bims-cesirm 2026-01-25 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2026–01–25
thirty papers selected by
Tigist Tamir, University of North Carolina

Modeling tissue-specific Drosophila metabolism identifies high sugar diet-induced metabolic dysregulation in muscle at reaction and pathway levels.
Mammalian fatty acid synthase and O-GlcNAc transferase preferentially interact via their respective N-terminal regions.
Clinical Applications of Phosphoproteomics: Illuminating Cancer Signaling and Enabling Rational Therapeutic Strategies.
Renal Ketogenesis Protects Against Ischemic Kidney Injury.
Pervanadate-induced oxidation relieves autoinhibition of the protein tyrosine kinase SRC.
Loss of the CoA-degrading enzyme NUDT19 exacerbates albuminuria and disrupts renal lipid homeostasis in high fat diet-fed mice.
Isoflavones impair response to anti-PD1 therapy in murine breast cancer models, irrespective of dietary fiber and fecal short chain fatty acid levels.
Metabolic reprogramming enhances oxidative stress resistance in differentiating cardiomyocytes.
Silencing lipid catabolism determines longevity in response to fasting.
Reprogramming the Rossmann Fold Signature Motif Creates Orthogonal Redox Biocatalysts.
The Escherichia coli PeptideAtlas Build: Characterizing the Observed Escherichia coli Pan-Proteome and Its Post-Translational Modifications.
Enhancing kcat prediction through residue-aware attention mechanism and pre-trained representations.
Protein tyrosine phosphatase inactivation by electrophilic tyrosine modification.
An alternative EGFR activation by patient-derived R252C mutation promotes cancer progression.
RIPK2 induces docetaxel resistance in prostate cancer through the NF-κB/P-gp signaling pathway.
The multifaceted role of post-translational modifications in macrophage polarization: from mechanisms to therapeutic targets.
ACSL5 Mediates Adaptation to the Palmitic Acid-Enriched Pulmonary Microenvironment to Enhance Metastatic Breast Cancer Cell Survival and Lung Metastasis.
Mitochondrial Calcium Uniporter Drives Chemoresistance in Pancreatic Cancer via Glutathione-Mediated Stemness Maintenance.
AKT signaling in hepatocytes rapidly increases glucose phosphorylation and contribution to glycogen without affecting metabolite pool sizes or glycogen breakdown.
Membrane curvature enhances lipid peroxidation in a composition-dependent manner.
A proteomics and redox proteomics approach to understanding ARDS heterogeneity.
CysDuF database: annotation and characterization of cysteine residues in domain of unknown function proteins based on cysteine post-translational modifications, their protein microenvironments, biochemical pathways, taxonomy, and diseases.
A data-driven pan-cancer proteogenomic analysis reveals the characteristics of human cancer protein expression.
Serine/arginine-rich splicing factor 1 inhibits ferroptosis and promotes glycolysis in endometrial cancer via activating mTOR and β-catenin.
Acetyl-CoA as a metabolic switch for selective mitophagy.
Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance.
ATGL-catalyzed biosynthesis mediates the upregulation of Fatty Acid Hydroxy Fatty Acids (FAHFA) levels in white adipose tissue with fasting.
Site-saturation functional screens identify PALB2 missense variants associated with increased breast cancer risk.
The pseudouridine synthase PUS7 is associated with stemness and represents a potential therapeutic target in triple-negative breast cancer cells.
Src-dependent modulation of IFNγ-induced PD-L1 expression in human breast cancer cell lines.

Nat Commun. 2026 Jan 19.

Modeling tissue-specific Drosophila metabolism identifies high sugar diet-induced metabolic dysregulation in muscle at reaction and pathway levels.

Sun Jin Moon, Yanhui Hu, Monika Dzieciatkowska, Ah-Ram Kim, John M Asara, Angelo D'Alessandro, Norbert Perrimon.

Individual tissues perform highly specialized metabolic functions to maintain whole-body metabolic homeostasis. Although Drosophila serves as a powerful model for studying human metabolic diseases, modeling tissue-specific metabolism has been limited in this organism. To address this gap, we reconstruct 32 tissue-specific genome-scale metabolic models (GEMs) by integrating a curated Drosophila metabolic network with pseudo-bulk single-nuclei transcriptomics data, revealing distinct metabolic network structures and subsystem coverage across tissues. We validate enriched pathways identified through tissue-specific GEMs, particularly in muscle and fat body, using metabolomics and pathway analysis. Moreover, to demonstrate the utility in disease modeling, we apply muscle-GEM to investigate high sugar diet (HSD)-induced metabolic dysregulation. Constraint-based semi-quantitative flux and sensitivity analyses identify altered NAD(H)-dependent reactions and distributed control of glycolytic flux, including GAPDH. This prediction is further validated through in vivo 13C-glucose isotope tracing study. Notably, decreased glycolytic flux, including GAPDH, is linked to increased redox modifications. Finally, our pathway-level flux analyses identify dysregulation in fructose metabolism. Together, this work establishes a quantitative framework for tissue-specific metabolic modeling in Drosophila, demonstrating its utility for identifying dysregulated reactions and pathways in muscle in response to HSD.

DOI: https://doi.org/10.1038/s41467-026-68395-3
Biochem Biophys Rep. 2026 Mar;45 102427

Mammalian fatty acid synthase and O-GlcNAc transferase preferentially interact via their respective N-terminal regions.

Dimitri Vanauberg, Céline Schulz, Guillaume Brysbaert, Nessim Raouraoua, Peggy Mistarz-Gruau, Marc F Lensink, Anne-Sophie Vercoutter-Edouart, Tony Lefebvre.

  Fatty Acid Synthase (FASN) is a central enzyme in the de novo lipogenesis pathway. By producing fatty acids, FASN is implicated in numerous crucial cellular processes, but it is also frequently overexpressed in cancer. O-GlcNAc Transferase (OGT) governs the addition of N-acetylglucosamine residues onto cytosolic, nuclear and mitochondrial proteins. Like FASN, OGT actively participates in carcinogenesis. We previously showed that OGT regulates FASN in different ex vivo and in vivo models. Reciprocally, FASN promotes OGT expression and activity. The two enzymes physically interact together and contribute to cancer cell survival. It is therefore fundamental to define the respective interaction region of each enzyme to explore new therapeutic solutions for patients suffering from cancer. By using the hepatocarcinoma cell line Hep3B, we show thanks to two series of deletion mutants that both enzymes preferentially interact via their respective N-terminal regions. Analysis of the O-GlcNAc status of the various FASN deletion mutants shows that stronger interaction with OGT correlates with higher glycosylation, suggesting that OGT catalyzes the transfer of GlcNAc with limited substrate specificity.

Keywords:  Fatty acid synthase; Liver cancer cells; N-terminal region; O-GlcNAc transferase; O-GlcNAcylation

DOI:  https://doi.org/10.1016/j.bbrep.2025.102427
Cancer Sci. 2026 Jan 22.

Clinical Applications of Phosphoproteomics: Illuminating Cancer Signaling and Enabling Rational Therapeutic Strategies.

Hirokazu Shoji, Narikazu Boku, Jun Adachi.

