bims-cagime 2026-02-01 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–02–01
thirty papers selected by
Kıvanç Görgülü, Technical University of Munich

Ether lipids influence cancer cell fate by modulating iron uptake.
Lysosomes as hubs of metabolic sensing and cellular homeostasis.
Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia.
Computational modeling of cellular influence delineates functionally relevant and distinct cellular neighborhoods in primary and metastatic pancreatic ductal adenocarcinoma.
Membrane Stress and Ferroptosis: Lipid Dynamics in Cancer.
Nuclear mechanobiology in confined cell migration.
Inhibition of Calcium-Dependent Lipid Droplets Relocation of ACSL4-PKCβ-ALOX15 Complex Alleviates Ferroptosis and Acute Pancreatitis.
Simultaneous resection of pancreatic cancer and liver metastases following total neoadjuvant therapy: A case series and analysis of the National Cancer Database.
A Patient-Derived Organ-on-Chip Platform for Modeling the Tumor Microenvironment and Drug Responses in Pancreatic Cancer.
A Thermodynamic Constraint on GPx4 Flux Links Glutathione Redox State to Ferroptotic Commitment.
Comprehensive Curation and Harmonization of Small-Molecule MS/MS Libraries in Spectraverse.
Landscape expansion microscopy reveals interactions between membrane and phase-separated organelles.
Distance From the Root of the Splenic Artery to the Tumor as a Predictor of Para-Aortic Lymph Node Metastasis in Left-Sided Pancreatic Cancer.
Live-cell atomic force microscopy nanoprofiling reveals protease-responsive membrane protein dynamics and cell-type-specific surface codes.
Lipid Droplets are rigid and physically suppress phagocytosis, unless cell compression or stretching activates actomyosin.
Arsenite sensitizes to ferroptosis by disrupting selenium metabolism and reducing GPx4 expression.
Utility of pancreatic tumor scrapings for organoid development and precision medicine strategies.
Lipid scrambling via TMEM16F mediates the formation and release of extracellular vesicles.
Atg5/Autophagy inactivation in mouse bone microenvironment promotes tumor development.
Radiosynthesis and Preclinical Evaluation of [68Ga]Ga-NOTA-PTP Profiling Plectin-1 Expression for Pancreatic Cancer Imaging.
Exploring Biophysics at the Membrane with Single-Molecule TIRF Microscopy.
L-Fucose: a dietary sugar with multifaceted potential in the biology and therapy of cancer.
PathQC: Determining Molecular and Structural Integrity of Tissues from Histopathological Slides.
DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.
Simulation-based inference of cell migration dynamics in complex spatial environments.
p53 and fatty acids collaborate to trigger ferroptosis via the FBXO2-FABP5 axis in colorectal cancer.
Nanodomain formation in lipid bilayers II: The influence of mixed-chain saturated lipids.
Coordination of cell organelles to promote metabolon formation.
NMR metabolomics in genetically engineered mouse models.
New frontiers and applications of cell-free systems.

Nat Commun. 2026 Jan 27.

Ether lipids influence cancer cell fate by modulating iron uptake.

Ryan P Mansell, Sebastian Müller, Jia-Shu Yang, Sarah Innes-Gold, Sunny Das, Ferenc Reinhardt, Kim Janina Sigmund, Vaishnavi V Phadnis, Zhengpeng Wan, Jillian Stark, Daehee Hwang, Fabien Sindikubwabo, Laurène Syx, Nicolas Servant, Elinor Ng Eaton, Julio L Sampaio, George W Bell, Prathapan Thiru, Amartya Viravalli, Amy Deik, Clary B Clish, Paula T Hammond, Roger D Kamm, Adam E Cohen, Ilya Levental, Natalie Boehnke, Victor W Hsu, Kandice R Levental, Raphaël Rodriguez, Robert A Weinberg, Whitney S Henry.

Cancer cell fate has been widely ascribed to mutational changes within protein-coding genes associated with tumor suppressors and oncogenes. In contrast, the mechanisms through which the biophysical properties of membrane lipids influence cancer cell survival, dedifferentiation and metastasis have received little scrutiny. Here, we report that cancer cells endowed with high metastatic ability and cancer stem cell-like traits employ ether lipids to maintain low membrane tension and high membrane fluidity. Using genetic approaches and lipid reconstitution assays, we show that these ether lipid-regulated biophysical properties permit non-clathrin-mediated iron endocytosis via CD44, resulting in significant increases in intracellular redox-active iron and enhanced ferroptosis susceptibility. Using a combination of in vitro three-dimensional microvascular network systems and in vivo animal models, we show that loss of ether lipids from plasma membranes also strongly attenuates extravasation, metastatic burden and cancer stemness. These findings illuminate a mechanism whereby ether lipids in carcinoma cells serve as key regulators of malignant progression while conferring a unique vulnerability that can be exploited for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-026-68547-5
Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00031-6. [Epub ahead of print]

Lysosomes as hubs of metabolic sensing and cellular homeostasis.

Aakriti Jain, Roberto Zoncu.

  Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular degradation, including amino acids, lipids, and iron, are exported by dedicated transporters for utilization in the cytoplasm. Nutrient transport across the lysosomal membrane is coupled to its sensing by specialized signaling complexes on the cytoplasmic face, which, in response, mediate communication with other organelles and control cell-wide programs for growth, catabolism, and stress response. Lysosomes acquire specialized sensing-signaling features in immune cells, where they shape antigen processing, innate immune signaling, and inflammatory cell death, and in neurons, where they act as sentinels of proteostatic and mitochondrial stress, supporting local translation, organelle quality control, and neuroimmune crosstalk. We highlight recently identified pathways and players that position lysosomes as integrators of nutrient status and organelle health to drive tissue-specific physiology.

Keywords:  amyloid; autophagy; inflammation; lysosome; mTORC1; metabolites; neurodegeneration; organelle contacts; signaling

DOI:  https://doi.org/10.1016/j.molcel.2026.01.011
JCI Insight. 2026 Jan 27. pii: e200396. [Epub ahead of print]

Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia.

Bowen Xu, Aniket S Joshi, Meiricris Tomaz da Silva, Silin Liu, Ashok Kumar.

