bims-medica 2026-10-18 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–10–18
fifteen papers selected by
Brett Chrest, Wake Forest University

GLS2 reshapes glycolytic metabolism and bioenergetic homeostasis in glioblastoma cells.
Pharmacologically Targeting DHODH-Dependent Pyrimidine Metabolism with HSA-Conjugated BRQ Suppresses Leukemogenesis.
Dynamic protein phosphorylation shapes mitochondrial catalysis, import, and architecture.
MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss.
Genetic modulation of NAD(P)H homeostasis reveals distinct redox-coupled metabolic vulnerabilities.
Mitochondrial Supercomplex-Associated Proximity Increases in Malignant Glioma Tissue.
Substrate-bound structures of yeast ALA synthase reveal protein dynamics initiating heme biosynthesis.
Regulation of PDH via cysteine oxidation on DLAT.
Quantification of Mitochondrial Oxidative Phosphorylation in Skeletal Muscle.
Metabolic links between mitochondrial electron transport, glycolysis, and AMP-activated protein kinase signaling modulate hepatocellular carcinoma cell survival.
Warburg redefined: Metabolites, mitochondria and macrophages in immune regulation.
Common questions and misconceptions about diets: what does the scientific evidence really show?
Time-restricted feeding with resistance training is not superior to conventional feeding for body composition and muscle strength: a systematic review and meta-analysis.
A health-system-scale, episode-resolved multimodal atlas of cancer cachexia.
Research progress on ATP-citrate lyase and its inhibitors: a metabolic-epigenetic perspective.

Pharmacol Rep. 2026 Oct 14.

GLS2 reshapes glycolytic metabolism and bioenergetic homeostasis in glioblastoma cells.

Juan De Los Santos-Jiménez, José A Campos-Sandoval, Jessica Sudderth, Lauren G Zacharias, João Santos Patricio, Francisco J Alonso, Javier Márquez, Thomas P Mathews, Ralph J DeBerardinis, José M Matés.

   BACKGROUND: Glioblastoma (GBM) exhibits extensive metabolic reprogramming, including glucose and glutamine (Gln) addiction, with Gln being converted into glutamate by glutaminase, encoded by the GLS and GLS2 genes. GLS2 acts as a context-dependent tumor suppressor, although the underlying mechanisms remain poorly understood. GLS2 is silenced in GBM, and we previously showed that its re-expression modulates pyruvate dehydrogenase (PDH) activity and tricarboxylic acid cycle (TCAC) metabolism, suggesting a distinct metabolic rewiring associated with its tumor-suppressive function.
METHODS: LN229 and T98G GBM cell lines were used as experimental models. Metabolomic profiling by liquid chromatography-mass spectrometry was performed to compare changes in central metabolic pathways following GLS2 or GLS overexpression. Glutaminase and PDH enzymatic activities were measured, and Western blotting was performed to assess GLS, GLS2, and PDHA1 protein levels and PDHA1 phosphorylation. A Seahorse analyzer was employed to quantify real-time ATP production derived from glycolysis and oxidative phosphorylation.
RESULTS: Overexpression of GLS2, but not GLS, in LN229 cells caused the accumulation of TCAC-related metabolites, except for citrate, whose depletion is attributed to GLS2's effect on PDH phosphorylation, causing reduced PDH activity. This was accompanied by decreased levels of several acyl-carnitines. Furthermore, GLS2 induced the accumulation of glucose/fructose, while reducing levels of glucose-6-phosphate and pentose-phosphates, consistent with altered glycolysis. GLS2 also diminished the ATP/AMP ratio, confirmed by a reduced ATP synthesis rate, particularly glycolytic ATP, whereas mitochondrial ATP production remained unaltered.
CONCLUSIONS: GLS2 exerts an isoenzyme-specific effect on Gln and glucose metabolism in GBM, likely modulating the glycolysis/pentose-phosphate pathway (PPP)-TCAC-axis.

Keywords:  Cancer metabolism; GLS2; Glioblastoma; Glutaminase; Glutamine; Pyruvate dehydrogenase

DOI:  https://doi.org/10.1007/s43440-026-00908-9
Cancers (Basel). 2026 Sep 23. pii: 3091. [Epub ahead of print]18(19):

Pharmacologically Targeting DHODH-Dependent Pyrimidine Metabolism with HSA-Conjugated BRQ Suppresses Leukemogenesis.

