High-grade lung neuroendocrine carcinomas (Lu-NECs) are clinically refractory malignancies with poor prognosis and limited therapeutic advances. The biological and molecular features underlying the histological heterogeneity of Lu-NECs are not fully understood. In this study, we present a multi-omics integration of whole-exome sequencing and deep proteomic profiling in 93 Chinese Lu-NECs to establish the first comprehensive proteogenomic atlas of this disease spectrum. Our analyses revealed a high degree of mutational concordance among the subtypes at the genomic level; however, distinct proteomic profiles enabled a clear differentiation of histological subtypes, unveiling subtype-specific molecular and biological features related to tumor metabolism, immunity, and proliferation. Furthermore, RB1 mutations confer divergent prognostic effects through subtype-specific cis- and trans-proteomic regulation. In addition, we identified potential protein biomarkers for histological subtype classification and risk stratification, which were validated by immunohistochemistry in an independent cohort. This study provides a valuable proteogenomic resource and insight into Lu-NEC heterogeneity.

Increasing evidence indicates that oligodendrocyte (OL) numbers and myelin as a dynamic cellular compartment perform a key role in the maintenance of neuronal function. Inhibiting white matter (WM) demyelination or promoting remyelination has garnered interest for its potential therapeutic strategy against ischemic stroke. Our previous work has shown that low-intensity pulsed ultrasound (LIPUS) could improve stroke recovery. However, it is unclear whether LIPUS can maintain WM integrity early after stroke or promote late WM repair. This study evaluated the efficacy of LIPUS on WM repair and long-term neurologic recovery after stroke. Male adult C57BL/6 mice underwent a focal cerebral ischemia model and were randomized to receive ultrasound stimulation (30 min once daily for 14 days). The effect of LIPUS on sensorimotor function was assessed by modified neurological severity score, rotarod test, grip strength test, and gait analysis up to 28 days after stroke. We found that ischemic stroke-induced WM damage was severe on day 7 and partially recovered on day 28. LIPUS prevented neuronal and oligodendrocyte progenitor cell (OPC) death during the acute phase of stroke (d7), protected WM integrity, and reduced brain atrophy and tissue damage during the recovery phase (d28). To further confirm the effect of LIPUS on remyelination, we assessed the proliferation and differentiation of OPCs. We found that LIPUS did not increase the number of OPCs (PDGFRα⁺ or NG2⁺), but markedly increased the number of newly produced mature OLs (APC⁺) and myelin protein levels. Mechanistically, LIPUS may promote OL maturation and remyelination by down-regulating the interleukin-17A/Notch1 signaling pathway. In summary, LIPUS can protect OLs and neurons early after stroke and promote long-term WM repair and functional recovery. LIPUS will be a viable strategy for the treatment of ischemic stroke in the future.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been proposed to benefit cardiometabolic health. However, the relationship between the intake of DHA and EPA and type 2 diabetes (T2D) risk remains equivocal, and the effects of DHA and EPA on skeletal muscle, the primary organ for glucose metabolism, merit further investigation. Here, we show that habitual fish oil supplementation was associated with a 9% lower T2D risk and significantly interacted with variants at GLUT4 in a prospective cohort of 48,358 people with prediabetes. Muscular metabolome analysis in the animal study revealed that DHA and EPA altered branched-chain amino acids, creatine, and glucose oxidation-related metabolites, concurrently with elevated muscular glycogen synthase and pyruvate dehydrogenase contents that promoted glucose disposal. Further myotube investigation revealed that DHA and EPA promoted muscular GLUT4 translocation by elevating Rab GTPases and target-SNARE expression. Together, DHA and EPA supplementation provides a promising approach for T2D prevention through targeting muscular glucose homeostasis, including enhancing GLUT4 translocation, glycogen synthesis, and aerobic glycolysis.

