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Beneficial and detrimental effects have been ascribed to the different Thrombospondin (Thbs) proteins in the adult mammalian heart. Here, the authors show that Thbs1-mediated activation of PERK-eIF2α-ATF4-induced autophagy regulates adult cardiomyocyte size in the stressed heart.

iExoKras^G12D are engineered exosomes for the delivery of siRNA targeting KRAS^G12D. Here the authors describe the results of a phase I trial of iExoKrasG12D in patients with metastatic pancreatic cancer, reporting safety and clinical activity, as well as immunological correlates informing on tumor immune microenvironment reprograming and future combination with immune checkpoint inhibitors.’

In the Tumor Profiler proof-of-concept observational study, a multiomics approach for profiling tumors from patients with melanoma was feasible, returning data within 4 weeks and informing treatment recommendations in 75% of cases.

Nichols et al. identify an SHP2 inhibitor that disrupts SOS1-mediated RAS–GTP loading with demonstrated efficacy in various types of tumour driven by mutant BRAF, NF1 or RAS.

ERK signaling involves complex spatiotemporal dynamics, making it difficult to quantify in many systems. In this study, live-cell activity measurements are combined with multiplexed immunofluorescence in a quantitative framework, allowing ERK dynamics to be quantified within fixed-cell samples.

A potent and selective inhibitor of KRAS^G12D, the most common mutant form of the KRAS oncoprotein, has anti-tumor efficacy in multiple pre-clinical cancer models, opening the possibility to therapeutically target this highly prevalent oncogenic driver.

Activation of G_s signaling at mitochondria by mitoDREADD-G_s increases mitochondrial metabolism, leading to better memory in mouse models of dementia, directly linking brain mitochondrial deficits to cognitive symptoms of neurodegenerative diseases.

The unfolded protein response has an important role in prostate cancer tumorigenesis. Here, the authors discuss its involvement in prostate cancer development and progression, interactions with androgen receptor signalling, and the therapeutic implications for the treatment of metastatic disease.

Mucosal melanoma (MM) is a cancer with poor prognosis derived from mucosal melanocytes. Here, the authors implement a combination of genetic changes that occur in MM patients in a zebrafish model, revealing the potential MM cell of origin and showing that patient and zebrafish MMs share a gene signature that is more metastatic and immune-evasive.

RMC-7977, a multi-selective RAS(ON) inhibitor, exhibits potent tumour-selective activity in multiple pre-clinical models of pancreatic ductal adenocarcinoma through a combination of pharmacology and oncogene dependence.

Myotonic dystrophy type 2 is characterized by large CCUG repeats in the CNBP gene that result in myopathy. Here, the authors show that recognition of aberrant protein translation derived from these repeats leads to ER stress and mitochondrial DNA release, leading to cGAS/STING activation and type-I IFN responses.

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.

Here the authors provide a deep tissue analysis of patients with autoimmune kidney diseases, identifying a conserved spatiotemporal immune program for the development of glomerular crescents and sclerosis.

Activating mutations of the non-receptor protein tyrosine phosphatase SHP2 can cause cancer. Here the authors present the crystal structure of SHP2^E76K, the most frequent cancer-associated SHP2 mutation, which adopts an open-state structure and show that the allosteric inhibitor SHP099 can revert SHP2^E76K to its closed, autoinhibited conformation.

LYMTACs are heterobifunctional small molecules that take advantage of lysosomal membrane proteins to degrade membrane targets via relocalization and lysosomal degradation, offering a modular approach to drug otherwise intractable membrane proteins.

Optogenetic activation of β2-adrenergic receptors (β2-AR) has been achieved, but not characterized in detail. Here, Siudaet al. show that light-controlled opto-β2AR mimics endogenous β2AR activity in vitro and in vivo, and develop novel, optically active, functionally selective receptors to bias β2AR intracellular signaling mechanisms.

Repair processes in kidney are impaired in severe disease. Here, the authors show that in kidney failure, genetic or pharmacologic inhibition of IL11 releases the brake on regeneration, reverses tissue damage and restores kidney function.

Inhibitors of the protein kinase Wee1 are promising drugs for cancer therapy. Here, the authors show that these drugs activate the integrated stress response via GCN2, synergising with mRNA translation defects. They suggest strategies such as PROTACs or ISR inhibitors to improve WEE1 mediated toxicity.