  Protein phosphorylation is a central post-translational modification regulating cellular signaling, frequently dysregulated in cancer. Mass spectrometry (MS)-based phosphoproteomics has emerged as a powerful approach to systematically profile phosphorylation events, thereby revealing aberrant kinase activity and therapeutic vulnerabilities that are not captured by genomic or transcriptomic analyses. Recent advances across the workflow-including optimized sample preparation and phosphopeptide enrichment, isotope- or label-free quantitative strategies, high-resolution mass spectrometry platforms, specialized algorithms for site identification and quantification, and integrative informatics analyses-have enabled the detection of tens of thousands of phosphorylation sites even from small clinical specimens. These developments have facilitated the characterization of signaling pathways across diverse cancer types, leading to the identification of targetable kinases and informing therapeutic strategies. In this review, we highlight studies that employed phosphoproteomic analyses of clinical specimens or patient-derived cancer cells to delineate signaling characteristics and to propose and validate therapeutic targets. Collectively, MS-based phosphoproteomics is poised to become a cornerstone of precision oncology. By enabling comprehensive and quantitative mapping of phosphorylation events, this technology allows mechanistic dissection of cancer signaling pathways and uncovers therapeutic vulnerabilities that may be exploited with targeted agents.

Keywords:  cancer signaling; kinases; mass spectrometry; phosphoproteomics; therapeutic targets

DOI:  https://doi.org/10.1111/cas.70323
J Am Soc Nephrol. 2026 Jan 21.

Renal Ketogenesis Protects Against Ischemic Kidney Injury.

Kyle Feola, Andrea H Venable, Mina Rasouli, Emma-Grace Haley, Chetana Jadhav, Ricardo Monroy, Tatyana McCoy, Sarah C Huen.

BACKGROUND: Abnormal renal fatty acid oxidation in kidney disease suggests that dysregulated metabolism is a key component of kidney disease pathogenesis. While the liver is the main ketogenic organ, the rate-limiting enzyme for ketogenesis, mitochondrial Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), is induced in the proximal tubule of the kidney during fasting. We previously demonstrated that HMGCS2 induced in the kidney does not contribute to the circulating pool of ketones during fasting and cannot compensate for hepatic ketogenic deficiency. We hypothesized that kidney HMGCS2 may be acting locally within the kidney to maintain normal function during metabolic stress or injury.
METHODS: Mice with kidney or liver specific deletion of Hmgcs2 were subjected to ischemia/reperfusion injury (IRI). Kidney histology, metabolomics and lipidomics were analyzed. Mice were placed on a ketogenic diet for four days to increase plasma and kidney ketone content. Using novel mouse models with proximal tubular hemagglutinin-tagged mitochondria with or without Hmgcs2 deletion, proximal tubular-specific mitochondria were isolated and fatty acid oxidation capacity was measured after IRI.
RESULTS: Mice with kidney specific Hmgcs2 deletion had significantly more kidney injury after IRI compared to wild-type controls. Kidneys lacking HMGCS2 exhibited a decrease in ketone content and an increase in lipid droplet accumulation after IRI. Proximal tubular-specific mitochondria lacking HMGCS2 had significantly lower fatty acid oxidation capacity both at baseline and after ischemic injury. Administration of a ketogenic diet for four days prior to IRI was sufficient to decrease kidney injury and augment mitochondrial fatty acid oxidation in kidney Hmgcs2 knockout mice. Kidney tissue lipidomics revealed that the loss of kidney HMGCS2 was associated with a decrease in both arachidonic acid containing phospholipids and prostaglandin levels.
CONCLUSIONS: Loss of renal HMGCS2 and resultant ketogenesis increased ischemia-induced injury and decreased mitochondrial fatty acid oxidation capacity, suggesting a role in renal ketogenesis in limiting acute kidney injury.

DOI: https://doi.org/10.1681/ASN.0000001014
Sci Signal. 2026 Jan 20. 19(921): eady9437

Pervanadate-induced oxidation relieves autoinhibition of the protein tyrosine kinase SRC.

Katie E Mulholland, Maxime Bourguet, Nuo Cheng, Oisharja Rahman, Daria Ezeriņa, Leonard A Daly, Tiffany Lai, Silvia Aldaz Casanova, Therese Featherston, Pau Creixell, Claire E Eyers, Joris Messens, Patrick A Eyers, Dominic P Byrne, Hayley J Sharpe.

Dynamic regulation of protein tyrosine phosphorylation (pTyr) by kinases and phosphatases enables cells to sense and respond to environmental changes. The widely used chemical pervanadate induces the accumulation of pTyr in mammalian cell lines. This effect is primarily attributed to its inhibition of protein tyrosine phosphatases (PTPs), leading to the assertion that PTPs are master gatekeepers of intracellular pTyr homeostasis. Here, we used several approaches to reveal that pervanadate disrupted cellular redox homeostasis and directly activated tyrosine kinases of the SRC family through the oxidation of specific cysteine residues. Mass spectrometry and biophysical approaches showed that pervanadate-induced oxidation of cysteine-188 and cysteine-280 activated SRC by disrupting autoinhibitory intramolecular interactions between the catalytic domain and the SH2/SH3 domains and by impairing SH2 domain binding to phosphopeptides, including the regulatory carboxyl-terminal tail phosphotyrosine-530. Redox-sensitive cysteine residues were essential for SRC to promote the overgrowth of mouse fibroblasts. Our findings call for a reevaluation of pervanadate-based experiments and demonstrate that SRC cysteines control its oncogenic properties.

DOI: https://doi.org/10.1126/scisignal.ady9437
Sci Rep. 2026 Jan 20.

Loss of the CoA-degrading enzyme NUDT19 exacerbates albuminuria and disrupts renal lipid homeostasis in high fat diet-fed mice.

Dominique C Saporito, Rachel D King, Schuyler D Vickers, Emily A Wyda, Sruthi Balaji, Saravanan Kolandaivelu, Neil Billington, Judy A King, Roberta Leonardi.

  Nudix hydrolase 19 (NUDT19) is a peroxisomal enzyme that hydrolyzes CoA species at the phosphodiester bond and has been linked to peroxisomal dysfunction in the context of diabetic kidney disease. Despite its predominant expression in mouse kidneys, the physiological role of NUDT19 remains poorly understood. To investigate its function under metabolic stress, we fed Nudt19-/- mice a high fat diet (HFD) for 15 weeks. Nudt19 deletion exacerbated HFD-induced albuminuria, suggesting a previously unrecognized role in kidney function. This phenotype was associated with altered lipid metabolism in the kidneys, including reduced levels of non-esterified fatty acids and specific mono-acyl lipids, as well as differential expression of proteins involved in lipid metabolism. These included ECH1, THIKB, and ECHD2, enzymes involved in peroxisomal and mitochondrial β-oxidation; C19orf12, a lipid droplet-associated protein; and the lipolysis-stimulated lipoprotein receptor (LSR). These findings support the conclusion that NUDT19 contributes to the regulation of renal lipid homeostasis and that its loss exacerbates kidney dysfunction under conditions of dietary lipid overload.