  Cachexia is a debilitating syndrome characterized by progressive skeletal muscle wasting, commonly affecting cancer patients, particularly those with pancreatic cancer. Despite its clinical significance, the molecular mechanisms underlying cancer cachexia remain poorly understood. In this study, we utilized single-nucleus RNA sequencing (snRNA-seq) and bulk RNA-seq, complemented by biochemical and histological analyses, to investigate molecular alterations in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Our findings demonstrated that KPC tumor growth induced myofiber-specific changes in the expression of genes involved in proteolytic pathways, mitochondrial biogenesis, and angiogenesis. Notably, tumor progression enhanced the activity of specific transcription factors that regulate the mTORC1 signaling pathway, along with genes involved in translational initiation and ribosome biogenesis. Skeletal muscle-specific, inducible inhibition of mTORC1 activity further exacerbated muscle loss in tumor-bearing mice, highlighting its protective role in maintaining muscle mass. Additionally, we uncovered new intercellular signaling networks within the skeletal muscle microenvironment during pancreatic cancer-induced cachexia. Together, our study revealed previously unrecognized molecular mechanisms that regulates skeletal muscle homeostasis and identified potential therapeutic targets for the treatment of pancreatic cancer-associated cachexia.

Keywords:  Cancer; Cell biology; Expression profiling; Muscle; Muscle biology

DOI:  https://doi.org/10.1172/jci.insight.200396
Cancer Immunol Res. 2026 Jan 23.

Computational modeling of cellular influence delineates functionally relevant and distinct cellular neighborhoods in primary and metastatic pancreatic ductal adenocarcinoma.

Yeonju Cho, Jae W Lee, Sarah M Shin, Alexei G Hernandez, Xuan Yuan, Jowaly Schneider, Jody E Hooper, Laura D Wood, Elizabeth M Jaffee, Atul Deshpande, Won Jin Ho.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with liver metastases significantly worsening outcomes. However, features of the tumor microenvironment (TME) that are distinct between primary and metastatic sites remain poorly defined. Cellular neighborhoods within the TME are recognized as functional units that influence tumor behavior. Conventional spatial methods, which assign equal weights to all cells in a region, fail to capture the nuances of cellular interactions. To address this, we report here the development of Functional Cellular Neighborhood (FunCN) quantification, which integrates both the proportion and proximity of surrounding cells. Applying FunCN to PDAC imaging mass cytometry data, we identified neutrophil-enriched interactions in liver metastases compared to primary tumors, correlating with elevated VISTA expression by tumor cells. Additionally, FunCN clusters around CD8⁺ T cells in pancreas and liver were associated with higher TIGIT and LAG3, respectively. These findings demonstrate the importance of spatial immune landscapes in PDAC and identify potential therapeutic opportunities.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0844
Int J Mol Sci. 2026 Jan 09. pii: 690. [Epub ahead of print]27(2):

Membrane Stress and Ferroptosis: Lipid Dynamics in Cancer.

Jaewang Lee, Youngin Seo, Jong-Lyel Roh.

  Membrane rupture, induced by lipid peroxidation, is a severe threat to osmotic balance, as membrane pores contribute to ferroptosis, an iron-dependent cell death. To alleviate osmotic stress, membrane constituents dynamically reconstruct the membrane and interact with intracellular molecules. Tumor-derived acidosis shift glycolysis-dependent metabolism toward lipid metabolism, increasing polyunsaturated fatty acids (PUFAs). PUFAs enhance membrane fluidity but make cancer susceptible to lipid peroxidation. Also, the ionization of phospholipids under low pH can accelerate membrane rupture. This stress can be mitigated by the redistribution of cholesterol, which maintains tension-compression balance and acts as antioxidants. When excessive reactive aldehydes-byproducts of lipid peroxidation-overwhelm cholesterol's protective role, lipid peroxides promote membrane cracks. Moreover, a deficiency in glutathione can alter cholesterol's function, turning it into a pro-oxidant. In contrast, ceramide, derived from membrane lipids, indirectly prevents ferroptosis by facilitating cytochrome c release. This review integrates recent findings on how membrane components and environmental stressors influence ferroptosis. It also suggests potential therapeutic strategies. This could advance our understanding of ferroptosis in cancer.

Keywords:  EMT; aldehydes; cholesterol; lipid peroxidation; pH; plasma membrane

DOI:  https://doi.org/10.3390/ijms27020690
Nucleus. 2026 Dec;17(1): 2620879

Nuclear mechanobiology in confined cell migration.

Hailee Patel, Simran Kaur, Richard B Dickinson, Tanmay P Lele.

  Nuclear deformation is a central challenge for migration of cells through confined spaces in the tissue interstitium. In this paper, we review studies on the mechanical roles of the nucleus in confined cell migration. We focus on mechanical force generation by the cytoskeleton on the nuclear surface, the properties of sub-nuclear structures in the process, and functional responses of the nucleus in response to mechanical forces, all in the context of confined cell migration. An emerging theme is that the nucleus acts not only as a barrier for confined migration, but also as a mechanoresponsive organelle whose deformation feeds back to modify cell behaviors. Deciphering these complex processes will be key to understanding how cells navigate complex tissues in development, immunity, and cancer.

Keywords:  Cellular mechanics; confined cell migration; mechanotransduction; nuclear deformation; nuclear mechanobiology; sub-nuclear structures

DOI:  https://doi.org/10.1080/19491034.2026.2620879
Adv Sci (Weinh). 2026 Jan 27. e15768

Inhibition of Calcium-Dependent Lipid Droplets Relocation of ACSL4-PKCβ-ALOX15 Complex Alleviates Ferroptosis and Acute Pancreatitis.

Guoyuan Hou, Jing Luan, Xiaoyong Xu, Jianhua Qin, Shuang Ma, Jiyuan He, Na Sun, Wei Zhang, Minghui Gao.

  Ferroptosis, an iron-dependent form of programmed cell death driven by toxic lipid peroxide accumulation, plays a critical role in various diseases, making its modulation a promising therapeutic strategy. In this study, we identified several L-type calcium channel blockers as novel inhibitors of ferroptosis. We further elucidated that calcium-dependent activation of PKCβ drives ferroptosis by phosphorylating two key enzymes, ACSL4 and ALOX15, at multiple sites. We generated phosphorylation-specific antibodies targeting these sites and confirmed their specificity in the context of ferroptosis. Furthermore, upon induction of ferroptosis, the ACSL4-PKCβ-ALOX15 complex relocates to lipid droplets, highlighting a critical role of lipid droplets in ferroptosis. Notably, elevated PKCβ levels enhance the efficacy of ferroptosis-inducing cancer therapies, while inhibition of the Ca2 +-PKCβ signaling pathway protects against acute pancreatitis by suppressing ferroptosis. These findings underscore the therapeutic potential of targeting Ca2 +-PKCβ-mediated ferroptosis, offering new avenues for the treatment of cancer and acute pancreatitis.