Antibodies that lock KRAS mutants in inactive conformations facilitate drug discovery.

CellOT combines the benefits of optimal transport and input convex neural architectures to directly learn and uncover maps between control and perturbed cell states at the single-cell level.

Proliferation of cardiomyocytes typically ceases shortly after birth. Here the authors show that decreasing fatty-acid oxidation extends the perinatal cardiomyocyte proliferative window and can reintroduce cell-cycle activity in adult cardiomyocytes.

Oncogenic RAS mutants remain difficult to target with small molecules. Here, the authors show that RAS-binding Affimer proteins inhibit RAS signaling while binding diverse regions on the RAS surface, suggesting the potential to use Affimers as tools to identify new binding pockets and pharmacophores.

Most oncogenic RAS mutants remain undruggable. Here, the authors developed monobodies that selectively recognize the active state of KRAS(G12V) and KRAS(G12C) and demonstrated their utility in inhibiting RAS functions through inhibition and degradation.

Molecular, pharmacological and functional data show that haematopoietic stem cells (HSCs) are predisposed to ER-stress-mediated apoptosis compared to closely related progenitors; a framework for understanding how stress signalling is coordinated within the hematopoietic hierarchy and integrated with stemness is provided, and may have implications for the improvement of clinical transplantation of HSCs.

Using somatic genome editing and Tuba-seq, Tang et al. uncover a previously uncharacterized role for HRAS and NRAS in impairing KRAS–KRAS interaction to suppress lung tumour growth.

Recent work suggested that diploblast embryos (Cnidaria) may have germ layers that are similar to those seen in bilaterians, but how these are specified remained unclear. Here, they use scRNA-seq and functional analyses to identify the signaling involved in germ layer segregation in Cnidaria.

Responses to hypoxia are orchestrated not only through activation of the hypoxia–inducible factor family of transcription factors (HIFs), but also through HIF–independent signalling pathways. How are these pathways integrated?

The molecular mechanisms underlying malignant transformation of the Schwann lineage in Schwann cell tumours remain to be explored. Here, the authors suggest that NF2 inactivation leads to PAK activation leading to NF1-mutant Schwann cell tumour de-differentiation and resistance to selumetinib.

Analyses in supported lipid bilayers and in cells shed light on the roles of multiple SOS-membrane interactions in SOS's membrane recruitment and association, processive activation of Ras and signal attenuation.

Advances in animal magnetoreception have been limited by a lack of tractable vertebrate laboratory models. Here, the authors demonstrate light-independent magnetoreception in mature zebrafish and medaka, as well as magnetosensitive locomotion in juvenile medaka associated with neuronal activation in the lateral hindbrain.

Ponsioen et al. use a FRET‐based ERK biosensor EKAREN5 in patient‐derived organoids to show that EGFR activity amplifies signal transduction efficiency in KRAS or BRAF mutant MAPK pathways.

Systematic studies are needed to discover molecular determinants of blood brain barrier dysfunction in Alzheimer’s disease. This study identifies perturbed pericytic SMAD3-astrocytic VEGFA interactions as a potential driver of this dysfunction.

The authors show that astrocytes produce high levels of the adenosine receptor A2A in Alzheimer brains. Reducing the levels of astrocytic A2A boosted memory in young and aging mice and mouse models of Alzheimer disease, whereas activating a related molecular pathway impaired memory. Thus, astrocytes regulate memory and abnormal receptor activity in these cells may contribute to memory disorders.

A study of dependencies associated with cancer-causing mutations has identified a small molecule that binds to SHOC2 and inhibits RAS signalling in cells carrying NRAS Q61 mutations, a common oncogenic driver in melanoma.

Some bacteria interact with the endoplasmic reticulum (ER) to generate intracellular compartments that promote bacterial replication. However, conditions of physiological stress in the ER elicit the unfolded protein response (UPR), which is a cytoprotective response that is also involved in innate immune sensing. Here, Celli and Tsolis discuss how bacteria and the ER interact, including how bacteria induce the UPR, how subversion of the UPR promotes bacterial proliferation and how the UPR participates in innate immune responses against intracellular bacteria.

A cell's response to stress is often linked to protein synthesis and folding. These responses must have been conserved through evolution — otherwise, how would multicellular organisms ever have arisen? An evolutionary link has now been found in the form of a newly cloned mammalian stress-response protein called PERK. This protein has features of two gene products that are involved in the stress response in yeast.