Targeting IGF1 to alleviate obesity through regulating energy expenditure and fat deposition.

Insulin-like growth factor 1 (IGF1) is a regulator of both cellular hypertrophy and lipogenesis, which are two key processes for pathogenesis of obesity. However, the in vivo role of IGF1 in the development of obesity remains unclear. Here, we show that IGF1 expression is increased in adipose tissue in obese human patients and animal models.

Multi-TACs: Targeting Solid Tumors with Multiple Immune Cell Co-engagers.

Multiple immune components in the complex and heterogeneous tumor-immune microenvironment (TIME) work cooperatively to promote or impede cancer immunotherapy. Synergistically co-managing multiple immune cells with single agents for advanced antitumor immunity remains desirable but challenging. This In Focus article introduces a triple orthogonal linker (T-Linker)-based multimodal targeting chimera (Multi-TAC) platform, enabling the single-agent-mediated tumor-targeted co-engagement of multiple immune cell types within TIME for potentiated immunotherapy.

Infiltrating plasma cells maintain glioblastoma stem cells through IgG-Tumor binding.

Glioblastoma is a highly aggressive primary brain tumor with glioblastoma stem cells (GSCs) enforcing the intra-tumoral hierarchy. Plasma cells (PCs) are critical effectors of the B-lineage immune system, but their roles in glioblastoma remain largely unexplored. Here, we leverage single-cell RNA and B cell receptor sequencing of tumor-infiltrating B-lineage cells and reveal that PCs are aberrantly enriched in the glioblastoma-infiltrating B-lineage population, experience low level of somatic hypermutation, and are associated with poor prognosis.

Cellular Feimin enhances exercise performance by suppressing muscle thermogenesis.

Exercise can rapidly increase core body temperature, and research has indicated that elevated internal body temperature can independently contribute to fatigue during physical activity. However, the precise mechanisms responsible for regulating thermogenesis in muscles during exercise have remained unclear. Here, we demonstrate that cellular Feimin (cFeimin) enhances exercise performance by inhibiting muscle thermogenesis during physical activity.

Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion.

The cerebrospinal fluid (CSF) border accommodates diverse immune cells that permit peripheral cell immunosurveillance. However, the intricate interactions between CSF immune cells and infiltrating cancer cells remain poorly understood. Here we use fate mapping, longitudinal time-lapse imaging and multiomics technologies to investigate the precise origin, cellular crosstalk and molecular landscape of macrophages that contribute to leptomeningeal metastasis (LM) progression.

HCC Model Induced by P53 and Pten Knockout in HBV-Transgenic Mice Mirrors Human HCC at the Transcriptome Level.

With a multitude of HCC mouse models available, choosing the one that most closely resembles human HCC can be challenging. This study addresses this gap by conducting a comprehensive transcriptomic similarity analysis of widely used HCC mouse models. In this study, RNA-seq was performed on a model induced by double knockout of P53 and Pten via CRISPR/Cas9 in HBV-transgenic mice.

SLC25A1 regulates placental development to ensure embryonic heart morphogenesis.

22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion syndrome.

Direct reprogramming of fibroblasts into spiral ganglion neurons by defined transcription factors.

Degeneration of the cochlear spiral ganglion neurons (SGNs) is one of the major causes of sensorineural hearing loss and significantly impacts the outcomes of cochlear implantation. Functional regeneration of SGNs holds great promise for treating sensorineural hearing loss. In this study, we systematically screened 33 transcriptional regulators implicated in neuronal and SGN fate.

Potassium ion channel modulation at cancer-neural interface enhances neuronal excitability in epileptogenic glioblastoma multiforme.

The central nervous system (CNS) is increasingly recognized as a critical modulator in the oncogenesis of glioblastoma multiforme (GBM), with interactions between cancer and local neuronal circuits frequently leading to epilepsy; however, the relative contributions of these factors remain unclear. Here, we report a coordinated intratumor shift among distinct cancer subtypes within progenitor-like families of epileptic GBM patients, revealing an accumulation of oligodendrocyte progenitor (OPC)-like subpopulations at the cancer-neuron interface along with heightened electrical signaling activity in the surrounding neuronal networks. The OPC-like cells associated with epilepsy express KCND2, which encodes the voltage-gated K channel K4.

MGAT4A/Galectin9-Driven N-Glycosylation Aberration as a Promoting Mechanism for Poor Prognosis of Endometrial Cancer with TP53 Mutation.

