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The potency of a class of RAF kinase inhibitors was found to depend on cancer cell signaling activity. This insight informed reengineering of a clinically approved MEK inhibitor to block this cancer-driving pathway more effectively in combination.

Native top-down proteomics reveals epidermal growth factor receptor–estrogen receptor-alpha (EGFR–ER) signaling crosstalk in breast cancer cells and dissociation of nuclear transport factor 2 (NUTF2) dimers to modulate ER signaling and cell growth.

An annular carbon-nanotube nanosensor array integrated onto a medical-grade catheter enables near-infrared, in situ spatial mapping of bladder cancer-associated protein biomarker release in the bladder with 182-fold higher sensitivity than urine sampling.

This study reveals that glycogen metabolism is crucial for the sensory activation of POMC neurons, which is necessary for proper feeding behaviour and metabolic health in mice.

An analysis of diet-induced obesity using MouseMapper—a suite of foundation-model-based deep-learning algorithms—identifies structural alterations of the infraorbital branch of the trigeminal ganglia.

Small cell lung cancer (SCLC) cells show inherently low antioxidant defenses, making them prone to lethal oxidative stress induced by thioredoxin reductase 1 (TXNRD1) inhibitors. Here, authors demonstrate that activating NRF2 mediated tissue protection allows increased therapeutic dose of TXNRD1 inhibitors to enhances SCLC cell killing in vivo without added toxicity to healthy tissues.

Target-directed microRNA degradation is driven by the atypical ZSWIM8–CUL3 E3 ubiquitin ligase that uses a two-RNA-factor authentication mechanism to specifically recognize AGO–miRNA–trigger RNA complexes and polyubiquitylate AGO.

N-desethyl-fluornitrazene is a µ-opioid receptor agonist derived from nitazenes that has supramaximal intrinsic efficacy that produces analgesia with minimal adverse effects in rodent models.

Androgens have distinct roles in the brain, acting as immune-based tumour suppressors through neuroinflammation and neuroendocrine mechanisms.

In targeted protein degradation, a degrader molecule brings a neosubstrate protein proximal to a hijacked E3 ligase for its ubiquitination. Here, pseudo-natural products derived from (−)-myrtanol—iDegs—are identified to inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs prime apo-IDO1 ubiquitination and subsequent degradation using its native proteolytic pathway.

Insulin controls adipocyte metabolism through changes in protein localisation. Here, the authors use cell-wide subcellular proteomics to uncover extensive insulin-regulated protein redistribution and identify C3ORF18 as a regulator of adipocyte insulin sensitivity.

Adaptive laboratory evolution enables cyanobacteria to tolerate fluctuating light by acquiring beneficial mutations. Key mutations improve photosystem performance or reduce light harvesting, enhancing survival under stressful light conditions.

A small molecule, CLEO4-88, was identified that acts as a molecular glue, linking the E3 ligase subunit GID4 with ACAA1. Instead of triggering ACAA1 degradation, the compound inhibits its enzymatic activity.

Using single-cell tissue imaging and spatial proteomics to study mitochondria–lipid droplet coupling in hepatocytes, PLIN5 phosphorylation is identified as a mediator of lipid flux and nutrient stress responses.

Androgen activity in the male embryonic hindbrain prolongs hindbrain differentiation in male individuals and drives sex differences in the incidence and prognosis of posterior fossa type A (PFA) ependymoma, an aggressive childhood brain tumour.

MitoCatch is a cell-type-specific mitochondrion-targeting system that links mitochondria and the cell surface by protein binders and delivers mitochondria into the target cell.

Effective target engagement of drugs relies on them achieving sufficient intracellular concentrations. Here, using a multimodal imaging pipeline the authors demonstrate that uneven distribution and uptake of PARP inhibitors in ovarian cancer patient-derived explant models correlates with therapeutic response.

