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Insulin signaling plays a crucial role in coordinating skeletal development with whole‑body energy metabolism. Here, the authors use phosphoproteomics to show insulin-signaling rewiring in aged, insulin-resistant bone and identify defective phosphorylation of AFF4 as a key mechanism for regulating gene-specific transcriptional activation.

Wei et al. perform spatial transcriptomic profiling on synovial tissue biopsy samples from individuals with recent-onset rheumatoid arthritis, finding TGFβ signaling and fibrogenic fibroblast activation drive a treatment-refractory tissue phenotype.

Glioblastoma (GBM) is characterized by a high degree of heterogeneity and plasticity due to interplay with neural developmental programs. Here, the authors develop a model of GBM by introducing sequential oncogenic mutations in human neural stem cells and using this, identify INSM1 as a driver of a neural progenitor gene network promoting tumorigenesis.

Haines et al. developed an MEK–RAF molecular glue called IK-595 that blocks MAPK pathway activation in RAS-mutant and BRAF-mutant cancer cells. IK-595 exhibited high tolerability and strong antitumor effects in preclinical models across cancer types.

Targeting neurons that regulate energy balance may offer new approaches for obesity treatment. Here, authors show that chemogenetic and pharmacological manipulation of GABAergic neurons in the DRN/vlPAG increases adaptive thermogenesis and reduces weight gain in mice fed a highfat diet.

Metastatic triple negative breast cancer (mTNBC) has limited treatments options. Here, this group presents a combination of low-dose cyclophosphamide, anti-CSF1R, and anti-PD-1 therapies to boost immune cell infiltration and reduce recurrence in aggressive TNBC models.

The inability of intrinsically photosensitive retinal ganglion cells to shift the circadian clock in the suprachiasmatic nucleus during daytime is caused by light-dependent depolarization block of these cells.

A Fab-IL-10 fusion protein that binds to LDL suppresses vascular inflammation in atherosclerotic mouse models.

Somatic instability plays a role in Huntington’s disease. Here, the authors show that lowering HTT levels by transcriptional repression suppresses somatic instability. This can also be done without affecting HTT levels by direct CAG repeat binding.

Inherited mitochondrial DNA mutations can result in diverse clinical phenotypes. Here, the authors characterise a heteroplasmic tRNA^Ala mutation (m.5019A>G) in mice and demonstrate that macrophages carrying this mutation display altered function and metabolism in vitro, along with increased type I IFN release following LPS challenge in vivo.

Khan et al. report a non-catalytic function of the methyltransferase SETD2 in regulating nuclear morphology and genome integrity. The SETD2 amino terminus functions as a scaffold helping CDK1 associate with lamins during nuclear-envelope disassembly

Mossy fiber synapses are key in CA3 microcircuit function. Here, the authors profile the mossy fiber synapse proteome and cell-surface interactome. They uncover a diverse repertoire of cell-surface proteins and identify the receptor IgSF8 as a regulator of CA3 microcircuit connectivity and function.

Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

This Perspective reviews tools developed over the past five years in the macromolecular modeling, docking and design software Rosetta.

Pediatric AML is traditionally treated with chemotherapy and stem cell transplant but some subsets of patients have a poor response to therapy. Here, the authors perform a high throughput screen and identify several FDA approved drugs that might be useful in treating this disease.

Using data from a cohort of patients (n = 346) with lung adenocarcinoma and from multiple independent cohorts, DNA methylation signatures were evaluated to build and validate an accurate model predicting the development of brain metastasis.

Electrospray deposition is a promising technique for depositing functional coatings at the micro-/nano-scale. Here, the authors establish the necessary conditions for high efficiency electrospray deposition of small targets, establishing promise as an alternative to other conformal coating methods.

In this work, authors study a molecular signature in STING protein that is critical for distinguishing activation from inhibition and demonstrates therapeutic potential in correcting STING-related mutations in autoimmune conditions like STING-Associated Vasculopathy with onset in Infancy (SAVI).

Here, the authors identify mechanisms of glycosylation of intrinsically disordered regions present in streptococci membrane proteins, uncovering a functional role for glycosylation in Streptococcus mutans chaperone PrsA.

Several β-secretase (BACE) inhibitors exhibit unexplained ocular toxicity in preclinical studies. Here the authors generate a clickable photoaffinity probe to interrogate off-targets in cells and animals, and identify inhibition of cathepsin D as a driver of ocular toxicity.

Glycosylation of human IgG antibodies in bacterial hosts has proven challenging. Here, the authors identify a bacterial enzyme enabling E. coli to glycosylate IgGs at native sites, thereby advancing therapeutic antibody development in this host.