Keywords:  ACSL4; ALOX15; PKCβ; acute pancreatitis; calcium; ferroptosis; lipid droplets

DOI:  https://doi.org/10.1002/advs.202515768
Ann Hepatobiliary Pancreat Surg. 2026 Jan 28.

Simultaneous resection of pancreatic cancer and liver metastases following total neoadjuvant therapy: A case series and analysis of the National Cancer Database.

McKenzie L Schaefer, Patrick L Quinn, Alexander H Shannon, Laith Abushahin, Jordan M Cloyd, Mary E Dillhoff, Ning Jin, Ashish Manne, Arjun Mittra, Anne M Noonan, Timothy M Pawlik, Shafia Rahman, Aslam Ejaz.

   Backgrounds/Aims: The role of surgery for pancreatic ductal adenocarcinoma (PDAC) with synchronous liver metastases remains controversial. Previous studies assessing the outcomes of combined surgery for primary PDAC and liver metastases have been limited by the inconsistent application of neoadjuvant chemotherapy (NAC).
Methods: We identified patients with PDAC and fewer than three liver metastases who received at least six months of NAC and underwent simultaneous pancreas and liver resection between January 2018 and March 2023 at a single institution. Additionally, we queried the National Cancer Database (NCDB) from 2010 to 2019 to identify patients with synchronous metastatic PDAC to the liver who received NAC before simultaneous resection, serving as a comparison group.
Results: Ten patients met the inclusion criteria for the institutional case series, with seven ultimately undergoing simultaneous resection. Among 224 patients in the NCDB who underwent simultaneous pancreas and liver resection, 70 patients (31.2%) received NAC. After a median follow-up of 59 months in the institutional cohort, five patients experienced recurrence, resulting in a median disease-free survival of four months (95% confidence interval [CI] 3, not reached). After controlling for confounding factors in the NCDB cohort, the administration of NAC was associated with improved survival (hazard ratio: 0.44, 95% CI 0.29-0.65, p < 0.001) compared to those who underwent upfront surgery.
Conclusions: Neoadjuvant therapy followed by simultaneous liver and pancreas resection for metastatic PDAC is safe and feasible, and it may provide a survival benefit in carefully selected patient populations.

Keywords:  Hepatectomy; Neoplasm metastasis; Pancreatectomy; Pancreatic neoplasms

DOI:  https://doi.org/10.14701/ahbps.25-209
Adv Sci (Weinh). 2026 Jan 29. e08934

A Patient-Derived Organ-on-Chip Platform for Modeling the Tumor Microenvironment and Drug Responses in Pancreatic Cancer.

Darbaz Adnan, Natan Roberto de Barros, Luca S Santovito, Xuhong Cheng, Kristi M Lawrence, Mariah K Barnett, Martine D Boetto, Neal Mehta, Ajaypal Singh, Lin Cheng, Xiangsheng Huang, Faraz Bishehsari.

  Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy. Current conventional chemotherapeutics are inadequate in controlling the disease; hence, there is an urgent need for precision medicine. Ex vivo models that replicate the tumor and its microenvironment can advance precision medicine in PDAC. Patient-derived organoids (PDOs) offer a promising solution by retaining the functional features of the tumor, allowing for individualized study of cancer biology and drug response. However, PDOs fall short in replicating the tumor microenvironment (TME), which includes various stromal and immune cells influencing tumor growth and chemoresistance. We hypothesize that combining PDO technology with organ-on-a-chip (OoC) systems can enhance ex vivo cancer modeling. Here, we develop a patient-derived platform by incorporating PDOs with key components of the TME (fibroblasts, endothelial cells, and immune cells) within a microfluidic system. This OoC model represents the crosstalk between cancer and stroma observed in PDAC in vivo. Targeting the stroma improves the effectiveness of standard chemotherapy in this OoC. Further, using this platform, we are able to model and assess the efficacy of immune checkpoint blockade for T cell cytotoxicity in PDAC. The OoC provides a pathophysiologically applicable system to support future investigations aimed at utilizing precision medicine and testing therapeutics in PDAC.

Keywords:  microfluidic; organ on chip; pancreatic cancer; patient derived organoids; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202508934
Free Radic Biol Med. 2026 Jan 23. pii: S0891-5849(26)00057-2. [Epub ahead of print]

A Thermodynamic Constraint on GPx4 Flux Links Glutathione Redox State to Ferroptotic Commitment.

Fulvio Ursini, Antonella Roveri, Matilde Maiorino, Laura Orian.

  Ferroptosis is a non-accidental form of cell death driven by lipid peroxidation and critically controlled by the selenoenzyme Glutathione Peroxidase 4 (GPx4). By integrating molecular modeling, redox thermodynamics, and enzymatic evidence, we propose that ferroptosis is governed by the redox potential of the glutathione couple, elevating current mechanistic descriptions to a quantitative physical-chemical framework. The terminal step of the GPx4 catalytic cycle-responsible for enzyme regeneration and oxidized glutathione (GSSG) formation-is intrinsically endergonic, and its driving force declines continuously as the glutathione redox potential becomes less reducing. As a result, GPx4 activity decreases linearly in accordance with Nernstian principle, independently of discrete inhibitory events. Within this framework, ferroptosis is not initiated by a discrete molecular trigger or canonical signaling cascade; rather, it emerges when a critical biological threshold is surpassed, such that GPx4-dependent detoxification capacity is no longer sufficient to counteract ongoing lipid peroxidation within a given pro-oxidant context. Thus, a discrete cell-death outcome executed by GSSG emerges from the continuous variation of a thermodynamic control variable. This mode of regulation is unique to selenium chemistry and provides a physical-chemical rationale for the indispensability of selenocysteine in the redox control of cellular life and death.

Keywords:  Ferroptosis; GPx4; Glutathione peroxidases; Glutathione redox potential; Lipid peroxidation; Redox homeostasis; Redox thermodynamics; Selenocysteine

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.039
Anal Chem. 2026 Jan 25.

Comprehensive Curation and Harmonization of Small-Molecule MS/MS Libraries in Spectraverse.

Vishu Gupta, Hantao Qiang, Hsin-Hsiang Chung, Ehud Herbst, Michael A Skinnider.