Xiaoxu Zhang, Changhao Tian, Yang Ding, Lei Dong, Jia Yu, Rui Su, Min Gao.

  Background: Metabolic reprogramming is a hallmark of acute myeloid leukemia (AML) and provides a rich source of therapeutic vulnerabilities. Among these, de novo pyrimidine biosynthesis has emerged as an important metabolic dependency, yet its contribution to AML progression remains incompletely defined. DHODH, a rate-limiting enzyme in this pathway, represents a promising therapeutic target; however, the clinical development of DHODH inhibitors has been constrained by limited efficacy and dose-limiting toxicity. Thus, defining the mechanistic role of DHODH in AML and developing strategies to improve the therapeutic index of DHODH inhibition remain important unmet needs. Methods: The Cancer Dependency Map (DepMap) database was utilized to identify AML-essential genes that were preferentially required for AML cell survival. Gene set enrichment analysis (GSEA) was used to characterize metabolic dependencies and identify candidate targets. The functional role of DHODH was subsequently evaluated by using genetic knockout in AML cell lines and patient-derived xenograft (PDX) cells. NSGS mice were used in the "human-in-mouse" xenograft mice model. Metabolic profiling coupled with 13C isotope tracing was performed to define DHODH-dependent metabolic alterations, while RNA-seq and genetic rescue assays were used to investigate the mechanisms underlying DHODH-mediated leukemogenesis and ferroptosis. Pharmacologically, we evaluated the DHODH inhibitor BRQ and developed an HSA-based BRQ delivery strategy to improve therapeutic efficacy and reduce systemic toxicity. Results: Our study identified DHODH as a critical vulnerability in AML. DHODH knockout (KO) significantly suppressed AML cell growth, induced apoptosis in vitro, and markedly inhibited AML progression in vivo, supporting a crucial role of DHODH in leukemogenesis. Metabolic profiling further confirmed the dependence of AML cells on DHODH-mediated de novo pyrimidine biosynthesis for leukemic progression. RNA-seq revealed marked activation of the ferroptosis pathway following DHODH KO, with HMOX1 identified as a functionally essential target of DHODH depletion-induced ferroptosis. Pharmacologically, the DHODH inhibitor BRQ phenocopied the antileukemia effects of genetic DHODH depletion both in vitro and in vivo. Of note, we have developed an HSA-based delivery strategy aimed at improving therapeutic efficacy while reducing systemic toxicity. Targeting DHODH, particularly with HSA-conjugated BRQ, represents a promising therapeutic strategy for AML.

Keywords:  PHGDH; acute myeloid leukemia (AML); ferroptosis; human serum albumin (HSA) conjugation; metabolism; therapeutic target

DOI:  https://doi.org/10.3390/cancers18193091
bioRxiv. 2026 Sep 29. pii: 2026.09.28.755151. [Epub ahead of print]

Dynamic protein phosphorylation shapes mitochondrial catalysis, import, and architecture.

Andrew J Smith, Patrick Forny, Sean W Rogers, Merima Forny, David J Pagliarini.

Phosphorylation is a pervasive mitochondrial protein post-translational modification, yet the extent of its influence over mitochondrial functions remains unclear. To identify dynamic mitochondrial phosphoisoforms, we profiled the phosphoproteome of AML12 cells following individual genetic perturbations of 10 resident mitochondrial phosphatases. Guided by these results, we investigated the functional implications of phosphorylation on mitochondrial processes related to catalysis, import, and morphology. We find that phosphorylation of adenylate kinase 2 suppresses its nucleotide binding and catalytic activity. Elevated phosphorylation proximal to the mitochondrial targeting sequence of branched chain ketoacid dehydrogenase kinase disrupts its import and processing, resulting in enhanced catabolism of branched chain amino acids. Most notably, we discover extensive phosphorylation on proteins involved in mitochondrial cristae architecture, including multiple members of the MICOS complex and ATP synthase, upon silencing the phosphatase PGAM5. Collectively, our work connects reversible phosphorylation and resident phosphatases to the regulation of diverse mitochondrial processes.
HIGHLIGHTS: Perturbation of 10 mitochondrial resident phosphatases maps dynamic phosphosites.AK2 S151 phosphorylation tunes catalysis by augmenting adenine nucleotide binding.MTS-proximal BCKDK phosphorylation impairs protein import and gates BCAA catabolism.MIC19 and ATP5I phosphorylation remodels cristae and modulates bioenergetics.