Background: A century ago, a mystery between a virus and Parkinson’s disease (PD) was described. Owing to the limitation of human brain biopsy and the challenge of electron microscopy in observing virions in human brain tissue, it has been difficult to study the viral etiology of PD. Recent discovery of virobiota reveals that viruses coexist with humans as symbionts. Newly developed transcriptomic sequencing and novel bioinformatic approaches for mining the encrypted virome in human transcriptome make it possible to study the relationship between symbiotic viruses and PD. Nevertheless, whether viruses exist in the human substantia nigra (SN) and whether symbiotic viruses underlie PD pathogenesis remain unknown. Methods: We collected current worldwide human SN transcriptomic datasets from the United States, the United Kingdom, the Netherlands, and Switzerland. We used bioinformatic approaches including viruSITE and the Viral-Track to identify the existence of viruses in the SN of patients. The comprehensive RNA sequencing-based virome analysis pipeline was used to characterize the virobiota in the SN. The Pearson’s correlation analysis was used to examine the association between the viral RNA fragment counts (VRFCs) and PD-related human gene sequencing reads in the SN. The differentially expressed genes (DEGs) in the SN between PD patients and non-PD individuals were used to examine the molecular signatures of PD and also evaluate the impact of symbiotic viruses on the SN. Findings: We observed the existence of viruses in the human SN. A dysbiosis of virobiota was found in the SN of PD patients. A marked correlation between VRFC and PD-related human gene expression was detected in the SN of PD patients. These PD-related human genes correlated to VRFC were named as the virus-correlated PD-related genes (VPGs). We identified 3 bacteriophages (phages), including the Proteus phage VB_PmiS-Isfahan, the Escherichia phage phiX174, and the Lactobacillus phage Sha1, that might impair the gene expression of neural cells in the SN of PD patients. The Proteus phage VB_PmiS-Isfahan was a common virus in the SN of patients from the United Kingdom, the Netherlands, and Switzerland. VPGs and DEGs together highlighted that the phages might dampen dopamine biosynthesis and weaken the cGAS-STING function. Interpretation: This is the first study to discover the involvement of phages in PD pathogenesis. A lifelong low symbiotic viral load in the SN may be a contributor to PD pathogenesis. Our findings unlocked the black box between brain virobiota and PD, providing a novel insight into PD etiology from the perspective of phage–human symbiosis.

DEAD-box ATPase 10 (DDX10), a prominent RNA-binding protein in the DDX family, has a critical function in cancer progression. Nevertheless, its well-defined mechanisms in oral squamous cell carcinoma (OSCC) are still not well understood. Here, we identify that DDX10 is substantially increased in OSCC, which is positively correlated with poor prognosis and malignant behavior. Mechanistically, we found that DDX10 had physical interaction with Rab27b by undergoing phase separation. Knockdown of DDX10 inhibited Rab27b-mediated exosome secretion and the expression of programmed cell death-ligand 1 (PD-L1) within its contents. Furthermore, knocking down DDX10 could restore the function and infiltration of T cells, hence inhibiting the progression of OSCC. These findings highlight that the oncogenic role of DDX10 in promoting exosomal PD-L1 secretion via phase separation with Rab27b has been preliminarily validated in T cell exhaustion in OSCC. A potential strategy for improving OSCC immunotherapy may involve the inhibition of DDX10.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and addressing its intrinsic heterogeneity has emerged as a valuable avenue for novel clinical treatment strategy. Here, we put forward an innovative strategy for TNBC treatment by simultaneously suppressing both p21-activated kinase 1 (PAK1) and histone deacetylase (HDAC) class IIb (HDAC6/10). A series of pyrido [2,3-d]pyrimidin-7(8H)-one moiety derivatives was successfully designed and synthesized to target PAK1/HDAC6/HDAC10 by utilizing structure-based screening and pharmacophore integration. ZMF-25 demonstrates marked inhibitory activity against PAK1, HDAC6, and HDAC10 with respective IC₅₀ values of 33, 64, and 41 nM, remarkable selectivity over HDACs and PAKs, as well as prominent antiproliferative efficiency in MDA-MB-231 cells. Additionally, ZMF-25 effectively suppresses TNBC proliferation and migration by inhibiting PAK1/HDAC6/HDAC10. Moreover, it was found to impair glycolysis and trigger reactive oxygen species generation, resulting in autophagy-related cell death by inhibiting the AKT/mTOR/ULK1 signaling. Furthermore, ZMF-25 exhibits remarkable therapeutic potential with no obvious toxicity in vivo and good pharmacokinetics. In summary, these observations indicate that ZMF-25 is a novel and potent triple-targeting PAK1/HDAC6/HDAC10 inhibitor, which is expected to provide a novel and effective strategy for TNBC treatment.

