2026年 · 第139卷第02期

Interorgan crosstalk refers to the bidirectional communication and interaction between different organs in the body. It plays a crucial role in maintaining metabolic homeostasis and is essential for proper physiological function. Dysregulation of organ crosstalk has been associated with the development of various metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is a growing health issue worldwide, affecting approximately 30% of the global population. There has been a growth in literature to address the dysregulated crosstalk between multiple extrahepatic organs and the liver; thus, many striking findings have been published. However, the underlying mechanisms remain largely obscure. In this study, we focused on the perspective of circulating proteins, metabolites, neuroendocrine signals, and extracellular vesicles, summarizing systematically how they affect extrahepatic organs and the liver in the pathogenesis of MASLD. Furthermore, particular attention is placed on the potential novel therapeutic strategies.

Obesity, a global public health crisis driven by complex interactions of genetic, environmental, and behavioral factors, necessitates innovative therapeutic strategies. This review explores the pathogenesis of obesity, emphasizing genetic determinants, metabolic dysregulation, gut microbiota alterations, and energy imbalance. The evolution of anti-obesity pharmacotherapy has progressed from the use of high-risk agents such as amphetamines and thyroid extracts to modern gut hormone-based therapies, notably glucagon-like peptide-1 receptor agonists (GLP-1RAs), which effectively suppress appetite and improve glycemic control. Current pharmacologic agents target central appetite regulation or peripheral mechanisms. However, there are still risks such as muscle loss and long-term safety issues. Emerging therapeutic strategies are focusing on novel targets such as growth differentiation factor 15 (GDF15) and its specific receptor glial cell-line derived neurotrophic factor family receptor α-like (GFRAL), inhibin βE (INHBE), as well as bile acid receptors including the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Concurrently, the field is advancing multi-targeted drugs and drug combinations to enhance weight loss efficacy and reduce side effects. Furthermore, the development of oral formulations such as oral Semaglutide is expected to provide convenience for patients and enhance their willingness to receive treatment. In the future, with the development of multi-omics technologies and the widespread application of artificial intelligence, it is expected to support personalized therapies, thereby improving treatment efficacy and accuracy.

Long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) is a critical component of nuclear paraspeckles, influencing gene expression through epigenetic, transcriptional, and post-transcriptional mechanisms. The dysregulated expression and function of NEAT1 are associated with diverse human disorders ranging from inflammatory diseases to cancers. However, the emerging pathophysiological roles and therapeutic strategies of NEAT1 in skin disorders have not yet been thoroughly reviewed and discussed. This review offers a comprehensive perspective and discusses the recent therapy progress on NEAT1 in skin disorders, mainly, including skin cancers and immune-related conditions. NEAT1 is always upregulated in various skin disorders, such as systemic lupus erythematosus (SLE), atopic dermatitis (AD), and melanoma, which primarily functions as a competitive endogenous RNA (ceRNA) via targeting microRNA and regulates multiple immune cells to exert pathogenic effects. Notably, the expression levels of NEAT1 in psoriasis studies present contrary results, with some studies showing increased expression and others indicating downregulation, making its role in the pathophysiology of psoriasis appear complex, and its specific regulation of different cells requires further research. Moreover, technologies focusing on NEAT1 inhibition with upstream element regulation and direct silencing, and NEAT1 overexpression based on drug induction and exogenous introduction, are growing vigorously. In conclusion, this review provides significant insights into potential diagnostic biomarkers and therapeutic targets of NEAT1 for these disorders.

Prostate cancer (PCa) presents a significant global health challenge, and cachexia in end-stage PCa further reduces survival time and deteriorates patient quality of life. This necessitates nuanced approaches to prevention, diagnosis, and treatment. This review analyzes the complex role of growth differentiation factor 15 (GDF15) in various aspects of PCa, including metabolism, chemoresistance, metastasis, and clinical implications. Mechanically, the interactions of GDF15 with PCa lipid metabolism and stromal activation are hypothesized to drive PCa progression and promote cachexia. GDF15’s role in PCa bone metastasis is mediated through interactions with osteoblasts and osteoclasts. Furthermore, GDF15’s role in chemoresistance emphasizes its impact on drug responses and suggests a potential therapeutic target. Clinically, GDF15 has shown potential as a biomarker, offering diagnostic precision and prognostic value, particularly when combined with established markers such as prostate-specific antigen. The review concludes with a discussion on several monoclonal antibodies targeting GDF15 in clinical trials, such as AV-380, NGM120, Visugromab, and AZD8853, highlighting promising strategies for novel therapies and precision medicine.

Peptide-drug conjugates (PDCs) have emerged as a promising strategy in cancer therapy, offering improved therapeutic efficacy and reduced toxicity. Compared to antibody-drug conjugates (ADCs) and small molecule-drug conjugates (SMDCs), PDCs possess distinct advantages, such as lower immunogenicity, improved tumor penetration, and simpler synthesis. This review discusses the latest advancements in PDC design, including novel peptide targeting mechanisms, linker selection, and formulation improvements for increased stability. Additionally, it explores the expanding clinical applications of PDCs and examines their limitations. The aim of this review is to provide a comprehensive overview of current PDC progress and outline future directions for their role in cancer treatment.