Keywords:  Coenzyme A; Kidney; NUDT19; Nudix hydrolase; Peroxisomes

DOI:  https://doi.org/10.1038/s41598-026-36136-7
bioRxiv. 2025 Dec 09. pii: 2025.12.05.692375. [Epub ahead of print]

Isoflavones impair response to anti-PD1 therapy in murine breast cancer models, irrespective of dietary fiber and fecal short chain fatty acid levels.

Fabia de Oliveira Andrade, Kerrie B Bouker, Melike Ozgul-Onal, Lu Jin, Idalia Cruz, William Helferich, Audrey Gao, Karla Andrade, Vivek Verma, Christopher Staley, Patricia L Foley, Leena Hilakivi-Clarke.

Background: Fermentable dietary fibers, also called microbiota-accessible carbohydrates (MAC), and the consequent increase in fecal short-chain fatty acids (SCFAs) are linked to improved responsiveness to immune checkpoint blockade (ICB) therapy in human and mouse studies. However, experimental diets high in MAC also often contain estrogenic isoflavones, which may counter fiber's beneficial effects by causing immunosuppression.
Methods: We studied the effects of feeding female C57BL/6Tac mice low-MAC (AIN93G), low-MAC supplemented with isoflavone genistein, high-MAC (5V5M) or high-MAC isoflavone (high-MACi; 5058D) diet on their gut microbiome and response to anti-PD1 therapy against E0771 allografted triple negative breast cancer (TNBC) and 7,12-dimethylbenz[a]anthracene (DMBA)-initiated estrogen receptor α positive (ERα+) mammary tumors. We also determined whether blocking ERα with tamoxifen (TAM) impacted responsiveness to anti-PD1 therapy in mice fed different diets. The effect of diet and treatments on immune cell signaling pathways was investigated using NanoString PanCancer Immune Profiling Panel.
Results: High-MAC and high-MACi diets increased fecal microbial alpha-diversity and the abundances of SCFA producing families Lachnospiraceae, and Oscillospiraceae as well as fecal SCFA levels, compared with low-MAC diet. E0771 tumors responded to anti-PD1 in mice fed high-MAC, while mice fed high-MACi did not respond. Low-MAC fed mice with single E0771 allograft also responded to anti-PD1, but genistein supplementation eliminated responsiveness. E0771 tumors in high-MAC fed mice contained elevated levels of exhausted CD8+ T cells, which were decreased after anti-PD1 therapy. Opposite effects were seen in mice fed high-MACi diet. Mice with DMBA-initiated ERα+ mammary tumors did not respond to anti-PD1. TAM converted TNBC and ERα+ tumors to become sensitive to anti-PD1 therapy in mice fed high-MACi or low-MAC diets, respectively. Genes in TH17 differentiation pathways were linked to TAM-induced improved anti-PD1 response both in TNBC and ERα+ mammary tumors.
Conclusions: Our results highlight the role of diet in impacting the effectiveness of ICB therapies. We found that increased SCFA levels alone are not predictive of response to anti-PD1, but if tumor expresses ERα or if diet contains ERα activating compounds, such as isoflavones, blocking ERα+ might convert unresponsive tumors responsive to anti-PD1. Word count : 339.
What is already known on this topic: Dietary fiber is proposed to improve response to checkpoint inhibitor therapy against melanoma, but this has been challenged by a recent preclinical study in which different mouse tumor models were used. None of the studies have been done in breast cancer or preclinical breast cancer models.
What this study adds: Our study showed, using triple negative breast cancer (TNBC) and estrogen receptor positive (ER+) breast cancer models, that indeed high levels of microbiota accessible carbohydrates (MACs) in diet did not alone determine responsiveness to anti-PD1 therapy, but diet high in plant isoflavones/ hormones impaired anti-PD1 effectiveness, regardless of whether diet contained high fiber levels or not. We also found that the adverse effects of isoflavones were counteracted by tamoxifen, partial estrogen receptor antagonist.
How this study might affect research practice or policy: Our findings could indicate that breast cancer patients, both those with TNBC and ER+ disease, should not consume diets high in isoflavones when treated with anti-PD1.

DOI: https://doi.org/10.64898/2025.12.05.692375
Sci Rep. 2026 Jan 20.

Metabolic reprogramming enhances oxidative stress resistance in differentiating cardiomyocytes.

Lara Basseres Novais, Beatriz Rocha Ilidio Rodrigues, Flávia Oliveira Borges Pereira, Alan Gonçalves Amaral, Sofya Castilho Lapa, Lucas Lopes Maldonado, Pedro Víctor-Carvalho, Isabela Aparecida Moretto, Hans Rolando Zamora-Obando, Mariana Conceição da Silva, Ana Paula Samogim, Ingridi Rafaela de Brito, Maria das Graças de Souza Carvalho, Antonio Thiago Pereira Campos, Michelle Bueno de Moura Pereira Antunes, Carlos Lenz Cesar, Hernandes F Carvalho, Ana Valéria Colnaghi Simionato, André Alexandre de Thomaz, Aline Mara Dos Santos.

  Cardiomyocyte differentiation is a complex process involving significant metabolic remodeling, but its impact on cellular redox state and cell damage remains poorly understood. Using metabolomics, biophysical, and biochemical approaches, we characterized, in vitro, the metabolic shift of differentiating cardiomyocytes and its implications for oxidative damage. We found that differentiating cardiomyocytes undergo a broad metabolic reprogramming from a glycolytic to an oxidative state, marked by increased activity in key pathways, including malate-aspartate shuttle, glutathione metabolism, and tricarboxylic acid cycle. This metabolic transition was associated with mitochondrial enlargement and increased reactive oxygen species (ROS) production. Intriguingly, despite ROS increase, differentiated cells maintained similar levels of DNA damage as cardiomyoblasts and were more resistant to a H₂O₂ challenge. Our findings suggest that metabolic adaptations during cardiomyocyte differentiation enhance their capacity to mitigate oxidative stress damage, providing an adaptive avenue that enables cardiomyocyte survival upon exposure to an oxygen-rich environment.

Keywords:  Cardiomyocytes; Differentiation; Metabolic shift; Mitochondria; ROS

DOI:  https://doi.org/10.1038/s41598-026-35263-5
Nat Commun. 2026 Jan 22.

Silencing lipid catabolism determines longevity in response to fasting.

Lexus Tatge, Juhee Kim, Rene Solano Fonseca, Kyle Feola, Jordan M Wall, Gupse Otuzoglu, Ann C Johnson, Kielen R Zuurbier, Jaeyoung Oh, Shaghayegh T Beheshti, Victor A Lopez, Anthony J Daley, Emma G Werner, Patrick Metang, Sonja L B Arneaud, Abigail Watterson, Jeffrey G McDonald, Vincent S Tagliabracci, Michael E French, Peter M Douglas.

