling for precision therapy, and combinations with immune or DNA repair modulators. Non-apoptotic roles of BCL-2 in metabolism also warrant exploration. This review highlights the clinical success of BCL-2 inhibitors, addresses resistance mechanisms, and explores future directions, including sublethal MOMP, inflammatory outcomes, and novel inhibitors. Celebrating the collaborative, interdisciplinary efforts that transformed fundamental discoveries into life-saving therapies, this account underscores both the triumphs and the "potholes" encountered on the path to understanding apoptosis, while identifying open questions for ongoing research.

DOI: https://doi.org/10.1038/s41418-025-01607-3

FEBS J. 2026 Feb 18.

Current perspectives on KMT2A fusion proteins and menin inhibition in paediatric acute myeloid leukaemia.

Lydia Elaine Roets, Graeme Greenfield, Katrina Mairead Lappin.

The therapeutic landscape of acute myeloid leukaemia (AML) has evolved beyond the classic '7 + 3'/DA regimen, through the approval and incorporation of targeted treatments in both front-line and relapsed/refractory settings. Indeed, the use of selective BCL-2 antagonists (e.g. venetoclax) and FLT3 inhibitors (e.g. midostaurin, gilteritinib) which target specific molecular characteristics of leukaemic cells, has enhanced outcomes and survival rates. Arguably one of the most exciting advancements has been the clinical development of menin inhibitors for the treatment of patients harbouring specific genetic aberrations. These abnormalities include rearrangements of the lysine methyltransferase 2A (KMT2A) gene, and they occur in approximately one fifth of childhood/paediatric (i.e. infant, adolescent and young adult) AML patients. Spurred on by the recent FDA approval of revumenib, menin inhibitors hold the potential to further shift the treatment paradigm for this patient population. Here, we aim to provide a comprehensive overview of the pathogenesis of KMT2A rearrangements, with a focus on KMT2A fusion genes and proteins within paediatric AML patients. Additionally, we summarise the challenges arising from resistance to menin inhibitors, and we touch on the potential of combination therapies to expand the efficacy of menin inhibition and mitigate some of the resistance mechanisms employed by leukaemic clones.

Keywords: KMT2A fusion proteins; KMT2A rearrangements; acute myeloid leukaemia; childhood AML; paediatric AML

DOI: https://doi.org/10.1111/febs.70460

Cell Rep. 2026 Feb 18. pii: S2211-1247(26)00088-4. [Epub ahead of print]45(3): 117010

ACSL4-associated lipid metabolism is a distinct therapeutic vulnerability in KMT2A-rearranged acute myeloid leukemia.

Silvia Schäfer, Elahe Rahimian, Lola Schmitz-Hübsch, Mehak Shaikh, Silke Brilloff, Vida Kufrin, Sandra Küchler, Maria Fedorova, Natalie Kusebauch, Zhixu Ni, Dominic Helm, Irmela Jeremias, Denis M Schewe, Claudia R Ball, Martin Bornhäuser, Hanno Glimm, Meritxell Alberich-Jorda, Marius Bill, Alexander A Wurm.

Deregulated lipid metabolism contributes to leukemogenesis and the progression of acute myeloid leukemia (AML). By analyzing large-scale CRISPR-Cas9 screening data, we identified acyl-CoA synthetase long-chain family member 4 (ACSL4) as a selective vulnerability in lysine methyltransferase 2A-rearranged (KMT2Ar) AML. Functional validation using CRISPR interference and short hairpin RNA knockdown confirmed that ACSL4 loss impairs the growth of KMT2Ar but not non-KMT2Ar AML cells. ACSL4 knockdown reduced colony formation in cells derived from patients with KMT2Ar AML and murine MLL-AF9 cells and delayed leukemia onset in vivo in MLL-AF9 mice. A multi-omics approach, including transcriptomics, proteomics, and lipidomics, revealed depletion of polyunsaturated lipid species and compensatory activation of lipid metabolic pathways upon ACSL4 loss. Supplementation with exogenous polyunsaturated fatty acids (PUFAs) rescued the growth defect, linking ACSL4 dependency to defective PUFA utilization. Finally, we generated a KMT2Ar-ACSL4 dependency signature (KRADS12) that correlates with KMT2Ar status and predicts poor survival in patients with AML.

Keywords: CP: cancer; CP: metabolism; acute myeloid leukemia; chromosomal rearrangements; lipid metabolism

DOI: https://doi.org/10.1016/j.celrep.2026.117010