DOI: https://doi.org/10.64898/2026.09.28.755151
bioRxiv. 2026 Sep 28. pii: 2026.09.22.753556. [Epub ahead of print]

MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss.

Shuke Xiao, Alan Sheng-Hwa Tung, Jan Spaas, Sipei Fu, Xudong Chen, Tuan Kiet Trinh, Maria Dolores Moya-Garzon, Veronica L Li, Hannah T Cessna, Kentaro Ito, Saranya C Reghupathy, Chao Lin, Xuchao Lyu, Steffen H Raun, Miles D W Tyner, Arthur Germakovski, Jacob Tondreau, Megan Yeckley, Wei Wei, Michael R Howitt, Mark D Parker, Jason A Sprowl, Stephen M Hinshaw, Jonathan Z Long.

Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite Lac-Phe as a tractable system, we identify the orphan transporter MCT6 (SLC16A5) as a physiologic intestinal Lac-Phe exporter. This mechanism controls the extent to which intracellularly synthesized Lac-Phe acquires systemic activity. MCT6 transports Lac-Phe, mediates its cellular efflux, and is required for maintaining its blood levels in mice following strong glycolytic stimuli. Both global and intestinal epithelial-specific deletion of MCT6 confers resistance to metformin-associated weight loss on a high-fat diet. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-KO mice. Together, these data connect MCT6 to metformin pharmacology and intestinal lactate metabolism, and more generally underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.

DOI: https://doi.org/10.64898/2026.09.22.753556
Nat Metab. 2026 Oct 14.

Genetic modulation of NAD(P)H homeostasis reveals distinct redox-coupled metabolic vulnerabilities.

Xingxiu Pan, Austin L Zuckerman, Karl N Miller, Marcos G Teneche, Subrata Munan, Andrew Pon, Niklas B Thompson, Rasangi M Perera, Roya AminiTabrizi, Adarsh Rajesh, Sara Violante, Jiwu Wang, Justin R Cross, Peter D Adams, Hardik Shah, Valentin Cracan.

An elevated NADH/NAD+ ratio (NADH-reductive stress) is a hallmark of mitochondrial dysfunction, yet how it drives pathologies ranging from primary mitochondrial disorders to ageing remains poorly understood1,2. Here, we show that mitochondrial respiratory chain inhibition in primary human fibroblasts induces NADH-reductive stress that coexists with profound NADPH depletion. Using the Escherichia coli soluble transhydrogenase (EcSTH)3 to model this redox coupling in cells with intact mitochondria, we demonstrate that perturbation of both NAD(H) and NADP(H) redox pairs elicits metabolomic and transcriptomic reprogramming, culminating in proliferation arrest with senescence features. Notably, normalizing the NADH/NAD+ ratio alone while NADPH depletion persists fails to rescue proliferation in EcSTH-expressing primary human cells, unlike in transformed HeLa cells. Stable isotope tracing reveals that primary fibroblasts rely more on NADPH-driven reductive carboxylation than HeLa cells, explaining why NADH/NAD+ normalization alone is insufficient for rescue. To test this NADPH dependency, we develop a constitutively active Staphylococcus aureus NAD kinase (SaNADK) that expands the mammalian NADP(H) pool. In fibroblasts, SaNADK restores reductive carboxylation and de novo pyrimidine biosynthesis, and reverses proliferation arrest and senescence features. Furthermore, hepatic SaNADK expression in aged male mice partially alleviates transcriptional signatures of inflammation and metabolic dysregulation. Together, these findings establish EcSTH and SaNADK as xenotopic tools for dissecting NAD(P)H redox coupling and provide a framework for counteracting ageing-associated metabolic decline.

DOI: https://doi.org/10.1038/s42255-026-01640-7
FASEB J. 2026 Oct 31. 40(20): e72363

Mitochondrial Supercomplex-Associated Proximity Increases in Malignant Glioma Tissue.