Oscillations between lipid anabolism and catabolism are essential for maintaining cellular health during metabolic fluctuations. Fasting, a conserved determinant of aging, improves disease outcomes and extends lifespan, yet the relative contributions of lipid catabolism versus its attenuation to fasting-induced longevity remain unresolved. The metabolic flexibility of C. elegans under variable nutrient availability provides a powerful system to address this question. We show that lifespan extension from fasting depends not on sustained activation of lipid catabolism, but on its silencing upon nutrient replenishment. The fasting-responsive nuclear hormone receptor NHR-49 activates β-oxidation; however, unlike classical ligand-regulated receptors, NHR-49 is regulated through ligand-independent mechanisms involving cofactor-mediated transcriptional attenuation and protein turnover. We identify casein kinase 1 alpha 1 (KIN-19) as a key regulator of metabolic plasticity and fasting-induced longevity that silences β-oxidation via primed phosphorylation of NHR-49. Thus, cooperative ligand-independent silencing of this conserved nuclear hormone receptor promotes fasting-associated longevity.

DOI: https://doi.org/10.1038/s41467-026-68764-y
bioRxiv. 2025 Dec 03. pii: 2025.12.03.692188. [Epub ahead of print]

Reprogramming the Rossmann Fold Signature Motif Creates Orthogonal Redox Biocatalysts.

Yu Ping, Jin Young Kim, Minh-Anh L Dinh, Emma Luu, Youtian Cui, Edward King, William B Black, Justin B Siegel, Han Li.

Biological reducing power is carried by nicotinamide adenine dinucleotide (phosphate) (NAD(P)/H), which supports cellular functions and cannot be specifically directed to engineered metabolic pathways. Nicotinamide mononucleotide (NMN(H)) has emerged as an orthogonal redox cofactor to address this challenge, yet strategies remain elusive for creating NMN(H)-specific enzymes that no longer interact with the cellular NAD(P)/H pools. Previous designs avoided perturbing the most ancient and conserved GxGxxG motif in Rossmann fold enzymes, the root cause of persistent NAD(P)/H recognition. Herein, we demonstrated that this motif, though long considered essential, is in fact mutable to yield active NMN + -specific enzymes. This is implemented on two unrelated model enzymes chosen to garner orthogonal reducing power from either the cheap electron source phosphite or glycolysis. On phosphite dehydrogenase (PTDH), variants NRC-01 and NRC-02 eliminated electron leaking to numerous NAD(P)H-dependent side reactions in whole cells and crude cell lysates while driving NMNH-dependent biotransformation with ∼240-fold higher productivity than existing catalysts. On glyceraldehyde-3-phosphate dehydrogenase (GapA), variant RSQ featured a ∼2.9×10 4 -fold cofactor specificity switch to NMN + from NAD + . Combined Rosetta modeling, systematic structural alignment, and experimental results revealed that Rossmann fold reprogramming, paired with engineered structural reinforcement, may offer a general route to orthogonal redox biocatalysts.

DOI: https://doi.org/10.64898/2025.12.03.692188
J Proteome Res. 2026 Jan 22.

The Escherichia coli PeptideAtlas Build: Characterizing the Observed Escherichia coli Pan-Proteome and Its Post-Translational Modifications.

Caroline Jachmann, Zhi Sun, Kevin Velghe, Florence Arsène-Ploetze, Aurélie Hirschler, Jasper Zuallaert, Christine Carapito, Robbin Bouwmeester, Kay Nieselt, Eric W Deutsch, Lennart Martens, Ralf Gabriels, Tim Van Den Bossche.

  Escherichia coli is a widely used model organism in molecular biology. Despite its pivotal role, a comprehensive proteome resource covering the E. coli pan-proteome and its post-translational modifications (PTMs) has been lacking. Here we present the E. coli PeptideAtlas build, the first comprehensive pan-proteome analysis of E. coli, generated from 40 high-quality public and in-house data sets spanning a broad diversity of strains, sample types, and experimental conditions, and comprising over 73 million MS/MS spectra. All data sets were reprocessed using both a closed search (Trans-Proteomic Pipeline using MSFragger) and an open search (ionbot). The E. coli PeptideAtlas build provides evidence for 4755 proteins, including 1376 previously lacking protein-level support in UniProtKB. The resource offers protein coverage, modification sites, raw spectra with matched peptides, and manually annotated metadata for the E. coli pan-proteome. PTM profiling identified over 10,000 modification sites, including phosphorylation (3806), acetylation (754), methylation (730), glutathionylation (352) and phosphoribosylation (226). Analysis of the glutathionylation sites revealed potential links to metal binding regulation. We also detected proteins likely stemming from phages, underscoring the value of pan-proteomic approaches for studying host-phage interactions. All identifications are publicly accessible and traceable through the PeptideAtlas interface. We expect that the E. coli PeptideAtlas build will provide a useful resource for the community, which supports, for example, targeted MS experiment design, PTM enrichment method development, and strain typing. It allows straightforward lookups of protein and peptide identifications and facilitates comparative proteomic analyses by enabling the assessment of protein presence and variability across different E. coli strains. The build is available at https://peptideatlas.org/builds/ecoli/.

Keywords:  Escherichia coli; PeptideAtlas; modifications; open search; proteomics; reprocessing

DOI:  https://doi.org/10.1021/acs.jproteome.5c00902
Commun Biol. 2026 Jan 22.

Enhancing kcat prediction through residue-aware attention mechanism and pre-trained representations.

Yunxiang Cai, Fengya Ge, Chuanlei Zhang, Hao Chen, Xuan Qi, Xiaoping Liao, Lin Wang.

The turnover number (kcat) is a key parameter in enzyme kinetics that quantifies catalytic efficiency and underpins mechanistic understanding of enzyme activity. However, existing computational approaches for kcat prediction often suffer from limited accuracy and generalization, largely because most models rely only on substrate information and neglect the role of the full reaction context. Although TurNuP partially addresses this limitation by encoding entire reactions using binary fingerprints, its two-stage design separates enzyme and reaction modeling, limiting both predictive performance and interpretability. Here, we present PMAK, a deep learning framework that integrates pre-trained representations of enzyme sequences and reaction SMILES with a residue-aware attention mechanism. By jointly modeling enzymes and reactions, PMAK captures their interactions and highlights key residues contributing to catalytic activity. Comprehensive evaluations demonstrate that PMAK consistently outperforms existing methods, achieving average R2 improvements of approximately 16.9% and 10.0% over TurNuP under new-reaction and new-enzyme settings, respectively, in five-fold cross-validation. Beyond improved accuracy, PMAK provides interpretable insights into residues associated with enzyme catalysis, offering a robust and informative tool for enzyme kinetic prediction and related applications.

DOI: https://doi.org/10.1038/s42003-026-09551-9
Chem Sci. 2026 Jan 19.

Protein tyrosine phosphatase inactivation by electrophilic tyrosine modification.

Madeleine L Ware, David M Leace, Zihan Qu, Quentin Schaefer, Sagar D Vaidya, Mikayla L Horvath, Zhihong Li, Yunpeng Bai, Zhong-Yin Zhang, Ku-Lung Hsu.

Covalent protein tyrosine phosphatase (PTP) inhibitors principally target the catalytic cysteine, which is highly conserved and presents challenges for achieving selectivity across the PTP family. Here, we identified a tyrosine-reactive covalent inhibitor for SHP2 (DML189) with secondary molecular glue activity via a ligand induced protein tethering (LIPT) mechanism. We detected ligand binding at Y279, which is in proximity to the catalytic cysteine on SHP2 and has known functional and pathogenic properties. Covalent SHP2 modification by DML189 induced reversible disulfide tethering and monomer loss that was not observed to the same extent on PTP1B, LYP, or SHP1. Crosslinking mass spectrometry detected unique tethering events involving regulatory cysteines after DML189 modification on SHP2. Together, we discovered a tyrosine reactive inhibitor that targets functional sites on SHP2 and exhibits molecular glue activity through LIPT.