Reference libraries of tandem mass spectra (MS/MS) are widely used for metabolite identification in untargeted metabolomics and to train machine-learning models for metabolite annotation. However, public spectral libraries are scattered across disparate databases and contain spectra that are of low resolution or quality, missing critical metadata, or which have chemically incoherent annotations. Addressing these issues requires extensive preprocessing and considerable expertise in mass spectrometry, which presents a significant barrier to investigators interested in developing their own machine-learning models. Here, we present Spectraverse, a comprehensive and extensively curated library of public MS/MS spectra from small molecules. We assembled reference spectra from both major repositories and previously overlooked resources and then developed a preprocessing pipeline to harmonize metadata, standardize chemical structures, and remove low-quality or redundant spectra. These efforts led us to identify previously undocumented pitfalls in existing public libraries that may have confounded prior comparisons of machine-learning models or conversely have caused valid MS/MS spectra to have been discarded from the training sets of these models. The resulting resource affords the most comprehensive coverage of chemical space of any machine-learning-ready library of MS/MS spectra to date while also expanding the coverage of adducts and ionization modes encountered in metabolomics experiments. We intend to maintain and expand Spectraverse in order to encompass the growing number of publicly available reference MS/MS spectra that can be expected to accumulate in the future.

DOI: https://doi.org/10.1021/acs.analchem.5c06256
J Cell Biol. 2026 Apr 06. pii: e202502035. [Epub ahead of print]225(4):

Landscape expansion microscopy reveals interactions between membrane and phase-separated organelles.

Yinyin Zhuang, Zhao Zhang, Zhipeng Dai, Xiaoyu Shi.

Landscape expansion microscopy (land-ExM) is a light microscopy technique that visualizes both the lipid and protein ultrastructural context of cells. Achieving this level of detail requires both superresolution and a high signal-to-noise ratio. Although expansion microscopy (ExM) provides superresolution, obtaining high signal-to-noise images of both proteins and lipids remains challenging. land-ExM overcomes this limitation by using self-retention trifunctional anchors to significantly enhance protein and lipid signals in expanded samples. This improvement enables the accurate visualization of diverse membrane organelles and phase separations, as well as the 3D visualization of their contact sites. As a demonstration, we revealed triple-organellar contact sites among the stress granule, the nuclear tunnel, and the nucleolus. Overall, land-ExM offers a high-contrast superresolution platform that advances our understanding of how cells spatially coordinate interactions between membrane organelles and phase separations.

DOI: https://doi.org/10.1083/jcb.202502035
J Hepatobiliary Pancreat Sci. 2026 Jan 26.

Distance From the Root of the Splenic Artery to the Tumor as a Predictor of Para-Aortic Lymph Node Metastasis in Left-Sided Pancreatic Cancer.

Kotaro Kimura, Shoki Sato, Zen Naito, Hiroyuki Yamamoto, Tomohiro Suzuki, Noriaki Kyogoku, Hirokatsu Katagiri, Minoru Takada, Yoshiyasu Ambo, Satoshi Hirano.

   BACKGROUND/PURPOSE: Preoperative diagnosis of para-aortic lymph node (PALN) metastasis, particularly at station 16b1-a contraindication to pancreatic ductal adenocarcinoma (PDAC) resection-remains challenging. We investigated whether the distance from the root of the splenic artery (SPA) to the tumor (DST) is an objective predictor of PALN metastasis.
METHODS: We retrospectively analyzed 130 patients who underwent distal pancreatectomy with PALN sampling for PDAC from 2012 to 2022. DST was measured using preoperative contrast-enhanced computed tomography. Receiver operating characteristic (ROC) analysis was performed, and clinicopathological factors were analyzed.
RESULTS: PALN metastasis occurred in 7/130 (5.4%) patients. DST was significantly shorter in the PALN-positive group (median: 12.0 vs. 18.0 mm, p = 0.0001). ROC analysis indicated that the optimal cutoff value was 20.0 mm. In univariate and multivariate analyses, DST ≤ 20.0 mm was the only factor significantly associated with PALN metastasis (p = 0.0042 and p = 0.0093, respectively). All PALN-positive cases had DST ≤ 20.0 mm.
CONCLUSIONS: DST is a clinically useful metric for predicting PALN metastasis in left-sided PDAC. In patients with DST > 20 mm, the likelihood of PALN involvement appeared extremely low, suggesting that intraoperative lymph node sampling may be omitted in selected patients.

Keywords:  distal pancreatectomy; pancreatic ductal adenocarcinoma; para‐aortic lymph node metastasis; splenic artery; tumor location

DOI:  https://doi.org/10.1002/jhbp.70074
Biochem Biophys Res Commun. 2026 Jan 21. pii: S0006-291X(26)00102-6. [Epub ahead of print]802 153338

Live-cell atomic force microscopy nanoprofiling reveals protease-responsive membrane protein dynamics and cell-type-specific surface codes.

Xueyan Liu, Lin Liu.

  Cell membranes, as phospholipid-protein interfaces, regulate cellular recognition and communication. However, real-time nanoscale observation of native membrane proteins in live cells remains challenging. Here, we employed atomic force microscopy (AFM) to characterize the surface properties of live HeLa cells, and found that mild trypsin digestion reduced significantly surface roughness (Rq: ∼150 → 120 nm) and adhesion force (∼27 → 20 pN), whereas chemical fixation obscured these dynamic changes. Comparative AFM imaging across four cell lines revealed distinct topographies: MCF-7 cancer cells exhibited the highest surface roughness (Rq = 212 nm), versus smoother morphology of NIH-3T3 fibroblasts (Rq = 172 nm). These findings demonstrate that nanoscale surface morphology encodes cell identity, functional state, and malignancy, with increased roughness reflecting complex membrane protein organization. Live-cell AFM thus decodes membrane protein dynamics and cell-type-specific surface codes, offering a powerful platform for physiological studies and translational applications in biology, cancer research, neuroscience, and drug development.

Keywords:  AFM; Live cells; Membrane protein dynamic

DOI:  https://doi.org/10.1016/j.bbrc.2026.153338
Mol Biol Cell. 2026 Jan 28. mbcE25060294

Lipid Droplets are rigid and physically suppress phagocytosis, unless cell compression or stretching activates actomyosin.

Michael P Tobin, Irena L Ivanovska, Steven H Phan, Tianyi Bai, Jeneille Deans, Guilherme P F Nader, Dennis E Discher.

