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Sivanandan, Leitmann, and colleagues present the CellPaint-POSH platform, which combines pooled CRISPR screening with Cell Painting. Using self-supervised deep learning on cell images, the method enables discovery of gene function and biological networks.

The contribution of ether lipid species in cancer cell fate has not been fully understood yet. Here the authors show that malignant cancer cells employ ether lipids to modulate membrane biophysical properties, enhancing iron endocytosis and ferroptosis susceptibility.

DNA interstrand crosslinks induced by acetaldehyde are repaired by both the Fanconi anaemia pathway and by a second, excision-independent repair mechanism.

A combination of biochemical, cell biological and electron microscopy analyses reveal a ‘nucleotide code’ that coordinates Lis1–dynein binding stoichiometry, which in turn governs Lis1’s ability to relieve dynein autoinhibition.

Here they show that the adhesion GPCR Gpr126/Adgrg6 regulates trabeculation during heart development. Its N-terminal fragment is required for maintaining cell adhesion and compact wall integrity while its C-terminal fragment is essential to provide trabecular identity.

Ye et al. define the structure and mechanisms of a bacterial pathway that performs ubiquitination-like protein conjugation, revealing new insights into the evolution and biological roles of ubiquitination pathways across kingdoms.

PCNA–PAF15 has a key role in determining replisome dynamics during genome replication and protecting against genome instability.

Yersinia pseudotuberculosis senses fungal tyrosol signalling through EnvZ–OmpR which triggers T6SS activation and antifungal effector release to reduce fungal competitors in the mouse gut.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

Riechmann et al. uncover structural features governing ubiquitin transfer from ubiquitin-activating E1 enzymes UBA1 and UBA6 to specific E2 ubiquitin-conjugating enzymes, revealing a hierarchy of E2 activity with cognate E1s.

EGFR inhibitors are standard of care in patients with EGFR-mutant non-small cell lung cancer (NSCLC) but resistance often develops. Here the authors report that the evolution of EGFR inhibitor resistance in EGFR-mutant NSCLC results in a sensitivity to the compound, MCB-613, and investigate the underlying mechanism of action.

Cancer immunotherapy benefits from antibody-lectin chimeras that block glyco-immune checkpoints.

High-throughput chemical ligand discovery is challenged by false positives. Here, authors introduce a scalable enantioselective affinity-selection mass spectrometry approach for proteome-wide ligand discovery with high sensitivity and selectivity

STING–type-I interferon pathway regulates the immunogenicity of several cancer types, including head and neck squamous cell carcinoma. Here the authors describe that glutamine metabolism in the tumour microenvironment dampens the STING–type-I interferon pathway by epigenetically silencing the expression of BATF2, which functions as a tumour suppressor.

A two-component system, DbfRS, regulates biofilm formation in Vibrio cholerae. Here, Nguyen et al. identify a small periplasmic protein that controls the activity of the system’s receptor, and show that DbfRS responds to membrane stress and regulates additional processes such as metabolism and cell envelope biosynthesis.

Epichaperomes are chaperone assemblies that reorganize protein networks under stress. Here, authors reveal how HSP90 phosphorylation drives epichaperome formation, linking this process to cancer cell behaviors and pluripotent stem cell functions.

Acute depletion of NIPBL reveals a class of chromatin loops that are independent of NIPBL for their maintenance but not their establishment and that NIPBL is necessary for the expression of lineage-defining genes.

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

Zhang, Lahry, Cipurko et al. show that the microbial metabolites queuine and preQ₁ modify the same host tRNA. PreQ₁-tRNA reduces cell proliferation, slows tumour growth, decreases the translation of ribosomal proteins and is cleaved by IRE1 on the ER ribosome.

The functions of the vast majority of brain-expressed spliced isoforms are unknown. Here the authors describe an isoform-resolution perturbation system coupled to a single cell transcriptomics read-out, and through this approach identify neuronal microexons that control autism-linked signatures underlying neuronal maturation and function

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.

This study demonstrates that the reduced serum serine in patients with chemotherapy or women with poor sleep, is linked to the decline of ovarian function. Serine supplementation prevented ovarian damage in mice by inhibiting ferroptosis in ovarian granulosa cells, without affecting chemotherapy efficacy.

Here they show that mitochondria-localized NEK7 couples mitochondrial complex II subunit SDHB to maintain the homeostasis of electron transport in hepatocytes, thereby impeding the progression of liver fibrosis.

Avian influenza jumped from wild birds into dairy cattle. Here, the authors report that two mutations in the viral polymerase helped the virus to quickly adapt to cattle. Mutations increased the polymerase activity and made the virus better at replicating in human cells.