DOI: https://doi.org/10.1039/d5sc07398g
Nat Commun. 2026 Jan 21.

An alternative EGFR activation by patient-derived R252C mutation promotes cancer progression.

Yajuan Zhang, Qizhen Fei, Yan Li, Siyao Wang, Tong Rong, Xueyuan Wu, Hong Gao, Chen Chen, Dong Gao, Yun Zhao, Guohui Li, Huiying Chu, Wenfeng Li, Weiwei Yang.

Mutations in the extracellular or intracellular domains of epidermal growth factor receptor (EGFR) are implicated in the development of various cancers. While the intracellular mutations of EGFR have been extensively studied, the function of extracellular mutations remains poorly understood. In this study, we identify an EGFR mutant (EGFR R252C) in a patient with multifocal lung cancer and glioma, in which arginine (R) 252 is mutated to cysteine (C) in the EGFR extracellular domain. This mutation promotes C252-C252 disulfide-mediated EGFR dimerization and induces a conformational change of EGFR, leading to absent autophosphorylation and enhanced direct interaction between EGFR and extracellular signal-regulated protein kinase 1/2 (ERK1/2). Importantly, EGFR directly phosphorylates ERK1/2 at threonine (T) 202 / tyrosine (Y) 204 and activates ERK1/2, thereby promoting tumor cell proliferation and tumor growth in vivo. Afatinib, a second-generation EGFR tyrosine kinase inhibitor, effectively suppresses primary tumor growth and extends progression-free survival in the patient with multifocal lung cancer and glioma driven by EGFR R252C. Our finding elucidates the activation mechanism of this extracellular EGFR mutation and demonstrates the efficacy of afatinib in treating lung cancer or glioma patients with this variant.

DOI: https://doi.org/10.1038/s41467-026-68699-4
PLoS One. 2026 ;21(1): e0341445

RIPK2 induces docetaxel resistance in prostate cancer through the NF-κB/P-gp signaling pathway.

Shaoqiang Xing, Zhaoliang Xu, Sheng Zeng, Minghao Yue, Wenzhou Xing, Qian Liu.

Chemoresistance is a reason for treatment failure in prostate cancer. Receptor-interacting protein kinase 2 (RIPK2) has been shown to play a role in drug resistance in various cancers; however, its role and the underlying mechanism of chemoresistance in prostate cancer are unclear. We analyzed data from The Cancer Genome Atlas for RIPK2 expression in prostate cancer and its association with clinicopathological features. We also elucidated the role and mechanism of action of RIPK2 in prostate cancer cell resistance to docetaxel (DTX). The results showed that RIPK2 expression was upregulated in prostate cancer tissues and was associated with poor pathological grading. RIPK2 was also upregulated in 22RV1/DTX, C4-2/DTX, PC-3/DTX, and DU145/DTX cell lines and involved in DTX resistance. Mechanistic experiments revealed that RIPK2 was involved in DTX resistance by upregulating P-glycoprotein (P-gp) expression through the activation of the NF-κB signaling pathway. Xenograft tumor experiments confirmed that inhibition of RIPK2 or P-gp enhanced the efficacy of DTX in suppressing PC-3/DTX growth. Taken together, these results suggest that RIPK2 mediates DTX resistance in prostate cancer cells through the NF-κB/P-gp signaling pathway. RIPK2 and its downstream signaling molecules are potential targets for the treatment of chemoresistant prostate cancer.

DOI: https://doi.org/10.1371/journal.pone.0341445
Front Immunol. 2025 ;16 1749857

The multifaceted role of post-translational modifications in macrophage polarization: from mechanisms to therapeutic targets.

Rui Guo, Feng Qi.

  Macrophage polarization is central to immune homeostasis and disease pathogenesis. It is achieved through complex regulatory networks mediated by post-translational modifications (PTMs). This review synthesizes the roles of phosphorylation, ubiquitination, methylation, acetylation, and lactylation in shaping polarization outcomes through signal-responsive and metabolism-sensitive molecular networks. We integrate evidence that PTMs form interconnected circuits between signaling, epigenetic, and metabolic pathways, thereby enabling sophisticated immune interpretation. Therapeutically, we demonstrate that targeting PTM hubs rather than isolated pathways has transformative potential for reprogramming macrophages in cancer, inflammatory disorders, and tissue repair. However, applying these insights to clinical practice will require overcoming key challenges related to targeting specific pathogenic PTMs with precision, delivering them to specific cells, and validating their mechanisms in vivo.

Keywords:  disease treatment; immune regulation; macrophage polarization; nanotechnology; post-translational modification

DOI:  https://doi.org/10.3389/fimmu.2025.1749857
Cancer Res. 2026 Jan 22.

ACSL5 Mediates Adaptation to the Palmitic Acid-Enriched Pulmonary Microenvironment to Enhance Metastatic Breast Cancer Cell Survival and Lung Metastasis.

Shanchun Chen, Chao Chang, Xiaoqi Liu, Rui Wang, Yongcan Liu, Die Meng, Boxuan Wang, Yuhang Hai, Chaoqun Deng, Yanran Tong, Xiaojiang Cui, Siyang Wen, Guobing Yin, Manran Liu.

Solid tumors frequently preferentially metastasize to specific organs. Metabolites within metastatic niches have emerged as critical regulators of organotropic metastasis. Here, we found that palmitic acid (PA) accumulated in both pre- and macro-metastatic lung niches. Lung-preferential metastatic breast cancer (LM-BC) cells secreted exosomal USP47 that was taken up by lung-resident alveolar type II epithelial cells (AT2) and enhanced fatty acid synthesis via YAP activation, resulting in PA enrichment and subsequent lung metastasis. ACSL5 in LM-BC cells facilitated PA adaptation by inducing COX2-mediated PGE2 accumulation and subsequent activation of the PI3K/AKT and ERK signaling pathways through EP4, which promoted cell survival and lung metastasis. Moreover, ACSL5 boosted levels of palmitoyltransferases, further enhancing COX2 expression, which could be inhibited by the palmitoylation inhibitor 2-bromopalmitate (2-BP). Notably, the enrichment of PA, accumulation of PGE2, and activation of the ACSL5/COX2/EP4 axis in lung metastases of BC patients correlated with poorer clinical outcomes. Limiting PA intake or targeting the ACSL5/COX2/EP4 axis enhanced paclitaxel efficacy in a breast cancer mouse model. Collectively, these findings highlight the critical role of PA and ACSL5/COX2/EP4 signaling in lung metastasis, which can act as promising targets for enhancing the efficacy of chemotherapy in BC patients with lung metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0866
Adv Sci (Weinh). 2026 Jan 21. e07346

Mitochondrial Calcium Uniporter Drives Chemoresistance in Pancreatic Cancer via Glutathione-Mediated Stemness Maintenance.