Mitochondria play roles in sensing environmental and physiological stress, but their response can become maladaptive during chronic stress. Here they identify a protective miRNA response in C. elegans that maintains tissue health by attenuating mitochondrial stress signaling.

The susceptibility of mouse and human T cells to ferroptosis is determined by the balance of systemic polyunsaturated and monounsaturated fatty acids, highlighting a key role for lipid metabolism and dietary composition in regulating T cell function.

Endocrine-exocrine pancreas crosstalk is known to play a role in pancreatic ductal adenocarcinoma. Here, the authors discover that obesity induces the expression of the peptide hormone cholecystokinin (CCK) in β cells, affecting the peri-islet acinar cells and promoting islet-proximal tumor formation.

Despite improving therapeutic options, the prognosis for patients with metastatic castration-resistance prostate cancer (mCRPC) remains poor. Here, the authors identify MCL1 copy number alterations as a prognostic and predictive biomarker, demonstrating its therapeutic potential as a drug target, either alone or in combination, in patients with mCRPC.

This study discovers human SERF2 as a key partner in stress granule formation by binding specific RNA G-quadruplexes. SERF2 and these RNAs provide a detailed structural model of protein-RNA interactions driving liquid-liquid phase separation in condensates.

In mice, DHPS supports the maturation, maintenance and function of tissue-resident macrophages via the polyamine–hypusine axis, with implications for macrophage-targeting therapies.

While therapies targeting type I BRAF mutations have been developed, there are limited options for those with type II and III mutations. Here, the authors identify a subset of BRAF-mutant non-small cell lung cancer patients and characterise the pan-RAF inhibitor exarafenib, demonstrating efficacy in preclinical models and investigating subsequent resistance mechanisms.

A screen of lung-targeting lipids revealed lipid nanoparticles offering improved delivery of mRNA and genome editors to lungs. Probing structure–activity relationships revealed a unique ‘tripod-like’ shape associated with the improvements.

A widespread bacterial defence system called SNIPE is shown to localize to the cell membrane, where it identifies and cleaves the DNA of infecting phage as it is injected into the bacterial cell.

Mass spectrometry (MS)-based proteomics is increasingly central to systems biology. Here, the authors present a high-throughput, multi-organ workflow that profiles 11,472 proteins in 507 mouse samples, enabling rapid, system-level evaluation of drug efficacy and toxicity.

González-Gualda, Reinius et al. demonstrate that platinum-based chemotherapy-induced senescence promotes malignancy in ovarian and lung cancer via TGFβ ligands, with evidence in mouse models validated in clinical samples. Concomitantly blocking TGFβ signaling with chemotherapy reduces tumor burden and increases survival in mice.

KRAS mutations are keenly associated with pancreatic ductal adenocarcinoma and represent a potential therapeutic target. Here the authors present the findings from a phase I clinical trial testing pooled KRAS mutant peptides in combination with immune checkpoint blockade in patients with resected pancreatic ductal adenocarcinoma.

Integrated single-cell and spatial data analysis, combined with bidirectional CRISPR screens, identify the transcription factor GLIS3 as a key driver of chronic inflammation and fibrosis and a potential marker of disease severity in patients with ulcerative colitis.

Betaglycan is a co-receptor for selective TGF-β family ligands. Here, the authors solve its structure in complex with TGF-β and the signaling receptors, which explains its ligand selectivity and reveals its mechanism in potentiating TGF-β signaling.

Regulatory DNA screens often lack nucleotide-level resolution. Here, authors present an end-to-end CRISPR base-editing and sequencing framework that maps regulatory variants at single-nucleotide resolution, revealing enhancer mutations that alter CD19 expression and enable CAR-T therapy resistance.

Many genetic loci that are associated with coronary artery disease lack understanding of how they contribute to the disease. Here, the authors combine summary genetic statistics with cell type-specific data of regulatory elements to prioritize candidate disease genes, including non-coding RNA genes.