As with many cell types, macrophages are sometimes filled with micron-sized lipid droplets (LD's), but effects on phagocytosis of other cells, particulates, and microbes remain unclear. Here, we show LD's re-structure the cytoskeleton but remain round, consistent with a high interfacial tension, and they also impair actomyosin-driven uptake regardless of target size. Engulfment starts at the apical surface, but LD's displace apical actomyosin to the basal cortex. However, actomyosin is activated and phagocytosis rescued when applying tissue-relevant compressive stress to LD-loaded macrophages. Macrophages that are densely filled with LD's or pre-engulfed beads likewise activate actomyosin which again rescues phagocytosis relative to sparsely loaded cells. LD's and rigid beads also impede macrophage migration through small pores, and LD's pressed strongly into a nucleus can even cause rapid focal rupture independent of actin. LD's thus disrupt cytoskeleton organization and nucleus integrity, generally suppressing motility processes unless actomyosin is activated by cell compression or stretching.

DOI: https://doi.org/10.1091/mbc.E25-06-0294
Toxicology. 2026 Jan 25. pii: S0300-483X(26)00016-8. [Epub ahead of print]522 154409

Arsenite sensitizes to ferroptosis by disrupting selenium metabolism and reducing GPx4 expression.

Hayato Takashima, Reiko Makino, Hiroki Taguchi, Junya Ito, Eikan Mishima, Yoshika Takenaka, Yasutoshi Akiyama, Daigo Sumi, Marcus Conrad, Yoshihisa Tomikoka, Takashi Toyama, Yoshiro Saito.

  Arsenic (As), an environmental toxicant commonly found in groundwater, exerts its toxic effects primarily through oxidative stress. Selenium (Se) plays a crucial role in counteracting oxidative stress by promoting the synthesis of Se-containing antioxidant enzymes, such as glutathione peroxidases (GPx). To elucidate the impact of As on cellular Se metabolism, we investigated the effects of inorganic arsenic on cultured cells (HT-1080, Jurkat, and SH-SY5Y). Our findings indicate that As(III) disrupts Se metabolism and inhibits Se-induced GPx expression. By comparing different Se sources (selenoprotein P, selenocysteine, and selenite), we determined that As(III) primarily interferes with Se metabolism downstream of selenite, an inorganic form of Se. Notably, exposure to As(III) reduced Se incorporation into RNA, suggesting inhibition of Sec-tRNASec synthesis, a critical step in selenoprotein biosynthesis. Additionally, As(III) increased cellular susceptibility to ferroptosis, a form of oxidative stress-driven lipid peroxidation-mediated cell death primarily regulated by GPx4. Supporting this, genetic deletion of PRDX6, a recently identified regulator of cellular Se metabolism, further suppressed selenoprotein expression and exacerbated As(III)-induced ferroptosis. These findings provide new insights into the toxicological mechanisms of As compounds, highlighting their role in disrupting Se metabolism and potentially mitigating the side effects associated with arsenic-based anticancer therapies.

Keywords:  Arsenic; Ferroptosis; Glutathione peroxidase; Peroxiredoxin 6; Selenium; Vitamin E

DOI:  https://doi.org/10.1016/j.tox.2026.154409
J Pathol. 2026 Jan 26.

Utility of pancreatic tumor scrapings for organoid development and precision medicine strategies.

Caitlin F Tsang, Hardik Patel, Fatim M Kouassi, Binny Khandakar, Luce G St Surin, James A Rouse, Raditya Utama, Deepthi Budagavi, Julien T Hohenleitner, Adeline Chunton, Zhen Zhao, Sharon S Fox, Cristina C Valente, Matthew J Weiss, Arvind Rishi, Daniel A King, James M Crawford, Amber N Habowski, David A Tuveson.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers due to late diagnosis and chemoresistance. Patient-derived organoids (PDOs) hold promise for predicting individualized drug responses, but their establishment is often constrained by the limited availability of tumor material and prior neoadjuvant treatment. Standard PDO generation relies on dissected tissue slices from the cut surface of the tumor, which may include both the invasive front, where it is postulated that more aggressive cancer cells reside, and potentially fewer viable neoplastic cells in the tumor center. This study investigated whether scraping the cut surface of the PDAC enhanced PDO establishment compared to standard tissue samples, to take advantage of potential harvesting of viable neoplastic cells from the invasive front. Tumor scrapings from 26 patients and matched tissue slices from 20 patients were collected. PDOs were successfully established from 10 tumor scrapings and eight matched tissue slices, including three neoadjuvant-treated cases. Organoid histological architecture was comparable to the surgical tumor specimens, with paired scraping PDOs and tissue slice PDOs showing genomic and transcriptomic concordance. Pharmacotyping demonstrated that scraping PDOs reliably captured patient-specific chemosensitivity, highlighting the potential for a viable alternative method to standard tissue-slice PDOs. As proliferative and treatment-resistant neoplastic cells often originate from tumor edges, increasing representation of the periphery and across the tumor may offer a more clinically relevant model of PDAC biology, improving therapeutic decision-making and patient outcomes. © 2026 The Pathological Society of Great Britain and Ireland.

Keywords:  drug screening; in vitro model; pancreatic ductal adenocarcinoma; patient‐derived organoids; precision medicine

DOI:  https://doi.org/10.1002/path.70025
Mol Biol Cell. 2026 Jan 28. mbcE25050245

Lipid scrambling via TMEM16F mediates the formation and release of extracellular vesicles.

Trieu Le, Maria Eugenia Perez Collado, Yu Meng Li, Amra Saric, Joost C M Holthuis, Sergio Grinstein, Spencer A Freeman.

The ubiquitous and highly conserved programmed cell death pathways that are essential for tissue development and homeostasis are accompanied by distinct morphological alterations. Apoptotic cells undergo fragmentation that is concomitant with the exposure of phosphatidylserine (PS) on the membrane surface. Large fragments, called apoptotic bodies, as well as much smaller and more numerous vesicles are released. While the molecular mechanisms underlying apoptotic body formation have been explored, much less is known about vesicle biogenesis. We used an inducible, active form of TMEM16F to determine the role of lipid scrambling in vesiculation, separately from other apoptotic signaling events. Plasmalemmal lipid scrambling sufficed to release apoptotic-like vesicles without causing changes in cytosolic calcium or the submembrane cytoskeleton. The scrambled bilayer showed pronounced segregation of exofacial lipids and redistribution of detectable cholesterol to the inner leaflet. The clustering of raft-associated components with bulky headgroups-typified by glycophosphatidylinositol-linked proteins-formed domains of outward (convex) curvature, while regions of accumulation of phosphatidylethanolamine (PE) generated inward (concave) curvature that facilitated the scission of vesicles. Thus, scrambling of plasma membrane lipids suffices to induce regions of acute membrane curvature and facilitates detachment of vesicles analogous to those released from the surface of apoptotic cells.