Minou Tsujishita, Haesoo Bae, Anwaar Ali, Shanmuganathan Balakrishnan, Amina Abulimiti, Nelofer Syed, Kambiz N Alavian.

In rapidly growing tumors, including gliomas, heterogeneous microenvironments with fluctuating oxygen and nutrient availability impose strong selective pressure for metabolic adaptation. For over a century, mitochondria have been recognized as central to the reprogramming of cancer metabolism. However, it remains unclear whether and how remodeling of oxidative phosphorylation (OXPHOS), including organization of electron transport chain (ETC) complexes, contributes to the proliferation of cancer cells. Recent reports suggest that mitochondrial supercomplexes (SCs), higher-order assemblies of ETC complexes, are enriched in tumor cells and may support proliferation by increasing respiratory efficiency and stabilizing electron transfer. Here, we evaluated respiratory SC formation across glioma grades by quantifying ETC complex proximity within mitochondria in patient tissue using proximity ligation assay (PLA). We observed increased PLA signal between ETC complexes I and IV, consistent with increased respirasome assembly, that was associated with malignant glioma (Grades III and IV), and increased proximity between ETC Complexes III and IV that was most prominent in proliferating glioblastoma (Grade IV) cells. Although the precise functions of SCs remain debated, these increases in high-grade glioma relative to Grade II and control tissue suggest that SC remodeling may be a feature of malignant glioma metabolic remodeling.

DOI: https://doi.org/10.1096/fj.202600937RR
Sci Adv. 2026 Oct 16. 12(42): eaef7768

Substrate-bound structures of yeast ALA synthase reveal protein dynamics initiating heme biosynthesis.

Jenny U Tran, Thyandra A Martinez, Christopher Jurich, Margaret R Josling, Julian M Zhang, Pedro H Ayres-Galhardo, Jens Meiler, Zhongyue J Yang, Jason A MacGurn, Breann L Brown.

Heme is an essential prosthetic group involved in multiple biological processes in nearly all organisms. Heme biosynthesis is initiated by the pyridoxal 5'-phosphate-dependent enzyme aminolevulinic acid synthase (ALAS). Mutations in ALAS cause multiple hematological diseases. Despite sharing approximately 70% sequence similarity, ALAS homologs exhibit distinct expression and regulatory mechanisms. However, the molecular basis for their functional divergence remains poorly understood. Here, we used x-ray crystallography and molecular dynamics simulations to elucidate the structure and dynamics of Saccharomyces cerevisiae ALAS (scALAS) upon substrate binding. We identified critical conformational changes that occur during catalysis, regulating enzyme activity and protein-protein interactions specific to eukaryotic heme synthesis. Using evolution-guided engineering, we generated scALAS variants with altered catalytic activity and cellular metabolic profiles. Our findings reveal molecular and structural mechanisms underlying heme synthesis regulation and establish a framework for developing targeted therapeutics to treat heme-deficiency disorders and inform a rational design of next-generation therapeutic tools.

DOI: https://doi.org/10.1126/sciadv.aef7768
Nat Commun. 2026 Oct 14. pii: 10784. [Epub ahead of print]17(1):

Regulation of PDH via cysteine oxidation on DLAT.

Fabiola Garcia-Cortizo, Tobias Weber, Hana Nůsková, Daniel Pfaff, Michael Büttner, Angela Wirth, Elisabeth Kliemank, Gernot Poschet, Marc Freichel, Thomas Fleming, Alba Sulaj, Peter Paul Nawroth, Julia Szendroedi, Aurelio A Teleman.

