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Xiao and Kennelly et al. show that Aster-mediated nonvesicular cholesterol transport in the liver regulates hepatic and systemic lipid homeostasis during fasting, as well as reverse cholesterol transport.

Wiskott-Aldrich syndrome is caused by mutations in WASP, but the underlying mechanisms remain to be explored. Here the authors reveal that WASP deficiency results in aberrant RNA splicing, and that WASP regulates the transcription of splicing factor genes and co-transcriptional RNA splicing via a phase-separation process that involves splicing factors and nascent RNA.

Zhang, Fang, et al. develop a method to perform an in-depth lysine succinylation analysis in the mouse liver. This approach allows them to identify a previously unappreciated mechanism of regulation of the urea cycle and ammonia detoxification.

Here the authors present NCATS-SM0225, a small molecule that inhibits ERAD and selectively kills cancer cells by binding VDACs, disrupting calcium homeostasis, and triggering the PERK-STIM1 pathway to degrade ERAD regulators.

Glycosylphosphatidylinositol (GPI) anchors are found on many cell surface proteins but their biosynthesis is not fully understood. Here, the authors identify genes involved in GPI galactosylation and reveal functional connections between GPI processing, glycosphingolipid biosynthesis and ER-associated degradation.

Three studies identify a transcription-coupled DNA–protein crosslink repair pathway that depends on the Cockayne syndrome proteins and the proteasome.

Mutations in the gene HADHA result in mitochondrial tri-functional protein (MTP) deficiency and can result in sudden infant death syndrome for which there is no treatment. Here the authors show that the MTP deficient pathology in human cardiomyocytes leads to an abnormal cardiolipin pattern and suggests that cardiolipin affecting compounds may serve as a potential therapy.

A next-generation proteolysis-targeting vaccine approach (PROTAR vaccine 2.0) was developed that attenuated influenza viruses by degrading multiple viral proteins and showed promising safety and efficacy in animal models with viral challenge.

Establishment and maintenance of appropriate cell size is a prerequisite for cells to function efficiently. Here, Kiriakopulos et al. reveal that the lncRNA CISTR-ACT maintains cell size across cell types in humans and mice by regulating cell morphogenesis genes in trans via guidance of the transcription factor FOSL2.

The mechanisms that mediate the effects of weight loss surgeries such as vertical sleeve gastrectomy (VSG) are incompletely understood. Here the authors show that intestinal FGF15 is necessary to improve glucose tolerance and to prevent the loss of muscle and bone mass after VSG, potentially via protection against bile acid toxicity.

Cancer cell-derived small extracellular vesicles bind to therapeutic nanoparticles leading them from tumours to the liver for degradation. This mechanism is another barrier for the development of efficient nanoparticle-based cancer therapies.

Ronchese and colleagues show that IL-13 secreted homeostatically by dermal ILCs contributes to the differentiation of a CD11b^lo type 2 dendritic cell subset, which supports the development of T_H2 cells and curtails the development of T_H17 cells in the skin of mice and humans.

Valosin-Containing Protein (VCP) is linked to diverse degenerative diseases. Here, the authors show that Small VCP Interacting Protein (SVIP) recruits VCP to lysosomes, with gain and loss of SVIP muscle expression modifying neural degeneration, animal behaviour and lifespan.

Enhanced IL-1β signaling pathway causes hematopoietic stem cell (HSC) to differentiate into myeloid cells and contributes to malignant hematopoiesis. Here the authors reveal that HSC differentiation is controlled by balanced levels of IL-1 receptor antagonist (IL-1rn) and IL-1β under steady-state, and that IL-1rn protects against pre-leukemic myelopoiesis by repressing IL-1β signaling.

Sweat, Cao et al. used different genetic and epigenetic approaches to show that Tbx5 is essential for the maintenance of atrial identity in postnatal cardiomyocytes by binding atrial-specific enhancers and maintaining the atrial-specific chromatin architecture, in a dose-dependent manner.

Ramabadran et al. identify a DNA methylation-independent role for DNMT3A in stem cell activation, mediated through recruitment of SF3B1 and splicing regulation.

BPAN is a rare neurodegenerative disease caused by WDR45 mutations. Here, the authors discover that WDR45 can competitively displace G3BP1 from Caprin-1 to promote stress granule disassembly, a function that is disrupted by BPAN-associated WDR45 mutations.

The functional significance of the observed heterogeneity of androgen receptor (AR) expression in prostate cancer is unknown. Here the authors show AR expression heterogeneity is associated with distinct castration/enzalutamide responses and identify BCL-2 as a potential therapeutic target in castration-resistant prostate cancer.

The malate shuttle is understood to control the NAD⁺/NADH balance. Here the authors show that GOT1, a central enzyme in the malate shuttle, rather promotes antiviral CD8⁺ T cell responses by detoxifying ammonia.

Autophagy proteins differentially control Mycobacterium tuberculosis replication in human macrophages.

This study defines the consequences of ARID1A and ARID1B loss in dedifferentiated or undifferentiated endometrial carcinoma, finding that altered SWI/SNF chromatin remodeler complex subtypes support oncogenesis, informing potential therapeutic opportunities.

Multiomic analysis of blast-phase myeloproliferative neoplasms identifies a chromosome 21 amplicon harboring DYRK1A as a clonal and therapeutically targetable event in around a quarter of cases.