Zekun Li, Chenyang Meng, Guangcong Shen, Yueying Shan, Junjin Wang, Diliyaer Abudukeremu, Rui Zhao, Bo Ni, Chao Xu, Xiaofan Guo, Jun Yu, Kaiyuan Wang, Shengyu Yang, YunZhan Li, Yongjie Xie, Tianxing Zhou, Jihui Hao, Xiuchao Wang.

  Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with poor prognosis due to chemoresistance. Using integrative single-cell RNA sequencing, we identified that the upregulation of mitochondrial calcium uniporter (MCU) may contribute to chemoresistance and stemness maintenance in PDAC. MCU was highly expressed in chemotherapy-resistant PDAC tumors and correlated with enhanced cancer stem cell properties. Mechanistically, MCU-mediated mitochondrial Ca2+ influx triggered endoplasmic reticulum (ER) stress and the downstream PERK-eIF2α pathway. This cascade activated ATF4 and NRF2, which enhanced the transcriptional regulation of PSAT1 and SLC7A11. These changes promoted de novo glutathione (GSH) synthesis to scavenge reactive oxygen species (ROS) and sustain stemness. Genetic knockdown or pharmacological inhibition of MCU disrupted GSH synthesis, suppressed stemness, and restored sensitivity to nab-paclitaxel plus gemcitabine (AG). High-throughput screening identified MCU inhibitor NB-598, which synergized with AG to inhibit tumor growth in preclinical models. These findings offer a potential novel therapeutic strategy to address chemoresistance in PDAC.

Keywords:  chemoresistance; glutathione synthesis; mitochondrial calcium uniporter; pancreatic ductal adenocarcinoma; stemness maintenance

DOI:  https://doi.org/10.1002/advs.202507346
bioRxiv. 2025 Dec 03. pii: 2025.12.01.691331. [Epub ahead of print]

AKT signaling in hepatocytes rapidly increases glucose phosphorylation and contribution to glycogen without affecting metabolite pool sizes or glycogen breakdown.

Megan Stefkovich, Won Dong Lee, Talia Coopersmith, Joseph A Baur, Joshua D Rabinowitz, Paul M Titchenell.

Background and aims: Hepatic insulin action is essential for whole body glucose homeostasis. Insulin's inhibition of glycogen breakdown, suppression of gluconeogenesis, and activation of glycogen synthesis are critical for postprandial glucose disposal. AKT, a serine-threonine kinase and well-established insulin signaling target, regulates hepatic glucose metabolism through transcriptional and posttranslational mechanisms. However, current knowledge about AKT's regulation of hepatic glucose metabolism largely stems from genetic loss of function models, precluding observation of rapid, transcription-independent effects.
Methods: Stable isotope tracing using [U- 13 C]-glucose was coupled with pharmacological inhibition of AKT using MK-2206 in primary rat hepatocytes. Bulk metabolomics was performed on AKT knockout livers and primary rat hepatocytes treated with MK-2206. Radiolabeled glucose was used to quantify short-term changes to glycogen synthesis.
Results: MK-2206 treatment decreased glucose contribution to glucose 6-phosphate and uridine diphosphate glucose within minutes without significantly affecting total metabolite pool sizes or changes to glucokinase protein levels. This was accompanied by a decrease in glucose contribution to glycogen, independent of changes to glycogen breakdown or glycogen synthase phosphorylation.
Conclusions: Together, these results demonstrate that AKT acutely regulates glucose contribution to glycogen and its upstream precursors, suggesting a transcription-independent, glucokinase-centered mechanism for glycogen synthesis through the direct pathway.

DOI: https://doi.org/10.64898/2025.12.01.691331
bioRxiv. 2025 Dec 07. pii: 2025.12.03.692219. [Epub ahead of print]

Membrane curvature enhances lipid peroxidation in a composition-dependent manner.

Juhee Kim, Stephanie N Bartholomew, Wade F Zeno.

Excessive production of reactive oxygen species (ROS) in cells results in oxidative stress, which can promote lipid peroxidation in cellular membranes. This oxidation of membrane lipids accompanies various diseases and can even result in cell death through processes such as ferroptosis. The complex compositions and diverse morphologies of cellular membranes make understanding the mechanisms of lipid peroxidation challenging, especially when attempting to investigate membrane composition and curvature simultaneously. Here, we utilize reconstituted lipid membranes and the fluorescent oxidation probe C11-BODIPY to quantify lipid oxidation as functions of both lipid composition and membrane curvature. By tethering synthetic lipid vesicles to glass substrates, we were able to monitor lipid oxidation on a per vesicle basis using fluorescence microscopy. Our results demonstrate that highly curved membranes markedly increase both the rate and extent of lipid peroxidation across diverse membrane compositions. This effect arises from greater exposure of lipid tails to the aqueous environment, which allows more efficient transport of ROS into the hydrophobic core of the bilayer. Compositional effects on lipid peroxidation are most pronounced in membranes with low curvature (i.e., greater than 100 nm diameter) and become progressively weaker as curvature increases. We found that low to moderate cholesterol levels (i.e., 10-25 mol%) suppress curvature-dependent oxidation by tightening lipid packing, whereas high cholesterol content (i.e., 50 mol%) restores curvature sensitivity by influencing lateral lipid mobility. Together, these findings establish membrane curvature and lipid composition as interdependent determinants of oxidative susceptibility, offering new insight into how cells regulate or resist oxidative stress.
Statement of significance: Oxidative stress drives lipid peroxidation in cellular membranes, but the combined influence of membrane curvature and composition remains poorly defined. Using reconstituted lipid vesicles and a fluorescent oxidation probe, we show that lipid peroxidation is enhanced in smaller vesicles (i.e., highly curved membranes). The oxidation rate increases with unsaturated lipids, while cholesterol suppresses this effect. Measurements of membrane packing and diffusivity support these findings, demonstrating how curvature and composition together govern membrane susceptibility to oxidative damage. These results provide new insight into the physicochemical basis of membrane stability under oxidative stress and have broad implications for understanding the vulnerability of curved cellular membranes.

DOI: https://doi.org/10.64898/2025.12.03.692219
Sci Rep. 2026 Jan 23.

A proteomics and redox proteomics approach to understanding ARDS heterogeneity.

Thomas E Forshaw, Kirtikar Shukla, Hanzhi Wu, Susan Sergeant, Jingyun Lee, Allen W Tsang, Peter E Morris, Kevin W Gibbs, D Clark Files, Cristina M Furdui.

DOI: https://doi.org/10.1038/s41598-026-35606-2
Database (Oxford). 2026 Jan 15. pii: baag002. [Epub ahead of print]2026

CysDuF database: annotation and characterization of cysteine residues in domain of unknown function proteins based on cysteine post-translational modifications, their protein microenvironments, biochemical pathways, taxonomy, and diseases.

Devarakonda Himaja, Debashree Bandyopadhyay.