DOI: https://doi.org/10.1091/mbc.E25-05-0245
Autophagy. 2026 Jan 29.

Atg5/Autophagy inactivation in mouse bone microenvironment promotes tumor development.

Marie-Charlotte Trojani, Marie Nollet, Olivier Camuzard, Sabine Santucci-Darmanin, Véronique Breuil, Fanny Burel-Vandenbos, Laurie Fradet, Morgane Le Gall, Virginie Salnot, Dominique Heymann, Georges F Carle, Valérie Pierrefite-Carle.

  Bone is an attractive site for cancer colonization, both for primary tumors such as osteosarcoma and for metastases of various malignancies. Preventing bone metastasis, which is associated with a poor prognosis, is a major challenge and identifying the factors involved in skeletal tumoral development is crucial to improve survival. In the present work, we showed that inactivation of the macroautophagy/autophagy-essential gene Atg5 in osteoblasts, the cells in charge of bone formation, stimulates osteosarcoma and breastbone metastasis growth as well as metastatic dissemination. We determined that Atg5 inactivation leads to systemic inflammation and bone proteome modifications including translation downregulation, stress granule formation, and upregulation of fatty acid beta-oxidation. In addition, Atg5 inactivation triggered lysosomal exocytosis through an autophagy-independent effect. Thus, our findings indicated that autophagy/ATG5 deficiency in the bone microenvironment generates a favorable environment for tumor development through several mechanisms and suggested that a bone-targeted autophagy inducer could be used to delay bone metastasis appearance.

Keywords:  Autophagy; bone metastasis; bone microenvironment; breast cancer; osteoblast; osteosarcoma

DOI:  https://doi.org/10.1080/15548627.2026.2624756
J Med Chem. 2026 Jan 28.

Radiosynthesis and Preclinical Evaluation of [68Ga]Ga-NOTA-PTP Profiling Plectin-1 Expression for Pancreatic Cancer Imaging.

Tingting Wang, Jingchao Li, Xiangping Chen, Xun Zhang, Dongsheng Zhang, Guangfa Wang, Jian Li, Yafei Zhang, Nian Liu, Xiao Chen, Xinhui Su.

Pancreatic ductal adenocarcinoma (PDAC) remains challenging to diagnose in its early stages. Capitalizing on the established overexpression of plectin-1 in PDAC, we developed a novel plectin-1-targeted positron emission tomography (PET) radiotracer, [68Ga]Ga-NOTA-PTP, for precise PDAC imaging. The NOTA-PTP conjugate was synthesized, characterized, and efficiently radiolabeled with 68Ga, achieving high radiochemical purity (>99%). The radiotracer displayed a strong binding affinity for plectin-1 (IC50 = 12.8 nM) and exhibited time-dependent accumulation in PDAC cells. In murine PDAC xenografts, PET imaging demonstrated the rapid and specific tumor uptake of [68Ga]Ga-NOTA-PTP, enabling the visualization of peritoneal metastases. Targeting specificity was further verified by both the significant reduction in tumor uptake upon preadministration of the unlabeled compound and the positive correlation between tracer accumulation and plectin-1 expression levels. Collectively, this work introduces the first plectin-1-targeted PET probe for specific and sensitive detection of PDAC and metastatic lesions through efficient plectin-1 engagement.

DOI: https://doi.org/10.1021/acs.jmedchem.5c02777
Adv Exp Med Biol. 2026 ;1497 117-141

Exploring Biophysics at the Membrane with Single-Molecule TIRF Microscopy.

R Charles Kissell, James T Pentikis, Austin M Baggetta, Leigh D Plant.

  Cellular functions result from the action of heteromeric protein machines that typically exhibit greater utility and dynamism than the sum of their parts. Therefore, the structural composition of these multimeric machines must be determined to delineate their functional attributes, including how information is transduced between the extracellular and intracellular environments, and between cells. While evaluating the activity of a protein complex at the population level provides valuable insights, measuring the activity of individual molecules offers a powerful approach for uncovering functional dynamics and reaction kinetics that are often obscured in ensemble measurements. Here we describe the background and application of Total Internal Reflection Fluorescence, or TIRF microscopy. We introduce the photo-physics that underpin TIRF and describe its utility in the study of membrane protein biophysics. We focus on applications of TIRF designed to determine the stoichiometry and real-time movement of protein complexes, especially ion channels and signaling receptors, in biological membranes.

Keywords:  Fluorescence photobleaching; Ion channel; Membrane protein; Particle tracking; Stoichiometry; TIRF microscopy

DOI:  https://doi.org/10.1007/978-3-032-07523-9_5
Nat Rev Cancer. 2026 Jan 27.

L-Fucose: a dietary sugar with multifaceted potential in the biology and therapy of cancer.

Amirreza Bitaraf, Maria Camila Jimenez, Chinmayee Kakirde, Eric K Lau.

Fucosylation, the conjugation of glycoproteins and glycolipids with the dietary sugar L-fucose, can have key functional and regulatory roles across a range of normal biological and developmental processes. Although the full repertoire of fucosylated proteins and their direct influence on signalling and cellular behaviour remains incompletely understood, it is not surprising that deregulated fucosylation has been increasingly associated with disease contexts, particularly cancer. Importantly, fucosylation regulates the biology of immune and other stromal cells, and emerging studies have elucidated how pathological aberrations in fucosylation can deregulate signalling that governs cellular interactions in the tumour microenvironment, thereby influencing tumour progression and therapeutic responses. Accordingly, fucosylated glycoproteins and glycans have been reported to exhibit potential biomarker utility, associating with cancer type and staging. Notably, fucosylation appears to be therapeutically actionable, as simply administering L-fucose orally can suffice to suppress tumour growth and stimulate antitumour immune responses in preclinical models. However, given that the blockade of fucosylation machinery can elicit similar antitumour effects reflects the diversity of cell-intrinsic and cell-extrinsic roles that fucosylation can divergently have across the tumour microenvironment. Here, we review recent glycobiology discoveries that shed light on the complexity of fucosylation, its mechanistic roles in immune and tumour biology, and how it might be strategically leveraged for the treatment of cancer.

DOI: https://doi.org/10.1038/s41568-025-00901-z
Bioengineering (Basel). 2025 Dec 21. pii: 5. [Epub ahead of print]13(1):

PathQC: Determining Molecular and Structural Integrity of Tissues from Histopathological Slides.