Microrobotic swarms hold great promise for the revolution of cancer treatment. The coordination of miniaturized microrobots offers a unique approach to treating cancers at the cellular level with enhanced delivery efficiency and environmental adaptability. Prior studies have summarized the design, functionalization, and biomedical applications of microrobotic swarms. The strategies for actuation and motion control of swarms have also been introduced. In this review, we first give a detailed introduction to microrobot swarming. We then explore the design of microrobots and microrobotic swarms specifically engineered for cancer therapy, with a focus on tumor targeting, infiltration, and therapeutic efficacy. Moreover, the latest developments in active delivery methods and imaging techniques that enhance the precision of these systems are discussed. Finally, we categorize and analyze the various cancer therapies facilitated by functional microrobotic swarms, highlighting their potential to revolutionize treatment strategies for different cancer types.

Recent investigations into the mechanisms underlying inflammation have highlighted the pivotal role of immune cells in regulating cardiac pathophysiology. Notably, these immune cells modulate cardiac processes through alternations in intracellular metabolism, including glycolysis and oxidative phosphorylation, whereas the extracellular metabolic environment is changed during cardiovascular disease, influencing function of immune cells. This dynamic interaction between immune cells and their metabolic environment has given rise to the novel concept of “immune metabolism”. Consequently, both the extracellular and intracellular metabolic environment modulate the equilibrium between anti- and pro-inflammatory responses. This regulatory mechanism subsequently influences the processes of myocardial ischemia, cardiac fibrosis, and cardiac remodeling, ultimately leading to a series of cardiovascular events. This review examines how local microenvironmental and systemic environmental changes induce metabolic reprogramming in immune cells and explores the subsequent effects of aberrant activation or polarization of immune cells in the progression of cardiovascular disease. Finally, we discuss potential therapeutic strategies targeting metabolism to counteract abnormal immune activation.

Fusobacterium nucleatum (Fn), an oral anaerobic commensal, has recently been identified as a crucial oncogenic contributor to colorectal cancer pathogenesis through its ectopic colonization in the gastrointestinal tract. Accumulating evidence reveals its multifaceted involvement in colorectal cancer initiation, progression, metastasis, and therapeutic resistance to conventional treatments, including chemotherapy, radiotherapy, and immunotherapy. This perspective highlights recent advances in anti-Fn strategies, including small-molecule inhibitors, nanomedicines, and biopharmaceuticals, while critically analyzing the translational barriers in developing targeted antimicrobial interventions. We further propose potential strategies to overcome current challenges in Fn modulation, aiming to pave the way for more effective therapeutic interventions and better clinical outcomes.

Peripartum dairy cows commonly experience energy metabolism disorders, which lead to passive culling of postpartum cows and a decrease in milk quality. By using ketosis peripartum dairy cows as a model, this study aims to elucidate the metabolic mechanism of peripartum cows and provide a novel way for managing energy metabolic disorders. From a cohort of 211 cows, we integrated multi-omics data (metagenomics, metabolomics, and transcriptomics) to identify key microbes and then utilized an in vitro rumen fermentation simulation system and ketogenic hepatic cells to validate the potential mechanisms and the effects of postbiotics derived from key microbes. Postpartum cows with metabolic disorders compensate for glucose deficiency through mobilizing muscle proteins, which leads to marked decreases in milk protein content. Concurrently, these cows experience rumen microbiota disturbance, with marked decreases in the concentrations of volatile fatty acids and microbial protein, and the deficiency of alanine (Ala) in microbial protein is correlated with the metabolic disorder phenotype. Metagenomic binning and in vitro fermentation assays reveal that Ruminococcus_E bovis (MAG 189) is enriched in amino acid biosynthesis functions and responsible for Ala synthesis. Furthermore, transcriptomic and metabolomic analyses of the liver in metabolic disorder cows also show impaired amino acid metabolism. Supplementation with Ala can alleviate ketogenesis in liver cell models by activating the gluconeogenesis pathway. This study reveals that Ruminococcus_E bovis is associated with host energy metabolism homeostasis by supplying glucogenic precursors to the liver and suggests the use of Ala as a method for the treatment of energy metabolism disorders in peripartum cows.