Experimental characterization and annotation of amino acids belonging to domains of unknown function (DUF) proteins are expensive and time-consuming, which could be complemented by computational methods. Cysteine, being the second most reactive amino acid at the catalytic sites of enzymes, was selected for functional annotation and characterization on DUF proteins. Earlier, we reported functional annotation of cysteine on DUF proteins belonging to the COX-II family. However, holistic characterization of cysteine functions on DUF proteins was not known, to the best of our knowledge. Here, we annotated and characterized cysteine residues based on post-translational modifications (PTMs), biochemical pathways, diseases, taxonomy, and protein microenvironment. The information on uncharacterized DUF proteins was initially obtained from the literature, and the sequence, structure, pathways, taxonomy, and disease information were retrieved from the SCOPe database using DUF IDs. Protein microenvironments (MENV) around cysteine residues from DUF proteins were computed using protein structures (n = 70 342). The cysteine PTMs were predicted using the in-house cysteine-function prediction server, DeepCys https://deepcys.bits-hyderabad.ac.in). The accuracy of the prediction, validated against known experimental cysteine PTMs (n = 18 626), was 0.79. The information was consolidated in the database (https://cysduf.bits-hyderabad.ac.in/), retrievable in downloadable formats (CSV, JSON, or TXT) using the following inputs, DUF ID, PFAM ID, or PDB ID. For the first time, we annotated cysteine PTMs in DUF proteins belonging to seven different biochemical pathways and various species across the taxonomy, notably for the SARS-CoV-2 virus. The nature of MENV around cysteine from DUF proteins was mainly buried and hydrophobic. However, in the SARS-CoV-2 virus, a significant number of functional cysteine residues were exposed on the surface with hydrophilic microenvironment.

DOI: https://doi.org/10.1093/database/baag002
iScience. 2026 Jan 16. 29(1): 114500

A data-driven pan-cancer proteogenomic analysis reveals the characteristics of human cancer protein expression.

Ying Li, Xin Liu, Zhen Wang, Qiong Wu, Chulin Sha, Xiaolin Li.

  Genomics and epigenomics outline potential cellular changes, while proteomics reflects actual molecular events. To systematically bridge the molecular hierarchies and validate their functional interplay, we established the most comprehensive pan-cancer paired multi-omics resource to date, systematically integrating proteomic, transcriptomic, and genomic data from both tumor and adjacent normal tissues spanning 15 cancer types (2,555 tumor samples), thereby enabling a robust cross-omics exploration. Analysis revealed that tumor tissues exhibit higher correlation between transcriptomic and proteomic expression levels compared to normal tissues. Key tumor development pathways exhibited strong mRNA-protein correlations. Genes with high mRNA-protein correlation and high expression were associated with lower survival rates, highlighting potential therapeutic targets. We developed a comprehensive tool, the CPGTA R package, based on reintegrated datasets that facilitates multi-omics data integration and reanalysis. Our research enhances cancer molecular characterization while providing insights into mechanisms underlying cancer progression and treatment resistance.

Keywords:  Computational bioinformatics; Omics; Systems biology

DOI:  https://doi.org/10.1016/j.isci.2025.114500
Pathol Res Pract. 2026 Jan 15. pii: S0344-0338(26)00015-4. [Epub ahead of print]279 156364

Serine/arginine-rich splicing factor 1 inhibits ferroptosis and promotes glycolysis in endometrial cancer via activating mTOR and β-catenin.

Qing Zhu, Ao Zhang, Yang Gao, Zhenzhong Feng, Nan Li, Qiang Wu.

  Serine/arginine-rich splicing factor 1 (SRSF1) is a pre-mRNA-splicing factor functioning as an oncogene in multiple cancers. However, the biological roles of SRSF1 in endometrial cancer (EC) have not been explored. Here we demonstrated its pivotal function and the regulatory mechanism in regulating ferroptosis and glycolysis in EC. Results showed that SRSF1 inhibited ferroptosis in EC cells, indicated by decreased cell death rate, lipid peroxidation and Fe2 + concentration. SRSF1 accelerated glycolysis in EC cells, evidenced by enhanced glucose uptake, lactate production and adenosine triphosphate production. Mechanistically, SRSF1 elevated the levels of phosphorylated mTOR and β-catenin in EC cells. Besides, the regulation of glycolytic enzyme proteins by SRSF1 in EC cells was dependent on mTOR and β-catenin. Furthermore, rescue assays unveiled that mTOR, β-catenin, and glycolysis involved in the regulatory function of SRSF1 on ferroptosis in EC cells. Finally, animal study proved that SRSF1 knockdown restrained in vivo tumor growth and potentiated the antitumor efficacy of ferroptosis inducer through glycolysis inhibition. In conclusion, the present study uncovered that SRSF1 acts as a tumor promoter in EC through activating mTOR and β-catenin to inhibit ferroptosis and facilitate glycolysis, proposing a therapeutic target for EC.

Keywords:  Endometrial cancer; Ferroptosis; Glycolysis; MTOR; Serine/arginine-rich splicing factor 1; β-catenin

DOI:  https://doi.org/10.1016/j.prp.2026.156364
Autophagy. 2026 Feb;22(2): 235-237

Acetyl-CoA as a metabolic switch for selective mitophagy.

Daolin Tang, Rui Kang, Daniel J Klionsky.

  A recent study published in Nature by Zhang et al. reported that cytosolic acetyl-CoA functions as a signaling metabolite that regulates NLRX1-dependent mitophagy during nutrient stress. This discovery reveals a metabolic checkpoint for mitochondrial quality control and provides new insights into KRAS inhibitor resistance.

Keywords:  Acetyl-CoA; KRAS inhibitor; NLRX1; metabolic signaling; mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2593032
Nat Metab. 2026 Jan 19.

Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance.

Renhui Sun, Deyan Jiao, Wenjing Yuan, Hao Wang, Lingtong Ren, Zhendong Fu, Jiaxuan Zhang, Xuetian Yue, Zhuanchang Wu, Chunyang Li, Huili Hu, Jianping Wang, Lifen Gao, Chunhong Ma, Xiaohong Liang.

Psychological stress is increasingly linked to liver disease, but the underlying mechanisms remain unclear. Here we show that chronic stress disrupts a brain-liver circuit that impairs hepatic CD8+ T cell immunity and accelerates liver cancer progression. Using both oncogene-driven and carcinogen-driven liver cancer models in male mice, we find that psychological stress disrupts catecholamine/β2-adrenergic receptor (ADRB2) signalling, which suppresses the expression of quinolinate phosphoribosyl transferase (QPRT), an enzyme of the kynurenine pathway, in hepatocytes. QPRT loss diverts kynurenine metabolism away from nicotinamide adenine dinucleotide (NAD+) synthesis towards kynurenic acid (KA) accumulation. This shift results in mitochondrial impairment and reduced effector function of liver CD8+ T cells. We confirm that ADRB2/QPRT expression correlates with hepatic NAD+ and KA levels and with CD8+ T cell frequency and function in human liver tissues. Importantly, ADRB2/QPRT overexpression in hepatocytes, or nicotinamide administration, recovers CD8+ T cell function in stressed mice and reduces liver cancer progression. These findings identify a stress-responsive metabolic checkpoint in the liver that links the nervous system to immune surveillance and may be therapeutically targeted in liver cancers.