Inter-organellar contacts are hubs for several critical cellular processes, such as lipid synthesis. Here Ganji et al. show that the p97-UBXD8 complex modulates contacts by regulating membrane lipid composition and saturation.

Metabolic rewiring is involved in acute myeloid leukaemia (AML) maintenance. Here the authors show that the inhibition of mannose-6-phosphate isomerase in the mannose metabolism pathway sensitizes AML to FLT3-tyrosine kinase inhibitor and standard chemotherapy via enhancing lipid peroxidation and ferroptotic cell death.

Obesity-associated AT fibro-inflammation and metabolic disturbances are linked to PEPD activity and PEPD extracellular levels.

Mellor et al. report that deficiency of GABARAPL1, an ATG8-specific linking protein, impairs diastolic function in diabetic mice. This effect can be reversed by gene delivery of the gene encoding GABARAPL1 in diabetic mice and a human organoid model of type 2 diabetes.

The circadian clock protein REV-ERBα has been implicated in neuroinflammation but mechanisms are poorly understood. Here, the authors show that microglial REV-ERBα regulates inflammatory signaling and lipid droplet formation to exert sex-specific effects on tau pathology in mice.

Li et al. discovered that the cytotoxic synthetic small molecule BRD1732 is directly ubiquitinated in cells. Ubiquitination of BRD1732 is E3 ligase dependent and leads to inhibition of proteasomal degradation.

Genome-wide CRISPR knockout and activation screens in Calu-3 lung cells and Caco-2 colorectal cells identify host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs.

Tham and Bernardo et al. show that cardiomyocyte-specific knockout of estrogen receptor alpha induces increased adiposity and tissue metabolic alterations specifically in female mice, likely in part due to changes in the proteomic content of the heart-derived extracellular vesicles.

Aarrestad et al. show that, in contrast to psychedelics, the nonhallucinogenic psychoplastogen tabernanthalog promotes neuroplasticity through 5-HT_2AR activation without immediately increasing extracellular glutamate levels or immediate early gene expression.

Translation efficiency can be affected by mRNA stability and secondary RNA structures. Here the authors reveal that loss of DHX36 helicase activity leads to an accumulation of translationally inactive target mRNAs with G-rich structures in untranslated regions.

Monomethylation of histone H4 lysine 20 (H4K20me1) contributes to DNA replication but the mechanism is not well understood. Here, the authors identify a conserved tandem Tudor domain of BAHCC1 as a H4K20me1-specific reader, which promotes the recruitment of MCM complex to chromatin for efficient DNA replication.

Senescent cells in fat and liver are shown to attract M1-like macrophages with increased expression of the NAD-consuming enzyme CD38, leading to their local accumulation and providing a mechanism for the age-associated decline in tissue NAD⁺ levels.

A covariate-aware analysis reveals that microbiome changes in the gut of patients with chronic kidney disease are better explained by intestinal transit time than by kidney function.

Gut microbes are known to influence whole-body metabolism. Here Everard et al.show the adaptor protein MyD88 in intestinal epithelial cells is sensitive to changes in the diet and affects composition of the gut microbiota, which influences the development of obesity and associated diseases.

In vivo, cells migrate across a diverse landscape of extracellular matrix containing gaps which present a challenge for cells to protrude across. Here, the authors show that T-Plastin strengthens protrusive actin networks to promote protrusion, extracellular matrix gap-bridging, and cell migration.

Conditional genetic ferret models enable ionocyte lineage tracing, ionocyte ablation and ionocyte-specific deletion of CFTR to elucidate the roles of pulmonary ionocyte biology and function during human health and disease.

Here, the authors identify the host proteins LATS1/2 and YAP of the Hippo pathway to regulate Ebola virus transcription and virus production/egress. They show that YAP activity is important for virus particle production and release, while LATS1/2 are critical for EBOV mRNA synthesis and viral protein expression.

The pathways involved in exit from pluripotency in human embryonic stem cells are poorly understood. Here, the authors performed a CRISPR-based screen to identify genes that promote exit from naïve pluripotency and find a role for folliculin (FLCN) by regulating the mTOR and Wnt pathways.

Inhibition of the metabolic enzyme ATP-citrate lyase can attenuate atherosclerosis by preventing dyslipidemia and potentially also by reducing macrophage-mediated inflammation. Here, the authors show that specific targeting of ACLY in macrophages results in more stable atherosclerotic plaques.

Lipocalin 2 (LCN2) has been recently identified as an endogenous regulator of appetite. Here, using pancreatic cancer as a model of cachexia, the authors demonstrate that LCN2 is a critical mediator of cancer-associated anorexia and may be therapeutically targeted to improve patient outcomes.

Missense mutant p53 (mutp53) proteins often accumulate in cancers. Here the authors show that the lipogenic enzyme FASN enhances mutp53 protein stability to drive tumor growth by promoting mutp53 palmitoylation.

Developmental and epileptic encephalopathies are devastating neurological disorders. Here, the authors establish a cohort of patients with variants in the gene DENND5A and use human stem cells to discover a disease mechanism involving altered cell division.

A CRISPR–Cas9 screen of chromatin regulators in mouse tumour models treated with immune checkpoint blockade identifies SETDB1 as an epigenetic checkpoint protein that suppresses tumour-intrinsic immunogenicity.

Beta-arrestins have key roles in development and metabolic functions as euglycaemic control and insulin sentitivity. Here Zhuet al. show that beta-arrestin-2 regulates insulin secretion and glucose tolerance in mice by promoting CAMKII functions in beta cells.