Emerging evidence recognizes aberrant glycosylation as the malignant characteristics of cancer cells, but little is known about glycogenes' roles in endometrial carcinoma (EC), especially the most aggressive subtype carrying TP53 mutations. Using unsupervised hierarchical clustering, an 11-glycogene cluster is identified to distinguish an EC subtype associated with frequent TP53 mutation and worse prognosis. Among them, MGAT4A (alpha-1,3-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase A) emerges as the most consistently overexpressed glycogene, contributing to EC aggressiveness.

The TMEM63B Channel Facilitates Intestinal Motility and Enhances Proliferation of Intestinal Stem Cells.

The intestines are in a constant state of motion and self-renewal. The mechanical breakdown of food facilitates intestinal movement and aids digestion. It is believed that mechanical stimulation, triggered by changes in osmotic pressure within the intestines, plays a crucial role in regulating gastrointestinal motility.

AS160 is a lipid-responsive regulator of cardiac Ca homeostasis by controlling lysophosphatidylinositol metabolism and signaling.

The obese heart undergoes metabolic remodeling and exhibits impaired calcium (Ca) homeostasis, which are two critical assaults leading to cardiac dysfunction. The molecular mechanisms underlying these alterations in obese heart are not well understood. Here, we show that the Rab-GTPase activating protein AS160 is a lipid-responsive regulator of Ca homeostasis through governing lysophosphatidylinositol metabolism and signaling.

Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor-immune microenvironment.

Although immunotherapy has revolutionized cancer treatment, its efficacy is affected by multiple factors, particularly those derived from the complexity and heterogeneity of the tumor-immune microenvironment (TIME). Strategies that simultaneously and synergistically engage multiple immune cells in TIME remain highly desirable but challenging. Herein, we report a multimodal and programmable platform that enables the integration of multiple therapeutic modules into single agents for tumor-targeted co-engagement of multiple immune cells within TIME.

Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair.

Tissue damage and repair are hallmarks of inflammation. Despite a wealth of information on the mechanisms that govern tissue damage, mechanistic insight into how inflammation affects repair is lacking. Here, we investigated how interferons influence tissue repair after damage to the intestinal mucosa.

Rab2A-mediated Golgi-lipid droplet interactions support very-low-density lipoprotein secretion in hepatocytes.

Lipid droplets (LDs) serve as crucial hubs for lipid trafficking and metabolic regulation through their numerous interactions with various organelles. While the interplay between LDs and the Golgi apparatus has been recognized, their roles and underlying mechanisms remain poorly understood. Here, we reveal the role of Ras-related protein Rab-2A (Rab2A) in mediating LD-Golgi interactions, thereby contributing to very-low-density lipoprotein (VLDL) lipidation and secretion in hepatocytes.

SPOP downregulation promotes bladder cancer progression based on cancer cell-macrophage crosstalk via STAT3/CCL2/IL-6 axis and is regulated by VEZF1.

Cancer cells are intimately intertwined with tumor microenvironment (TME), fostering a symbiotic relationship propelling cancer progression. However, the interaction between cancer cells and tumor-associated macrophages (TAMs) in urothelial bladder cancer (UBC) remains poorly understood. UBC cell lines (5637, T24 and SW780), along with a monocytic cell line (U937) capable of differentiating into macrophage, were used in a co-culture system for cell proliferation and stemness by MTT, sphere formation assays.

Stub1 promotes degradation of the activated Diaph3: A negative feedback regulatory mechanism of the actin nucleator.

The formin protein Diaph3 is an actin nucleator that regulates numerous cytoskeleton-dependent cellular processes through the activation of actin polymerization. Expression and activity of Diaph3 is tightly regulated: lack of Diaph3 results in developmental defects and embryonic lethality in mice, while overexpression of Diaph3 causes auditory neuropathy. It is known that Diaph3 homophilic interactions include the intramolecular interaction of its Dia-inhibitory domain (DID)-diaphanous autoregulatory domain (DAD) domains and the intermolecular interactions of DD-DD domains or FH2-FH2 domains.

LOX-mediated ECM mechanical stress induces Piezo1 activation in hypoxic-ischemic brain damage and identification of novel inhibitor of LOX.

Hypoxic-ischemic encephalopathy (HIE) poses a significant challenge in neonatal medicine, often resulting in profound and lasting neurological deficits. Current therapeutic strategies for hypoxia-ischemia brain damage (HIBD) remain limited. Ferroptosis has been reported to play a crucial role in HIE and serves as a potential therapeutic target.