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Drugs targeting dysregulated ERK1/2 signaling can cause severe cardiac side effects, precluding their wide therapeutic application. Here, a new and cardio-safe targeting strategy is presented that interferes with ERK dimerization to prevent pathological ERK1/2 signaling in the heart and cancer.

Arteries are vital blood vessels for our body and their growth and patterning are critical for proper blood flow. Here they use a retina model to show that a balance of EphB4 receptor and ephrin-B2 ligand integrate a well-wired molecular network to control arteriovenous patterning and vascular growth.

Primary cilia have been proposed to regulate glucose metabolism and insulin secretion in beta cells, but it is not known how. Here the authors show that primary cilia play a role in adult β-cell function via a mechanism involving endosomal EphA-processing.

Bedoui and colleagues describe a sequential process of integration of innate and CD40-delivered signals in APCs, which optimizes their capacity to drive antiviral CD8⁺ T cell responses.

Oncogenic Ras mutations are common drivers in myeloid leukemia. Here, the authors show in patient cells and in mice that oncogenic K-Ras activates NLRP3 inflammasome to drive myeloproliferation, which can be reversed by genetic or pharmacologic NLRP3 blockade.

This study shows that inactivation of Pml in the mouse prostate turns indolent Pten-null tumors into lethal metastatic disease. The authors identify an aberrant SREBP prometastatic lipogenic program and show that a high-fat diet induces lipid accumulation in prostate tumors and is sufficient to drive metastasis.

Fibroblast-specific Il-11 expression causes heart and kidney fibrosis and organ failure, whereas IL-11 inhibition prevents fibroblast activation and organ fibrosis, indicating that IL-11 inhibition is a potential therapeutic strategy to treat fibrotic diseases.

Influenza virus infection causes injury to the lung. Here, Pervizaj-Oruqaj et al. show that Plet1 expressed by lung macrophages promotes epithelial repair by boosting epithelial cell proliferation and barrier function.

Overabundance of apolipoprotein C3 (ApoC3) is associated with atherosclerosis. Speer and colleagues demonstrate that ApoC3 activates the NLRP3 inflammasome via a non-canonical pathway contributing to inflammation and development of atherosclerosis.

Insulin enhances mRNA translation via the translation initiation factor eIF6. Here, Brina et al. show that insulin-mediated activation of eIF6 is associated with the selective translation of genes involved in glycolysis and lipid synthesis with characteristic G/C-rich and uORF sequences in their mRNA.

Genome-wide association analyses of intracranial and nine subcortical brain volumes in 74,898 participants of European ancestry identify 254 independent loci and yield polygenic scores accounting for brain variation across ancestries.

Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.

Nasopharyngeal carcinoma (NPC) lacks effective diagnostic and therapeutic strategies, in particular at advanced stages. Here, the authors show that expression of the somatostatin receptor 2 is induced by Epstein-Barr virus in NPC and has a key role in the diagnosis, imaging, targeted therapies and prognosis of NPC.

MicroRNAs regulate haematopoietic stem cell (HSC) development to ensure the correct generation of blood cells. Haetscher et al. show in mice that miR-193b controls the life-long self-renewal ability of HSCs via AKT and STAT5 pathways, with loss of miR-193b accelerating HSC expansion and reducing differentiation.

In this work, the authors compile a chemogenomics library for NR1 nuclear hormone receptors to advance studies on unexplored therapeutic potential of these transcription factors. Its application in phenotypic settings revealed NR1 involvement in autophagy.

A series of FRET-based β-arrestin2 biosensors are used to study the dynamics and conformational changes that occur when β-arrestin2 binds to and dissociates from the β₂-adrenergic receptor in living cells; results show that after β-arrestin2 dissociates from the β₂-adrenergic receptor, it stays at the cell membrane in an active conformation for a while, indicating that β-arrestin is able to signal in a G-protein-coupled receptor (GPCR)-free state.

Production of mature interleukin 1β (IL-1β) requires Il1b transcription and inflammasome-mediated processing of IL-1β protein. Ruland and colleagues show that the RNA virus sensor RIG-I signals via the adaptors CARD9 and Asc to facilitate both processes.

Before antigen exposure, T cell survival is dependent on signalling stimulated by IL-7. Koenen et al. show that upon encountering specific antigen, T cell receptor signalling initiates a different set of survival pathways, which actively suppress those that sustain naive T cells.

Endogenous retroviruses (ERV) can induce immune responses and the control of these viruses uses immune mechanisms also involved in autoimmunity. Here, the authors characterize the control of ERVs in mice and show age-associated B cell control and nucleic acid sensing TLR pathway involvement.

Liver X receptor drives epithelial Areg-mediated intestinal regeneration, while preventing tumour growth through adaptive immune responses.

Protein kinases have emerged as one of the most successful families of drug targets. To date, most selective kinase inhibitors have been discovered serendipitously either through broad selectivity screening or through the discovery of unique binding modes. Here we discuss design strategies that could lead to a broader coverage of the kinome with selective inhibitors and to a more rational approach for developing them.

Roesch and colleagues use clinical datasets and mouse models of BRAF-mutant melanoma to reveal a role for IL-17A in positive responses to anti-PD-1 and anti-CTLA-4 therapy, which they also link to infiltrating neutrophils.

Idiopathic pulmonary fibrosis is associated with myofibroblast activation in the lungs and metabolic alterations. Here, the authors show that the antidiabetic drug metformin has antifibrotic effects in human-derived samples and mouse models, by modulating a number of metabolic pathways to induce lipogenic transdifferentiation of myofibroblasts.

The strength and duration of interleukin-2 (IL-2) signals is known to regulate T cell memory. Here the authors show that T cell receptor signalling strength controls the requirement for IL-2 signals to form CD8⁺ T cell memory with high functional activity and a wide range of genes with open chromatin regions.

Liver resident CD8 T cells have an essential role in immunopathology in a mouse model of nonalcoholic steatohepatitis, by becoming auto-aggressive following sequential transcriptional and metabolic activation steps .

Drebrin is an actin-binding protein known to play a role in neuronal dendritic spines but its precise regulation is unclear. Here, the authors report that DBN is activated by oxidative stress in an ATM-kinase dependent manner and increases resistance to oxidative stress in mice and in C. elegans.

The regulatory role of calcitonin in bone homeostasis is well studied, yet its molecular activity is poorly understood. The authors show that calcitonin regulates bone cells function by inhibiting the osteoclast secretion of sphingosine 1-phosphate, a lipid mediator of osteoclast–osteoblast crosstalk.

Epithelial-to-mesenchymal transition (EMT) regulates both processes of organism development and changes in cell state causing disease. Here, the authors show that an E3 ubiquitin ligase, FBXO32, regulates EMT via CtBP1 and the transcriptional program, and also mediates cancer metastatic burden and neurogenesis.

Whole-genome sequencing identified recurrent fusions involving the MET oncogene, and MET inhibitors suppressed tumor growth in mouse models and in a human patient.

Single-cell RNA sequencing and spatial transcriptomics reveal that the somitogenesis clock is active in mouse gastruloids, which can be induced to generate somites with the correct rostral–caudal patterning.

Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

Nicotinamide phosphoribosyltransferase (NAMPT) regulates the biosynthesis of nicotinamide adenine dinucleotide (NAD), levels of which are decreased in various metabolic disorders and during ageing. Here, Antje Garten and colleagues discuss the physiological functions of NAMPT and its relevance in various human diseases and conditions such as obesity, nonalcoholic fatty liver disease, type 2 diabetes mellitus, cancer and ageing.