Pyruvate dehydrogenase (PDH) complex is a key regulator of metabolism, controlling flux from glycolysis into the tricarboxylic acid (TCA) cycle. PDH is often dysregulated in metabolic diseases and cancer. We discover here that in addition to its well characterized regulation by phosphorylation, PDH activity is also regulated via inhibitory oxidation of three cysteines of the DLAT subunit - Cys488, Cys586 and Cys618. Oxidation of these cysteines increases under oxidative stress, and is highly prevalent in mouse and human tissues. This mechanism enables cells to efficiently fight oxidative stress. Under oxidative stress, cells execute a metabolic shift, blocking glycolytic flux into the TCA cycle to shunt glycolytic carbons toward the pentose phosphate pathway. This generates NADPH which cells use to detoxify H2O2 and to reduce oxidized cysteines. We find that DLAT oxidation is required for cells to mount an effective antioxidant response. Mutations preventing DLAT oxidation render PDH resistant to oxidative inhibition, impair NADPH generation, reduce peroxide detoxification, and sensitize cells to oxidative damage and death. DLAT oxidation also drives a Warburg-like metabolic phenotype of increased glucose uptake, elevated lactate secretion, and reduced TCA cycle activity. Thus DLAT oxidation is a redox-sensing mechanism that regulates PDH activity and central carbon metabolism.

DOI: https://doi.org/10.1038/s41467-026-78266-6
Methods Mol Biol. 2026 ;3057 201-223

Quantification of Mitochondrial Oxidative Phosphorylation in Skeletal Muscle.

Aditya N Brahmbhatt, Christopher G R Perry.

  Mitochondrial oxygen consumption stimulated by ADP and inorganic phosphate is often measured as an index of ATP synthesis derived from oxidative phosphorylation. This measurement is typically performed by monitoring the rate at which oxygen disappears from a solution containing isolated mitochondria or either intact or permeabilized cells and tissue. Termed "respirometry," this method has become increasingly popular in numerous research disciplines focused on cellular metabolism, including the broader field of skeletal muscle physiology. Here, we describe how respirometry is performed in permeabilized skeletal muscle fiber bundles. This technique involves mechanically separating skeletal muscle fibers followed by exposure to a cell membrane-permeabilizing agent (e.g., saponin). This technique is thought to preserve the mitochondrial network, morphology, and interactions with surrounding intracellular structures. The method can be performed on small tissue samples and permits flexibility in designing substrate titration protocols to target specific mitochondrial pathways.

Keywords:  Mitochondria; Permeabilized fibers bundles; Polarographic oxygen sensor; Respirometry; Skeletal muscle

DOI:  https://doi.org/10.1007/978-1-0716-5396-8_16
Mol Cell Biochem. 2026 Oct 15.

Metabolic links between mitochondrial electron transport, glycolysis, and AMP-activated protein kinase signaling modulate hepatocellular carcinoma cell survival.

Momoko Uchida, Masato Higurashi, Hidetsugu Nakagawa, Fumihiro Ishikawa, Kazunori Mori, Motoko Shibanuma.

  Beyond ATP production, mitochondrial metabolism, due to its essential role in cell proliferation and survival, is a potential target for cancer therapy. However, translation into clinical practice is challenging owing to several limitations, including difficulty in distinguishing cancerous and non-cancerous mitochondria, which is further complicated by the heterogeneity of the former. Herein, we focused on cancerous mitochondria exhibiting low DNA/RNA levels and respiratory function compared with those demonstrated by normal cells, and determined the effects of low respiratory activity on the metabolic phenotypes of cancer cells. Interestingly, mitochondria low-type (mt-Low) cells derived from hepatocellular carcinomas were relatively sensitive to electron transport chain (ETC) inhibition. Specifically, cells died under the treatment with the ETC inhibitors, rotenone and antimycin A, at lower doses compared with cells exhibiting normal respiratory activity (mt-psNormal), although ATP levels were sustained in both cell types under these conditions. In mt-psNormal cells, upon ETC inhibition, glycolytic activity increased, and AMP-activated protein kinase was activated, which critically contributed to cell survival. However, these responses were not effectively induced in ETC inhibition-sensitive mt-Low cells. Similar to conventional ETC inhibitors, small interfering RNAs targeting core subunits of respiratory complexes I or III effectively inhibited proliferation (complexes I and III) or survival (complex I) of the tested mt-Low cancer cells, supporting innovative anticancer approaches that target respiratory function using next-generation technology.

Keywords:  AMP-activated protein kinase; Glycolysis; Mitochondrial electron transport; Respiratory chain complex

DOI:  https://doi.org/10.1007/s11010-026-05770-0
J Physiol. 2026 Oct 16.

Warburg redefined: Metabolites, mitochondria and macrophages in immune regulation.

