Cell reports最新文献

Nicotinamide adenine dinucleotide (NAD⁺) levels decline with age, which has been associated with the development of aging-associated diseases. However, it remains unknown whether low NAD⁺ levels in early life affect aging. This study demonstrates that deficiency of NAD synthetase (NADS), a critical enzyme of the deamidated NAD⁺ biosynthesis pathway, drastically reduced NAD⁺ levels in skeletal muscle and impaired muscle function at a young age. Intriguingly, NAD⁺ levels were restored to normal in middle-aged NADS-knockout mice, whereas muscle function remained compromised. Gene expression analysis showed that hyaluronic acid synthase 2 (Has2) was downregulated in both young NADS-knockout mice and aged wild-type mice. We also found that the α-ketoglutarate-JMJD3 axis downregulates Has2 expression. Then, impaired hyaluronic acid signaling dampened muscle stem cells, leading to decreased locomotor activity. These results suggest that maintaining NAD⁺ levels during early life is important for promoting healthy aging in skeletal muscle.

The hypothalamus contains multiple regions, including the ventromedial hypothalamus (VMH) and arcuate (ARC), which are responsible for sex-differentiated functions such as endocrine signaling, metabolism, and reproductive behaviors. While molecular, anatomic, and sex-differentiated features of the rodent hypothalamus are well established, much less is known about these regions in humans. Here, we provide a spatially resolved single-cell atlas of sex-differentially expressed (sex-DE) genes in the human ARC and VMH. We identify neuronal populations governing hypothalamus-specific functions, define their spatial distributions, and show enrichment of sex-DE in retinoid metabolism- and retinoid receptor-regulated genes. Within the ARC and VMH, we find correlated autosomal expression differences localized to ESR1/TAC3-expressing and corticotropin-releasing hormone receptor 2 (CRHR2)-expressing neurons and extensive sex-DE genes linked to sex-biased disorders, including autism, depression, and schizophrenia. Our molecular mapping of disease associations to hypothalamic cell types with established roles in sex-divergent physiology and behavior provides insights into the mechanistic bases of sex bias in neurodevelopmental and neuropsychiatric disorders.

Burn injury triggers sustained white adipose tissue (WAT) remodeling and hypermetabolism. While systemic catecholamines are considered primary drivers of this response, local mechanisms remain poorly defined. Here, we identify an intra-fat immune-neural axis that drives sympathetic remodeling and thermogenic reprogramming of WAT after burn. Using a murine scald model, we show that burn injury induces localized sympathetic activation, norepinephrine release, and WAT browning, all abolished by chemical or genetic denervation. Mechanistically, macrophage-derived Ccl12 recruits CCR2⁺ T cells that secrete nerve growth factor, promoting sympathetic neurite outgrowth and increasing intra-fat adrenergic tone. Disruption of this pathway through Ccl12 neutralization or T cell deficiency impairs WAT browning. Parallel features are observed in patients with burn injury, including increased sympathetic innervation, elevated uncoupling protein-1 expression, and enrichment of CCR2⁺ T cells in WAT. These findings reveal neural regulation of adipose function after burn and suggest potential targets for modulating hypermetabolism.

The role of neurotransmitters in suppressing anti-tumor immunity has garnered increasing attention. While glutamate has been extensively studied in neurological diseases, its potential role in regulating anti-tumor immunity, particularly in the context of neoadjuvant immunochemotherapy, remains underexplored. In this study, we find that glutamate levels are elevated in the plasma of head and neck squamous cell carcinoma (HNSCC) patients. The METTL3/m6A/CD98 axis in cancer-associated fibroblasts (CAFs) is a key driver of glutamate secretion. Glutamate induces CD8⁺ T cell exhaustion through SLC1A3 and impairs the formation of immune memory in secondary lymphoid structures. Additionally, glutamate promotes ferroptosis resistance in HNSCC. Notably, glutamate depletion enhances the efficacy of neoadjuvant immunochemotherapy. Our findings provide insights into how the METTL3/m6A/CD98 axis-mediated regulation of glutamate efflux may sensitize HNSCC to neoadjuvant immunochemotherapy.

The evolutionarily conserved Hippo signaling pathway, essential for development and tissue homeostasis, is intimately linked to cellular metabolism. While cellular α-ketoglutarate (α-KG) levels fluctuate with metabolic state, the functional significance of these fluctuations for development remains poorly defined. Here, this study uncovers an evolutionarily conserved mechanism whereby α-KG directly regulates Hippo signaling activity during development. We demonstrate that elevated α-KG promotes the degradation of Yki, the key Hippo pathway effector in Drosophila, in a concentration-dependent manner. Mechanistically, α-KG drives PH4αEFB-mediated prolyl hydroxylation of specific proline residues in Yki, thereby targeting it for ubiquitination and proteasomal degradation. Critically, mutation of these hydroxylation sites of Yki abolishes its sensitivity to α-KG, resulting in Yki protein hyperstabilization, aberrant activation of Hippo targets, and organ overgrowth in Drosophila. Overall, these findings establish α-KG as a central metabolic regulator of Hippo activity, thereby coupling metabolic status to developmental growth control.