DOI: https://doi.org/10.1038/s42255-025-01430-7
J Biol Chem. 2026 Jan 20. pii: S0021-9258(26)00039-6. [Epub ahead of print] 111169

ATGL-catalyzed biosynthesis mediates the upregulation of Fatty Acid Hydroxy Fatty Acids (FAHFA) levels in white adipose tissue with fasting.

Anna Santoro, Zhenlong Chen, Andrew T Nelson, Dionicio Siegel, Barbara B Kahn.

  FAHFAs are a family of bioactive lipids. A subclass of these, Palmitic Acid Hydroxy Stearic Acids (PAHSAs) have anti-inflammatory and anti-diabetic effects. Adipose tissue PAHSA levels are upregulated with increased de novo lipogenesis and fasting, and downregulated with insulin resistance and obesity. Adipose Triglyceride Lipase (ATGL) regulates FAHFAs through two distinct mechanisms: hydrolysis of triacylglycerol (TG)-containing FAHFAs and catalyzing formation of the ester bond found in all FAHFAs through a transacylase reaction. ATGL mediates the increase of PAHSAs with fasting in white adipose tissue (WAT), but the mechanism for this has not been determined. Here, we show that multiple FAHFAs are dynamically regulated with fasting and short-term refeeding in both perigonadal (PG) and subcutaneous (SQ) WAT due to ATGL transacylase activity. Our in vivo studies with stable isotopes demonstrate that de novo FAHFA synthesis is upregulated with fasting. This observation along with the fact that FAHFA-TGs are unchanged (SQ WAT) or increased (PG WAT) with fasting and FAHFA hydrolysis is unchanged, suggests that the primary mechanism by which FAHFAs increase in WAT with fasting is de novo synthesis. Using adipose tissue-specific ATGL knock out mice, we show that ATGL is required for the fasting-induced upregulation of endogenous levels and de novo synthesis of multiple FAHFAs. Altogether, this study shows that fasting upregulates multiple FAHFAs by increasing ATGL-mediated synthesis of FAHFAs, inferring that fasting, a physiologic state that is classically known to activate the lipase activity of ATGL, also stimulates its transacylase activity.

Keywords:  ATGL-KO mice; FAHFA; Hydroxy Stearic Acids; PAHSA; TG-FAHFA; adipose tissue metabolism; adipose triglyceride lipase (ATGL); lipid metabolism; lipid synthesis; triglyceride

DOI:  https://doi.org/10.1016/j.jbc.2026.111169
Nat Commun. 2026 Jan 19. 17(1): 775

Site-saturation functional screens identify PALB2 missense variants associated with increased breast cancer risk.

CZECANCA consortium

Loss-of-function variants in PALB2 give rise to defects in DNA damage repair by homologous recombination (HR), increasing the risk of breast cancer in female carriers. However, genetic testing frequently reveals missense variants of uncertain significance (VUS) for which the impact on protein function and cancer risk are unclear. Here we assay 84% of all possible missense variants in 11 out of 13 PALB2 exons using site-saturation functional screens with PARP inhibitor sensitivity as a readout for HR. These exons encode the coiled-coil and WD40 domains, which we identify as the minimal regions required for HR. Furthermore, we reveal the functional impact of 6718 missense variants, classifying 3904 variants as functional (58%), 2422 as intermediate (36%), and 392 as damaging (6%). A burden-type analysis shows that damaging missense variants in PALB2 are associated with a significantly increased risk of breast cancer, similar to that observed for truncating variants. These results will be valuable for the classification of PALB2 missense VUS and clinical management of carriers.

DOI: https://doi.org/10.1038/s41467-025-67252-z
Sci Rep. 2026 Jan 19. 16(1): 2411

The pseudouridine synthase PUS7 is associated with stemness and represents a potential therapeutic target in triple-negative breast cancer cells.

Lu Lu, Lian Xue, Shiyao Jiang, Guangchun He, Xiyun Deng.

  Triple-negative breast cancer (TNBC) represents a highly aggressive subtype of breast cancer characterized by increased recurrence rates and poor prognosis, primarily due to the lack of effective therapeutic targets. Pseudouridine synthases (PUSs) are a class of enzymes that are responsible for catalyzing the isomerization of uridine to pseudouridine in RNA, thereby contributing to cancer progression. In the present study, we examined the roles of PUSs in modulating the biological properties of TNBC using bioinformatics and experimental investigations. Increased gene expression levels of PUSs, particularly PUS7, were identified in TNBC tissues from the TCGA RNA-seq dataset and were found to be associated with unfavorable survival of TNBC patients. In addition, increased protein levels of PUS7 were identified in TNBC patient tissues and cell lines compared with non-TNBC. The increased PUS7 expression was in line with the stemness of TNBC cells. Knockdown of PUS7 in MDA-MB-231 and MDA-MB-468 cells inhibited stemness, migration, and colony formation. Transfection with a PUS7-Mut construct, which eliminated the enzymatic activity of PUS7, reversed the stimulating effects of PUS7 on stemness, migration, and colony formation in TNBC cells. This study highlights the influence of PUS7 on the biological properties of TNBC through its enzymatic activity, providing valuable insights and potential avenues for the identification of effective therapeutic targets for TNBC.

Keywords:  Pseudouridine synthase; Stemness; Targeted therapy; Triple-negative breast cancer

DOI:  https://doi.org/10.1038/s41598-025-25684-z
J Pharmacol Sci. 2026 Feb;pii: S1347-8613(25)00115-X. [Epub ahead of print]160(2): 132-141

Src-dependent modulation of IFNγ-induced PD-L1 expression in human breast cancer cell lines.

Chihiro Hayashi, Yuto Mizuno, Yu Iida, Akane Nagasako, Michiko Endo, Wakana Fukae, Eriko Yamashita, Yoshihiro Ishikawa, Masanari Umemura.

  Triple-negative breast cancer (TNBC), which lacks expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is associated with poor prognosis. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic option for TNBC, but their efficacy remains limited due to resistance. In this study, we investigated whether the non-receptor tyrosine kinase Src (Src tyrosine kinase) regulates interferon-gamma (IFNγ)-induced expression of programmed death-ligand 1 (PD-L1). IFNγ stimulation of TNBC and luminal A breast cancer cell lines induced time-dependent phosphorylation of Src at its activation site (Y419). Pharmacological inhibition of Src significantly suppressed IFNγ-induced PD-L1 mRNA and protein expression, as well as activation of PD-L1-related transcription factors, suggesting transcriptional regulation. In co-culture assays with CD8+ T-cells, TNBC cells were more susceptible to T-cell-mediated cytotoxicity compared with luminal A cells, and Src inhibition further enhanced this cytotoxicity. These findings indicate that Src plays a crucial role in IFNγ-mediated PD-L1 expression and immune evasion in TNBC cell lines. Src inhibition may represent a promising combinatorial strategy to enhance antitumor immunity in TNBC cell lines.

Keywords:  Cluster of differentiation 8 positive T-cell (CD8(+) T-cell); Interferon gamma (IFNγ); Programmed death-ligand 1 (PD-L1); Src tyrosine kinase (Src); Triple-negative breast cancer (TNBC)

DOI:  https://doi.org/10.1016/j.jphs.2025.12.004