Background: Although guidelines stress the importance of early screening for individuals at high risk of lung cancer in China, there is a lack of data on risk-adapted starting ages for screening. This study aims to determine the appropriate starting age for lung cancer screening in China, considering various risk factors associated with the disease. Methods: The data used were from the Cancer Screening Program in Urban China. A total of 413,725 eligible participants aged 40-74 years from eight cities in China were enrolled between 2013 and 2021. The outcomes of the study included lung cancer diagnosis and age at diagnosis. The risk-adapted starting age for screening was defined as the age at which individuals with varying levels of lung cancer risk reached a 10-year cumulative risk level similar to that of those aged 50 years in the general population. Results: Among the 413,725 individuals who participated in the study, 1607 were diagnosed with lung cancer with a median follow-up of 4.90 (3.01, 6.84) years. The participants were categorized into different risk groups based on their lung cancer risk scores, which were determined by various risk factors, such as gender, education level, body mass index, vegetable intake, smoking pack-years, and tea consumption. In the study, the optimal starting age for lung cancer screening was determined on the basis of an individual’s risk level. Using the 10-year cumulative risk of lung cancer at age 50 years in the general population as a benchmark (0.59% [95% confidence interval, 0.52-0.63%]), the study revealed that individuals with high, medium, or low risk of lung cancer should start screening at ages 46, 48, or 54 years and older, respectively. Conclusions: This study establishes the age at which lung cancer screening should begin on the basis of the principle of equal management and risk management. These findings have the potential to contribute to updates in the current screening guidelines.

Background: Neurological dysfunction is a common complication of traumatic brain injury (TBI), and early treatments are critical for the long-term prognosis. This study aimed to investigate whether hypidone hydrochloride (YL-0919) improves neurological function impairment in mice with TBI. Methods: TBI was induced in adult male C57BL/6J mice using the controlled cortical impact (CCI) method. First, the modified neurological severity score (mNSS), rotarod test, and Morris water maze (MWM) test were conducted to assess the impact of YL-0919 on neurological function in mice with TBI. Next, immunofluorescence and laser speckle contrast imaging were utilized to measure the number and activation of microglia and cerebral blood flow (CBF) after TBI. Enzyme-linked immunosorbent assay (ELISA) was employed to assess the inflammatory factors. Finally, Western blotting was performed to measure the expression of proteins. Golgi-Cox staining was utilized to investigate the structure of pyramidal neurons. Results: YL-0919 significantly alleviated neurological dysfunction in TBI+YL-0919 mice compared with TBI+Vehicle mice, increased the time spent on the rotarod (F = 1.297, P <0.05), and partially relieved cognitive dysfunction in TBI mice (for mNSS, F = 5.540, P <0.01; for MWM test, F = 30.78, P <0.05). Additionally, YL-0919 effectively inhibited the proliferation and activation of microglia (both P <0.01), promoted the recovery of CBF around the brain injury site and inhibited the expression of tumor necrosis factor-α (F = 9.142, P <0.05) and IL-1β (F = 4.662, P <0.05), and increased the concentration of IL-4 (F = 5.172, P <0.05). Furthermore, continuous gavage of YL-0919 (2.5 mg/kg) for seven days effectively increased the protein expression of brain-derived neurotrophic factor (BDNF), promoted the phosphorylation of mammalian target of rapamycin (mTOR), increased postsynaptic density protein 95 (PSD95) and synapsin1 levels, and increased the neuronal dendritic complexity and the dendritic spine density around the brain injury site (all P <0.05). Conclusions: Our findings indicated that YL-0919 can ameliorate neurological dysfunction in mice after TBI through the suppression of inflammation and the stimulation of the BDNF-mTOR signaling pathway. These findings provide an insightful perspective on the potential pharmacological mechanism involved in the neuroprotective effect of YL-0919.

Background: Chronic kidney disease (CKD) is a global health issue, with renal fibrosis being a common pathway in CKD development. Histone modification plays crucial roles in transcriptional regulation, but their pathological functions and mechanisms in CKD are not well understood. Methods: We utilized chromatin immunoprecipitation with next-generation DNA sequencing (ChIP-seq) and RNA-seq to evaluate the states and functions of H3 lysine 27 acetylation (H3K27ac) and H3 lysine 4 trimethylation (H3K4me3) in kidney of CKD mice. We identified epigenetic factors regulating H3K27ac through motif analysis. Expression of activating transcription factor 3 (ATF3) in CKD mouse models and patients’ kidneys was validated via immunofluorescence staining or Western blot. We further generated the Atf3 deficient (Atf3-/-) mice to explore its effect in kidney function and fibrosis. ChIP-seq of H3K27ac from Atf3-/- CKD mice was employed to validate ATF3’s regulatory effects. We explored how ATF3 maintains the state of H3K27ac by integrating the data sources from multiple databases. Results: The states of H3K27ac and H3K4me3 were changed during CKD, and positively correlated with differential gene expression. ATF3 was highly expressed in kidney of both patients and mice with CKD, and co-localized with H3K27ac in genome, epigenetically regulating H3K27ac state. Atf3 deficient in CKD mice significantly ameliorated kidney dysfunction and fibrotic phenotype, and reduced H3K27ac levels at the ATF3 binding sites. Mechanically, ATF3 may facilitate H3K27ac maintenance by corrodinating histone acetyltransferase (HATs)-associated regulatory machinery during CKD. Conclusion: ATF3 promotes kidney injury and fibrosis in CKD by maintaining the state of H3k27ac via coordinating HATs regulatory machinery.