Ranjit Kumar Sinha, Anamika Yadav, Sanju Sinha.

  Quantifying tissue, molecular, and structural integrity is essential for biobank development. However, current assessment methods either involve destructive testing that depletes valuable biospecimens or rely on manual evaluations, which are not scalable and lead to interindividual variation. To overcome these challenges, we present PathQC, a deep-learning framework that directly predicts the tissue RNA Integrity Number (RIN) and the extent of autolysis from hematoxylin and eosin (H & E)-stained whole-slide images of normal tissue biopsies. Advancing over prior QC methods focused on imaging quality control, PathQC provides sample-quality control through the direct quantification of molecular integrity (RIN) and structural degradation (autolysis). PathQC first extracts morphological features from the slide using a recently developed digital pathology foundation model (UNI), followed by a supervised model that learns to predict RNA Integrity Number and autolysis scores from these morphological features. PathQC is trained on and applied to the Genotype-Tissue Expression (GTEx) cohort, which comprises 25,306 non-diseased post-mortem samples across 29 tissues from 970 donors, when paired ground-truth RIN and autolysis scores were available. Here, PathQC predicted RIN with an average Pearson correlation of 0.47 and an autolysis score of 0.45, with notably high performance using adrenal gland tissue (R = 0.82) for RIN and colon tissue (R = 0.83) for autolysis. We provide a pan-tissue model for predicting RIN and autolysis scores for new slides from any tissue type (GitHub). Overall, PathQC enables a scalable assessment of tissue molecular and structural integrity from routine H & E images, enhancing biobank quality control and retrospective analyses across 29 tissues and multiple collection sites.

Keywords:  biobanking application; digital pathology; quality control

DOI:  https://doi.org/10.3390/bioengineering13010005
Science. 2026 Jan 29. 391(6784): eadx9445

DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.

Ines Tomaskovic, Cristian Prieto-Garcia, Maria Boskovic, Mateo Glumac, Tsung-Lin Tsai, Thorsten Mosler, Rubina Kazi, Rajeshwari Rathore, Jorge Andrade, Marina Hoffmann, Giulio Giuliani, Anne-Claire Jacomin, Raquel S Pereira, Elias Knop, Laurens Wachsmuth, Petra Beli, Koraljka Husnjak, Manolis Pasparakis, Andrea Ablasser, Daniela S Krause, Michael Potente, Stamatis Papathanasiou, Janos Terzic, Ivan Dikic.

DNA-protein cross-links (DPCs) are highly toxic DNA lesions that block replication and transcription, but their impact on organismal physiology is unclear. We identified a role for the metalloprotease SPRTN in preventing DPC-driven immunity and its pathological consequences. Loss of SPRTN activity during replication and mitosis lead to unresolved DNA damage, chromosome segregation errors, micronuclei formation, and cytosolic DNA release that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In a Sprtn knock-in mouse model of Ruijs-Aalfs progeria syndrome, chronic cGas-Sting signaling caused embryonic lethality through inflammation and innate immune responses. Surviving mice displayed aging phenotypes beginning in embryogenesis, which persisted into adulthood. Genetic or pharmacological inhibition of cGas-Sting rescued embryonic lethality and alleviated progeroid phenotypes.

DOI: https://doi.org/10.1126/science.adx9445
NPJ Syst Biol Appl. 2026 Jan 29.

Simulation-based inference of cell migration dynamics in complex spatial environments.

Jonas Arruda, Emad Alamoudi, Robert Mueller, Marc Vaisband, Ronja Molkenbur, Jack Merrin, Eva Kiermaier, Jan Hasenauer.

To assess cell migration in complex spatial environments, microfabricated chips, such as mazes and pillar forests, are routinely used to impose spatial and mechanical constraints, and cell trajectories are followed within these structures by advanced imaging techniques. In systems mechanobiology, computational models serve as essential tools to uncover how physical geometry influences intracellular dynamics; however, decoding such complex behaviors requires advanced inference techniques. Here, we integrated experimental observations of dendritic cell migration in a geometrically constrained microenvironment into a Cellular Potts model. We demonstrated that these spatial constraints modulate the motility dynamics, including speed and directional changes. We show that classical summary statistics, such as mean squared displacement and turning angle distributions, can resolve key mechanistic features but fail to extract richer spatiotemporal patterns, limiting accurate parameter inference. To solve this, we applied neural posterior estimation with in-the-loop learning of summary features. This learned summary representation of the data enables robust and flexible parameter inference, providing a data-driven framework for model calibration and advancing quantitative analysis of cell migration in structured microenvironments.

DOI: https://doi.org/10.1038/s41540-026-00648-9
Redox Biol. 2026 Jan 19. pii: S2213-2317(26)00041-8. [Epub ahead of print]90 104043

p53 and fatty acids collaborate to trigger ferroptosis via the FBXO2-FABP5 axis in colorectal cancer.

Jing Tong, Tao Han, Jun Deng, Yu Gan, Ruiwen Ruan, Wei Zhao, Chen Xiong, Quan Liao, Shiqi Chen, Huitong Bu, Jianping Xiong, Xiang Zhou, Qian Hao.

  In colorectal cancer (CRC), p53 can either suppress or potentiate tumor sensitivity to ferroptosis under oxidative stress conditions. However, it remains to be elucidated how p53 differentially regulates ferroptosis, and whether it can initiate ferroptosis. Our findings reveal that p53 induces ferroptosis in the presence of abundant polyunsaturated fatty acids (PUFAs). FBXO2, which is encoded by a p53-inducible target gene, interacts with FABP5 and promotes the lysosomal degradation of FABP5 through chaperone-mediated autophagy. This results in a decrease in the levels of PUFAs, thereby increasing resistance to ferroptosis in CRC. Notably, the supplementation of arachidonic acid not only reverses p53-mediated ferroptosis resistance, but also coordinates with p53 to initiate ferroptosis independently of additional oxidative stress, effectively suppressing the growth of CRC cells both in vitro and in vivo. Altogether, our study uncovers that the availability of PUFAs is crucial for p53 to exert a pro-ferroptotic function in CRC.

Keywords:  Cancer therapy; Chaperone-mediated autophagy (CMA); Ferroptosis; Polyunsaturated fatty acid (PUFA); p53

DOI:  https://doi.org/10.1016/j.redox.2026.104043
Biochim Biophys Acta Biomembr. 2026 Jan 26. pii: S0005-2736(26)00010-6. [Epub ahead of print] 184507

Nanodomain formation in lipid bilayers II: The influence of mixed-chain saturated lipids.