Yukun Min, Órlaith C Henry, Luke A J O'Neill.

  Nearly 100 years ago, Otto Warburg observed that cancer cells preferentially use glycolysis even in the presence of oxygen, supporting rapid cell growth. Since then, the concept of the Warburg effect has expanded far beyond tumour bioenergetics and is now recognised as a key feature of immune cell activation. A notable example is in macrophages, which, following pro-inflammatory stimulation, undergo Warburg-like metabolic reprogramming, characterised by increased glycolysis. Recent studies have shown that accumulated metabolites such as lactate have a range of immunoregulatory functions that shape macrophage inflammatory responses. In addition, glycolytic enzymes have been found to exert non-canonical functions that directly regulate macrophage immune signalling. Mitochondria, once considered suppressed during Warburg reprogramming, also undergo profound changes, with the electron transport chain generating reactive oxygen species and metabolites such as succinate, fumarate and itaconate playing complex immunoregulatory roles, and mitochondrial dynamics actively shaping metabolism and immune responses. Together, these findings redefine the Warburg effect in macrophages as a coordinated metabolic and signalling process that integrates glycolysis, mitochondrial function and immunometabolite signalling to optimise context-dependent immune responses.

Keywords:  ETC; TCA cycle; Warburg metabolism; glycolysis; itaconate; lactate; macrophage; mitochondria

DOI:  https://doi.org/10.1113/JP291073
J Int Soc Sports Nutr. 2026 Dec 30. 23(1): 2707252

Common questions and misconceptions about diets: what does the scientific evidence really show?

Jose Antonio, Brandi Antonio, Alan Aragon, Shawn M Arent, Bill Campbell, Darren G Candow, Hannah Eberhardt, Guillermo Escalante, Cassandra Evans, Scott Forbes, Drew Gonzalez, Chad M Kerksick, Erik Bustillo, Kworweinski Lafontant, Gianna Mastrofini, Scotty Mills, Michael J Ormsbee, Kieran Paterson, Flavia Pereira, Valeria Silva Ramirez, Antonella Schwarz, K Michelle Singleton, Abbie Smith-Ryan, Jeffrey Stout, Grant Tinsley.

  The study of diet and nutrition is often filled with numerous myths and misconceptions. A Google Scholar search of "diets health" yields over 4 million results. This review examines frequently asked questions about diets and dietary habits. These questions include the following: 1) Is a caloric surplus necessary for building skeletal muscle? 2) Is it possible to lose body mass or fat mass without caloric restriction? 3) Is intermittent fasting better than chronic caloric restriction for weight loss? 4) Are there sex differences in the response to fasting? 5) Can diet alone fulfill the macro and micronutrient needs of exercise-trained individuals? 6) Is there an ideal dietary macronutrient ratio? 7) Are most of the benefits of diets in overweight/obese individuals due primarily to the weight loss itself? 8) Do DNA-based diets induce greater fat mass loss? 9) Does eating late at night result in a gain in fat mass? 10) Are there data (i.e. observational, randomized controlled trials, etc.) on the carnivore diet? 11) Is there a diet that is best for healthy aging and longevity? 12) Is there such a thing as "superfoods?" 13) Can one consume adequate protein on a vegan diet? 14) Do high-protein diets harm the kidneys? 15) Does a greater meal frequency lead to greater weight loss? 16) Are carbohydrates more "fattening" than dietary fats? To answer these questions, we conducted an evidence-based scientific evaluation of the literature on these topics regarding the diet category.

Keywords:  Calories; macronutrients; nutrition; protein

DOI:  https://doi.org/10.1080/15502783.2026.2707252
An Acad Bras Cienc. 2026 ;pii: S0001-37652026000303005. [Epub ahead of print]98(3): e20240672

Time-restricted feeding with resistance training is not superior to conventional feeding for body composition and muscle strength: a systematic review and meta-analysis.

Anderson M O H Verdi, Jaqueline M Soares, Michel J Andrade, Caryna E Mazur, Daniela C Gonçalves.