Background: Interleukin-1 receptor-associated kinase 1 (IRAK1), an active serine/threonine kinase, is an indispensable mediator of inflammatory responses and innate immunity. Emerging evidence has highlighted the oncogenic role of IRAK1 in tumors. However, the role of IRAK1 in gastric cancer (GC) progression remains unclear. Methods: IRAK1 expression levels in patients with GC at Peking Union Medical College Hospital were assessed by Western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. To elucidate the role of IRAK1 in GC pathogenesis, we established GC cells with clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) mediated IRAK1 knockout and lentiviral vector-mediated IRAK1 overexpression and subsequently conducted in vitro and in vivo experiments. Additionally, we assessed the effect of IRAK1 expression levels in GC cells on the M2 polarization of tumor-associated macrophages (TAMs) via a Transwell coculture system. Functional assays were subsequently carried out to determine whether IRAK1 regulates the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of GC cells through the induction of TAM M2 polarization and to clarify the associated regulatory mechanisms. Results: IRAK1 expression was progressively increased during GC progression. Clinicopathological feature analysis revealed that high IRAK1 expression predicted poor survival outcomes. In vitro and in vivo experiments revealed that IRAK1 was highly expressed in GC cells and facilitated the proliferation, migration, invasion, and EMT of GC cells via the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. More interestingly, IRAK1 affected the malignant biological behavior of GC cells by inducing M2-like polarization of macrophages. Mechanistically, coculturing M0 macrophages with IRAK1-knockout GC cells suppressed interleukin (IL)-8 secretion, thereby inhibiting Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway activation in TAMs. Inactivation of the JAK2/STAT3 pathway suppressed the M2 polarization of TAMs, ultimately inhibiting GC progression. Conclusions: IRAK1 influences the malignant biological behavior of GC cells by activating the PI3K/AKT/mTOR pathway and inducing the M2-like polarization of macrophages via the IL-8/JAK2/STAT3 pathway in TAMs. Our findings provide a novel diagnostic biomarker and a promising therapeutic strategy for GC.

Background: Sevoflurane impairs neurogenesis and cognitive function in the developing brain; however, the underlying mechanisms remain unclear. This study aimed to investigate the role of fatty acid β-oxidation (FAO) in neural stem/progenitor cells (NSPCs) as a potential factor in sevoflurane-induced neurogenesis inhibition and cognitive deficits. Methods: NSPCs, NE-4C cells, and postnatal day 7 (PND 7) rats were exposed to sevoflurane. Cell viability was measured using the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Neurogenesis was assessed by immunohistochemistry. Apoptosis was detected via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Cognitive function was tested with the Morris water maze. Lipid metabolism profiles were analyzed through lipidomics. Messenger RNA (mRNA) expression levels of key FAO enzymes and the major carnitine transporter were quantified by real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR). Protein expression of carnitine palmitoyltransferase 1a (CPT1a) and nuclear peroxisome proliferator-activated receptor α (PPARα) was examined by Western blotting. CPT1a enzymatic activity was determined using a biochemical assay. FAO activity was measured with the FAOBlue assay. Results: Sevoflurane exposure impaired neurogenesis and cognitive function. In NSPCs, sevoflurane exposure induced extensive alterations in lipid metabolism intermediates, inhibited the mRNA expression of acyl-coenzyme A (CoA) oxidase 1 (ACOX1), acyl-CoA oxidase 3 (ACOX3), hydroxyacyl-CoA dehydrogenase beta subunit (HADHB), CPT1a, carnitine palmitoyltransferase 2 (CPT2), acyl-CoA dehydrogenase short-chain (ACADS), and solute carrier family 22 member 5 (SLC22A5), suppressed FAO activity, reduced CPT1a expression and activity, and decreased PPARα levels in the nucleus. Enhancing FAO activity in NSPCs ameliorated the negative effects of sevoflurane on neurogenesis. Overexpression of CPT1a rescued the sevoflurane-induced inhibition of FAO activity and neurogenesis in NE-4C cells. Pretreatment with palmitoylethanolamide (PEA), a PPAPα agonist, increased both the nuclear content of PPARα protein and the expression of CPT1a in NSPCs and rat hippocampus after sevoflurane exposure. Furthermore, pretreatment with PEA or the CPT1a substrate carnitine rescued sevoflurane-induced damage to FAO activity in NSPCs, neurogenesis, and cognitive function. Conclusion: Sevoflurane impairs neurogenesis and cognitive function by suppressing FAO in NSPCs of the developing brain. Boosting FAO activity in NSPCs could be a potential strategy to prevent sevoflurane-induced cognitive deficits.