Deeksha Mehta, Emily H Chaisson, Averi M Cooper, Maryam Ahmed, M Neal Waxham, Frederick A Heberle.

  An important class of lipids found in biological membranes is composed of two structurally different hydrocarbon chains. Among these, low-melting lipids possessing both a saturated and unsaturated chain have been intensely studied because of their biological abundance and influence on lipid rafts. In contrast, much less is known about the biophysical effects of mixed chains in high-melting lipids. Here, we investigated two such lipids-MSPC (14:0-18:0 PC) and SMPC (18:0-14:0 PC)-to determine how chain length mismatch and acyl chain position on the glycerol backbone influence lateral organization. We studied the temperature- and composition-dependent phase behavior of liposomes composed of either mixed-chain or symmetric-chain high-melting lipids plus DOPC and cholesterol, using techniques sensitive to domain formation at both microscopic and nanoscopic length scales. All studied mixtures exhibited liquid-ordered (Lo) + liquid-disordered (Ld) phase coexistence with domains that were visible in confocal microscopy experiments. FRET measurements showed that all mixtures also exhibited nanoscopic heterogeneity at temperatures above the microscopic miscibility transition temperature, and cryo-EM imaging further revealed bilayer thickness variation consistent with coexisting Ld and Lo phases. Both the microscopic miscibility transition temperature, μm-Tmix, and its nanoscopic counterpart, nm-Tmix, were strongly correlated with the melting transition temperature of the saturated lipid; the sole exception was SMPC/DOPC/Chol, whose μm-Tmix showed a significant negative deviation from the expected value, implying an enhanced propensity for nanoscopic phase separation in mixtures containing this high-melting species. These results point to strong effects of acyl chain position within mixed-chain high-TM lipids on the microscopic phase behavior of ternary mixtures.

Keywords:  Chain length mismatch; Cryo-EM; Lipid raft; Liquid-disordered; Liquid-ordered

DOI:  https://doi.org/10.1016/j.bbamem.2026.184507
Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2532504123

Coordination of cell organelles to promote metabolon formation.

Zhou Sha, Anthony M Pedley, Timothy D Iles, Shaoqing Zhang, Jack R Staub, Ruobo Zhou, Stephen J Benkovic.

  The spatial coordination between cellular organelles and metabolic enzyme assemblies represents a fundamental mechanism for maintaining metabolic efficiency under stress. While previous work has shown that membrane-bound organelles regulate metabolic activities and that membrane-less condensates conduct metabolic reactions, the coordination between these two organizations remains unaddressed. By using a combination of proximity labeling, superresolution fluorescence microscopy, and metabolite analyses using isotopic tracing, we investigated the relationships between these metabolic hotspots. Here, we show that nutrient deficiency elongates mitochondria and transforms the ER from a tubular to sheet-like morphology, coinciding with increased mitochondrial respiration and inosine 5'-monophosphate levels. These structural changes promote the colocalization of purinosomes with these organelles, enhancing metabolic channeling. Disruption of ER sheet formation via MTM1 knockout destabilizes purinosomes, impairs substrate channeling, and reduces intracellular purine nucleotide pools without altering enzyme expression. Our findings reveal that organelle morphology and interorganelle contacts dynamically regulate the assembly and function of metabolic condensates, providing a structural basis for coordinated metabolic control in response to nutrient availability.

Keywords:  biomolecular condensates; cell metabolism; de novo purine biosynthesis; metabolon; purine

DOI:  https://doi.org/10.1073/pnas.2532504123
Biophys Rev. 2025 Oct;17(5): 1373-1400

NMR metabolomics in genetically engineered mouse models.

Kamil N Aysin, Alexander Yu Rudenko, Sofia S Mariasina, Vladimir I Polshakov.

  Metabolomics has become a central approach for elucidating metabolic alterations associated with disease pathogenesis, therapeutic responses, and genetic perturbations. Among the dominant analytical platforms, nuclear magnetic resonance (NMR) spectroscopy is particularly valued for its reproducibility, quantitative accuracy, and minimal sample preparation. These strengths make NMR especially powerful for studies employing genetically engineered mouse models (GEMMs), which remain indispensable for investigating the molecular basis of human disease. This review examines key methodological aspects of NMR metabolomics, including data analysis platforms, the choice of pulse sequences, and strategies to enhance sensitivity and resolution. We summarize applications across major disease areas such as cancer, diabetes, and neurological disorders, with particular emphasis on stable isotope-resolved metabolomics, a powerful approach for dynamic pathway analysis and metabolic flux modeling in intact systems. We also highlight how NMR studies of knockout models have uncovered subtle metabolic perturbations and clarified gene-metabolism relationships. A recurring theme is the evaluation of reproducibility across GEMMs and the challenge of translating metabolic findings from mouse models to human pathophysiology. Finally, we outline current limitations and future directions for advancing the role of NMR metabolomics in preclinical and biomedical research.

Keywords:  Genetically engineered mouse models (GEMM); Isotope labeling; Model organisms; NMR metabolomics

DOI:  https://doi.org/10.1007/s12551-025-01378-8
Prog Mol Biol Transl Sci. 2026 ;pii: S1877-1173(25)00192-9. [Epub ahead of print]218 1-17

New frontiers and applications of cell-free systems.

Khushbu Panchal, Khushal Khambhati, Viswanathaiah Matam, Suresh Ramakrishna, Vijai Singh.

  Cell-free systems (CFS) have emerged as a key platform in the field of synthetic biology. This is used to understand natural biological systems outside living cells. It contains cell extracts from procaryotes, eucaryotes, which provides a controlled environment for complex biological processes that leads to the synthesis of valuable biomolecules. It lacks natural mechanisms, yet it contains all the necessary components, which are required for the synthesis of desired biomolecules. It is specifically designed for the elimination of barriers to molecular transport across cell membranes. This chapter highlights a basic CFS and its various applications, such as high-throughput protein synthesis and expression, non-canonical amino acids incorporation in proteins, biosensors, drug discovery and in the metabolic engineering. This chapter also focuses on the various case studies and recent advancements to study how these systems are used for the transformation of biotechnology and provides rapid, more adaptable, and affordable solutions in the field of research as well as industrial levels. Altogether, CFS emerged as promising platform in the field of biotechnology, biomedicine, and environmental sustainability.

Keywords:  CFS; Cell extracts; Drug discovery; High-throughput proteins; Metabolic engineering; Synthetic biology

DOI:  https://doi.org/10.1016/bs.pmbts.2025.10.002