Intermittent fasting is becoming popular for its quick benefits on body composition. With rising interest in weight loss, understanding its impact on fat-free mass is essential. It investigates the effects of time-restricted feeding compared to conventional diets on body composition in healthy adults undergoing resistance training. The registration is in PROSPERO (CRD42023423274), and ethical approval was not required. No financial support was received. Databases consulted included MEDLINE, CENTRAL, Embase, and Scopus, with the final search conducted on November 13, 2023. Only randomized controlled trials with healthy human participants aged 18 or older, who underwent TRF and strength training, were included. The risk of bias was assessed using the RoB2 tool. The review comprises 5 studies, with a final sample of 120 individuals. Among them, only 2 studies showed a statistically significant difference in the impact of fasting on body weight and fat mass. Regarding fat-free mass, it remained consistent across groups at the intervention's end. The meta-analysis suggested an estimate of -0.48kg (95% CI: -2.52 to 1.56), indicating that the average result did not significantly differ from zero. Contrary to the initial hypothesis, the findings do not provide statistically significant evidence that TRF increases fat-free mass.

DOI: https://doi.org/10.1590/0001-3765202620240672
Nat Med. 2026 Oct 12.

A health-system-scale, episode-resolved multimodal atlas of cancer cachexia.

Venise Jan Castillon, Amy X Xie, Sonia Boscenco, Ethan Tse, Neil Ruthen, Jamie Wang, Ziad Bakouny, Michele Waters, Chenlian Fu, Christopher Fong, Mustafa Saleh, Tarek Baroud, Wungki Park, Urvi A Shah, A Ari Hakimi, Puneeth Iyengar, Justin Jee, Eileen White, Alexander Gusev, Tobias Janowitz, Marcus D Goncalves, Ed Reznik.

Cancer cachexia is a wasting syndrome with outsized impact on morbidity and mortality, yet its drivers and systemic consequences remain poorly defined. In this study, we repurposed longitudinal clinicogenomic data from 52,236 patients with cancer profiled by MSK-IMPACT (2010-2024) at Memorial Sloan Kettering Cancer Center to define episode-resolved trajectories of consensus-defined cachectic weight loss and linked these events to outcomes, serology and tumor genotypes. Cachectic episodes clustered near periods of disease progression and were associated with inferior outcomes in nearly all cancer types. Across diverse malignancies, cachectic weight loss episodes exhibited a consistent serologic signature characterized by lower albumin and hemoglobin and higher levels of liver enzymes. Numerous somatic tumor genotypes, including TP53 mutation across several diseases, were also associated with more frequent onset of cachectic episodes. Motivated by these observations, we developed a multivariate model to predict impending risk of cachectic weight loss in patients with lung, colorectal and prostate cancer, validated in an independent, external cohort from Dana-Farber Cancer Institute (n = 5,785). Routine clinicogenomic data are, therefore, a scalable resource for discovery in cancer cachexia.

DOI: https://doi.org/10.1038/s41591-026-04689-9
J Enzyme Inhib Med Chem. 2026 Dec;41(1): 2744392

Research progress on ATP-citrate lyase and its inhibitors: a metabolic-epigenetic perspective.

Qinglin Liu, Hongbin Sun, Liang Dai.

  ATP-citrate lyase (ACLY) is a key enzyme in cellular metabolism that catalyses the cleavage of citrate to produce acetyl coenzyme A (acetyl-CoA), thereby bridging energy metabolism and epigenetic regulation. Acetyl-CoA serves as a common substrate for de novo lipogenesis (DNL) and histone acetylation. Aberrant ACLY activity is closely associated with various pathological conditions, including metabolic diseases, Immune-mediated inflammatory diseases (IMIDs), cancer, and neurodegenerative diseases, positioning ACLY as an important therapeutic target for these diseases. However, existing inhibitors face challenges such as insufficient selectivity and limited clinical efficacy and off-target effects. This review systematically summarises the molecular mechanisms and pathological significance of ACLY within the overarching framework of its dual metabolic-epigenetic functions, from three perspectives, namely its structure and function, disease relevance, and inhibitor development and optimisation strategies, aiming to provide a theoretical foundation for precision therapies targeting ACLY.

Keywords:  ACLY inhibitors; ATP-citrate lyase; drug discovery; structural biology; structure-activity relationships

DOI:  https://doi.org/10.1080/14756366.2026.2744392