Extracellular vesicles have been implicated in the transmission of pathogens from the arthropod to the human host. Here the authors show that tick-derived extracellular vesicles play a role in feeding and modulate the outcome of bacterial infection.

In this work, the authors reveal that three non-ribosomal peptides targeting a common protein quality system differentially alter the Mycobacterium tuberculosis proteome, providing new insight into the molecular mechanisms behind their antimycobacterial activity.

Hartono and colleagues develop an injectable albumin-based nanoprobe to enable urine detection of senescence burden. By exploiting the activity of MMP-7 as a context-specific biomarker of senescence, the probe enables real-time monitoring of treatment response in lung cancer and related pulmonary conditions.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

Dysregulation of H3K4 methylation is associated with neurodevelopmental disorders. Here, the authors perturb H3K4 methylation in the MGE and hypothalamus, resulting in altered gene expression and cell fate as well as changes in behavior that mimic NDD symptoms.

Brown adipocytes are embedded within an intricate network of blood vessels and sympathetic nerves that support their development and thermogenic function. This study shows that adipocyte progenitor cells control blood vessel growth and nerve wiring in brown fat during cold exposure. They do so by releasing Slit3, which is cleaved into fragments that coordinate angiogenesis and sympathetic innervation.

A bioelectronic device incorporating triphylite (LiFePO₄) as electrode is used for lithium-ion-specific inhibition of peripheral and central nervous system activities in rats and in mice.

Broadly neutralizing antibodies (bnAbs) for HIV have been difficult to elicit with one issue being the low B cell affinity required. Here the authors use a transgenic mouse bearing human-like antibody repertoires to show that low affinity B cells persist which enables vaccine expansion of antibodies against the CD4 binding site, a conserved HIV bnAb target.

Transcription factors (TFs) represent an emerging class of therapeutic targets in oncology. Here, the authors develop Epiregulon, a computational method that constructs gene regulatory networks from ChIP-seq, ATAC-seq and RNA-seq data for accurate prediction of TF activity at the single-cell level, thereby facilitating the discovery of therapeutics targeting TFs.

Splicing factors shape how genes are stitched into RNA, but their activity is hard to measure. Here, the authors benchmark network methods and show exon-inclusion signatures infer splicing factor activity, uncovering cancer programs linked to survival and hallmarks.

The regulation of cellular phosphatidylethanolamine (PE) acyl chain composition is poorly understood. Here, the authors show that TLCD1 and TLCD2 proteins mediate the formation of monounsaturated fatty acid-containing PE species and promote the progression of non-alcoholic steatohepatitis.

Here they combine in vivo imaging with proteomics to characterize a protein complex comprised of Ccdc78 and Ccdc33 that acts at the extreme distal tip of 9 + 2 motile cilia to control tip architecture, cilia length, and cilia beating.

Endosomal recycling relies on SNX17 to transport membrane proteins via Retriever. Here, authors reveal the mechanisms of SNX17 autoinhibition and its interaction with Retriever, uncovering a broader family of factors with similar binding strategies.

Dietary n-6 PUFAs enhance adipose tissue expandability through the PPARγ–LPCAT3 membrane remodelling axis.

KRAS is an oncogene that switches between a GDP-bound inactive state and a GTP-bound active state. Recently developed KRAS G12C inhibitors are specific to the GDP-bound inactive state. Here, the authors develop a class of covalent KRAS G12C inhibitors capable of targeting both states for the treatment of KRAS-driven cancer.

Understanding the mechanisms underlying the survival of drug tolerant persister cells following chemotherapy remains elusive. Here, multi-omics analysis and experimental approaches show that the germ-cell-specific H3K4 methyltransferase PRDM9 promotes metabolic rewiring in glioblastoma stem cells.

The consequences of postprandial IL-1β surges in white adipose tissue are unknown. Here the authors show IL-1β regulates WAT remodelling by promoting adipogenesis and energy storage, which is blocked by chronic elevation of this cytokine (as in obesity).