By selectively isolating and sequencing the rare RNA transcripts containing C9orf72 repeat expansion from ALS–FTD neurons, the authors uncover an alternative splicing mechanism that explains the retention of this intron segment in a translated mRNA.

Interim results from the low-dose cohort of the PROCLAIM trial show that AAV-based delivery of the progranulin gene in patients with frontotemporal dementia was safe and was associated with increased CSF progranulin.

Peptidoglycan recognition proteins (PGLYRPs) are implicated in the control of the intestinal microbiota. Here, combining in vitro and in vivo work, the authors show that PGLYRP-1 act as an intracellular pattern recognition receptor for the detection of peptidoglycan disaccharides that regulate host defense responses in the intestine.

The N-acyl-cyclolysine system regulates the expression of co-localized operons encoding diverse secreted molecules in Bacteroidota.

The humoral immune response role in cancer is unclear. Here the authors perform an in-depth proteomic profiling of immunoglobulin-bound proteins in plasma from pancreatic ductal adenocarcinoma patients and find cancer-cell specific antibodies neutralized by binding to cancer-cell derived exosomes.

roX (RNA on the X) are crucial for male development in Drosophila. Here, the authors propose a role for roX RNAs in regulating gene expression at specific autosomal loci, working in coordination with Polycomb repressive complexes (PRCs).

Utilising proteomic and transposon sequencing screens, Freiberg et al. identified arginine metabolism enzymes that impact tolerance to antibiotics in Staphylococcus aureus, including in animal models of skin and bone infections.

SCF–FBXO31 scans proteins for C-terminal amidation and marks them for subsequent proteasomal degradation.

The authors identify a molecular switch that regulates the balance between neurotoxic and neuroprotective astrocyte populations, with potential application in the treatment of glaucoma and other optic neuropathies.

Glutarate rewires cell metabolism through conjugation to proteins or fatty acids, but how glutarylation is regulated is unclear. ABHD11 was identified as a lipoyl-deglutarylase to maintain the TCA cycle and mitochondrial metabolism.

A study of gold nanospheres and nanorods shows that, even without internalization, they are very efficient for siRNA delivery and inducing gene silencing in mature plant leaves.

A structure-guided fragment screen identified a compound, which interacts with a ligand-binding site of unknown function in eukaryotic initiation factor 4E (eIF4E). X-ray crystallography was used to characterise binding and target engagment was shown in cells.

A CRISPR–Cas9 screen combined with heparan sulfate (HS)-binding reagents identifies genes involved in HS biosynthesis and assembly and reveals the unexpected role of histone demethylase KDM2B in regulating HS presentation on the cell surface.

Polymersomes are used as a delivery vehicle for protein, nucleic acid adjuvant and siRNA payloads by enhancing the encapsulation efficiency through copolymer design.

Free energy calculations are an essential tool to identify targets for individual proteins. Here, authors describe free energy perturbation (FEP+) calculations to optimise on target and off-target potencies for the discovery of potent Wee1 inhibitors with kinome-wide selectivity.

PTEN is a key cell signaling lipid phosphatase that is regulated by C-terminal phosphorylation. Biophysical methods were used to illuminate the structural basis for PTEN regulation, which involves a dynamic N-terminal helix that influences catalysis.

Protein citrullination regulates the physiological function of proteins and is linked to various autoimmune disorders. Here, the authors report on the allosteric targeting of PAD1-4 leading to broad inhibition of protein citrullination in neutrophils.

Mutations in histone acetyltransferases (HATs) CREBBP and EP300 are generally thought to lead to decreased function or absence of protein product. Here the authors describe a gain of function of several CREBBP mutations leading to baseline hyper-acetylation, increased homologous recombination and potential synergy between radiation and HAT inhibition in CREBBP/EP300 mutant tumors.

Manumycin natural products were found to target the E3 ligase UBR7 and engage in molecular glue interactions with p53, leading to the activation of p53 and cell death.

Cryo-electron and atomic force microscopy shed light on how fibrils of the protein tau, which accumulate in the brain of people with Alzheimer’s disease, can be disassembled by short peptides, providing a possible route towards developing treatments.

This study extends the natural code by which transcription activation–like effector nucleases (TALENs) recognize DNA and uses the resulting expanded repertoire of repeat divariable residues (RVDs) to improve TALEN performance.

Pierce et al perform genome-wide CRISPR screening and identify LKB1 as a regulator of chromatin accessibility and metastatic progression in lung cancer through a mechanism of SOX17-mediated epigenetic changes.

Deletion of the A-to-I double-stranded RNA-editing enzyme ADAR1 sensitizes tumour cells to immunotherapy.