Murphy et al. reveal a unifying pathogenetic mechanism according to which diverse mutations in the muscle-specific ribosomal protein RPL3L cause severe neonatal dilated cardiomyopathy, establishing a framework for interpreting the growing spectrum of RPL3L variants.

Peroxisomes import matrix proteins using a specialized membrane translocation system. Here, authors reveal the structure of an import complex from Trypanosoma cruzi, uncovering the protein-protein interactions and associated heterogeneity.

Healing of infected tendons is hindered by mechanical dysfunction, tissue adhesion, and immune imbalance. Here, Li et al. develop a multifunctional Janus hydrogel with asymmetric adhesion, antibacterial properties, and pH-responsive release of tendon stem cell-derived exosomes for infected tendon repair.

This study applies generalized linear mixed models (GLMM) and advanced transcriptome wide association study (TWAS) methods to improve the discovery of colorectal cancer risk transcription factors and genes, including potential druggable targets.

Information has been encoded into the quantum wavefunctions of a two-dimensional electron gas using electronic holograms constructed from single molecules. The information is stored in two spatial dimensions and one energy dimension and is read with a scanning tunnelling microscope, to enable information densities exceeding 20 bits nm⁻².

Engineering polymerases to synthesize alternative genetic polymers remains a challenging problem in synthetic biology. Using DNA shuffling and droplet microfluidics, the current study provides a short evolutionary path from a DNA polymerase to one with robust RNA-synthesizing activity.

Gram-negative bacteria use a multiprotein complex, LptB₂FGC, to transport lipopolysaccharides (LPS) to the outer membrane. Here, Fiorentino et al. present cryo-EM structures of the complex from Pseudomonas aeruginosa, revealing species-specific features and providing insights into LPS transport mechanisms.

Matthieu Reymond and colleagues show that natural genetic variants at the SRF3 locus underlie genetic incompatibilities between European and central Asian accessions of Arabidopsis.

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.

Moral-Sanz, Fernández-Carrasco and colleagues identify senolytic properties of sea anemone-derived pore-forming toxins, with selectivity mediated by senescence-associated lipid profiles. An optimized senotoxin improves the efficacy of chemotherapy in mouse models.

The role of protein UFMylation in cancer remains to be understood. Here the authors show that UFM1-specific ligase 1 and AKT positively regulate each other through UFMylation and phosphorylation in breast cancer cells, which could be therapeutically targeted by a cell-penetrating peptide through disrupting UFL1-AKT interaction.

This study reports that de novo germline missense variants in SF3B1, distinct from the somatic variants frequently observed in cancer, cause a neurodevelopmental disorder and disrupt global RNA splicing.

Metastatic cancer cells rely on metabolic flexibility to survive. Here, the authors show that metastatic breast cancer cells use lactate for mitochondrial oxidation via the CD147/MCT1/LDHB complex to sustain stemness and promote metastasis.

Understanding drug targets and their effects in living cells is challenging. Here, the authors develop SICFA, a label-free proteomics method that sensitively detects drug-induced protein stability changes, thereby identifying targets and downstream pathways directly in living cells.

PPARγ regulates glucose and lipid metabolism, yet safer PPARγ-targeted insulin sensitizers are needed to treat metabolic disorders. Here, Kuang-Ting et al. elucidate structure–function relationships of non-covalent inverse agonists that enhance receptor binding and improve insulin sensitivity, providing a framework for next-generation drug design.

Alzheimer’s disease is characterized by the accumulation of amyloid plaques in the brain. Here, Liu et al. develop a new method, Amyloid-ID, which uses light to label and analyze amyloid deposits in brain tissues, revealing their protein composition and associated molecules.

The STAR experiment at the Relativistic Heavy Ion Collider at Brookhaven National Laboratory demonstrates evidence of spin correlations in \(\Lambda \bar{\Lambda }\) hyperon pairs inherited from virtual spin-correlated strange quark–antiquark pairs during QCD confinement.

C16orf74/ calcimembrin (CLMB), a lipidated microprotein with roles in cancer, targets the calcineurin phosphatase to membranes. Here, authors show how CLMB uses a composite motif to form multimeric complexes with calcineurin that are required for dephosphorylation.

Here, the authors show that two residues in FDX1 control both protein lipoylation and copper-induced cell death, suggesting these roles are interconnected. They also identify DLD as an upstream regulator that strengthens FDX1’s link to the lipoylation pathway.

The lipodystrophy protein seipin defines the sites of lipid droplet biogenesis at the endoplasmic reticulum. Here, the authors show that a large, evolutionarily conserved region of seipin is dispensable in determining functional sites of lipid droplet formation.