Engineered macrophage-based therapies offer promising potential for cancer treatment but are limited by slow, uncontrolled drug release and the risk of macrophage reprogramming into tumor-promoting phenotypes. Here, we developed a thermally induced macrophage autolysis release system, the macrophage-microbe encapsulation bomb (MME-Bomb), which combines engineered macrophages loaded with indocyanine green-encapsulated nanoparticles and an antitumor attenuated Salmonella typhimurium strain. Photothermal therapy is used to induce controlled pyroptosis and rupture of the encapsulated macrophages within the tumor microenvironment, releasing intracellular bacteria to stimulate prolonged antitumor immunity. By integrating light-responsive biomodulation, our approach enables site-specific activation of engineered cells, enhancing the rapid delivery of therapeutic agents and maximizing the synergy between macrophage-based and bacterial therapies. In preclinical cancer models, the MME-Bomb significantly reduced the tumor burden and improved survival outcomes, both alone and in combination with checkpoint inhibitors. This innovative strategy offers a versatile and precise framework for advancing cancer immunotherapies.

The cGAS/STING-dependent innate immune pathway is central in the cellular response to cytosolic DNA derived from viral infections, genotoxic stress, or mitochondrial defects. While efficient activation of the pathway is crucial for defending against pathogens and cancer, maintaining its dormancy without stimuli is equally important to avoid autoimmunity. However, the precise control of the cGAS/STING pathway remains poorly understood. Here, we report that the ion channel TRPV2 regulates both the dormancy and activation of STING. TRPV2 associates with STING and suppresses spontaneous STING activation in the absence of cytoDNA but dissociates from STING and promotes its activation by releasing Ca²⁺ from the endoplasmic reticulum in the presence of cytoDNA, which facilitates STING translocation to Golgi. Consequently, TRPV2 governs type I interferon production and natural killer cell-mediated cytotoxicity through the cGAS/STING pathway. The dual roles of TRPV2 provide an elegant mechanism for a balanced innate immune response.

The maturation of spermatids to fertilization-competent sperm is a sophisticated process required for sexual reproduction, and biogenesis of the cytoplasmic droplet (CD) is a key event. Here, we demonstrate that two proteins with testis-specific expression, arrestin domain-containing 5 (ARRDC5) and testis expressed 38 (TEX38), physically interact, are required for normal sperm maturation, and play a critical role in CD formation and function. In the CDs of Arrdc5^-/- or Tex38^-/- mice, a key aspect of saccular element biogenesis is deficient, the proteome is abnormal, and migration from the neck down the flagellum does not occur. Furthermore, comparative proteomic profiling between sperm CDs and spermatids from knockouts and wild-type mice suggests that ARRDC5 and TEX38 facilitate cargo loading during CD biogenesis and deposition of proteins such as translocase of outer mitochondrial membrane 40 (TOMM40) from the CD to the sperm mitochondrial sheath during epididymal maturation. This protein-delivery mechanism is likely a key event in enabling sperm motility and therefore fertilization capacity.

Colorectal cancers (CRCs) display recurrent, non-random patterns of chromosome gains and losses, yet the functional contribution of these aneuploidies to colorectal tumorigenesis remains unclear. Mechanistic insights into the oncogenic driver potential of aneuploidy require improved experimental models that recapitulate CRC patient-relevant aneuploidy patterns. Developing such models demands a clear understanding of how aneuploidy evolves during the progression from pre-malignant adenoma to carcinoma and how aneuploidy patterns vary across CRC subtypes. In this review, we highlight and discuss context-dependent alterations in the aneuploidy landscape of CRC, examining associations with tumor subtype, tumor stage, whole-genome doubling, TP53 status, and metastatic organotropism. Through a synthesis of the current literature and meta-analysis of publicly available bulk sequencing datasets of colorectal carcinomas and colorectal adenomas, this review provides a comprehensive CRC aneuploidy framework to guide future studies aimed at unraveling the mechanistic and clinical implications of these copy-number alterations.

Janus kinases 1 and 2 and STAT transcription factors are critical signaling nodes for numerous growth factors. In the mammary gland, JAK2 and STAT5a/b are essential for alveolar cell differentiation and lactation, but little is known about the cooperative roles of JAKs and STATs before pregnancy. We examined female mice conditionally deficient in JAK1/2 and discovered that both kinases jointly regulate epithelial cell proliferation and ductal morphogenesis. To assess the role of downstream STATs, we generated genetic models co-deficient in STAT3/5a/5b with or without STAT1 or JAK1. Although loss of STAT3/5a/5b leads to a JAK1-dependent upregulation of STAT1, the formation of mammary ducts is unaffected by the lack of expression and activation of all seven STAT proteins. Additionally, STAT deficiency impairs the cytokine-induced autophosphorylation of JAK1/2. These findings suggest that mammary duct development is orchestrated by STAT-independent signaling mechanisms of JAK1 and JAK2, potentially beyond their roles as tyrosine kinases.