2026年 · 第139卷第05期

Cardiometabolic risk encompasses the interconnected conditions of cardiovascular diseases (CVDs), type 2 diabetes (T2D), and other metabolic diseases, which are leading global health challenges. The American Heart Association (AHA) has introduced "Life’s Essential 8" (LE8), a framework emphasizing eight key lifestyle and health factors, including diet, physical activity, smoking, sleep health, body weight, blood glucose, blood lipids, and blood pressure to optimize cardiovascular health and reduce the burden of cardiometabolic risk. This review examined the associations between individual and combined lifestyle factors and the development and progression of cardiometabolic risk, using CVD and T2D as representative conditions. Evidence highlighted that adherence to healthy lifestyle behaviors, such as maintaining a balanced diet, engaging in physical activity, avoiding smoking, and achieving a healthy weight, significantly reduced the risks of CVD, T2D, and hypertension. Studies showed that adherence to 3–4 healthy lifestyle factors lowers the risk of transition from baseline to diabetes, complications, and mortality. Despite the proven benefits, barriers such as limited access to healthy food and safe environments for physical activity hinder widespread adoption. Addressing these challenges requires innovative public health interventions and personalized strategies targeting high-risk populations. This review underscored the importance of promoting and adhering to LE8 principles to reduce the global burden of cardiometabolic risk and improve overall health outcomes.

Leucine-rich repeat kinase 2 (LRRK2) is a critical target for the treatment of Parkinson’s disease (PD) and potentially other diseases. LRRK2 is involved in intracellular signaling, immune response, and inflammation, with key roles in both the central nervous system and peripheral tissues. LRRK2 mutations are linked to cellular dysfunction including mitochondrial and neuronal damage and can disrupt signaling pathway balance, thereby contributing to PD and other disorders. Inhibiting LRRK2 kinase activity shows potential for treating PD by correcting cellular imbalances and reducing neuronal damage. However, risks associated with regulating a multifunctional protein must be addressed. Further research on the molecular partners and tissue-specific functions of LRRK2 is essential for developing targeted therapies and improving treatment options for related diseases. This review offers a comprehensive analysis of LRRK2, with a focus on its physiological functions, disease involvement, and emerging therapeutic strategies.

Heart failure (HF) is a chronic condition characterized by high morbidity and mortality worldwide, imposing a substantial burden on healthcare systems. In recent years, artificial intelligence (AI) technologies, including machine learning, deep learning, and large language models, have demonstrated great potential in HF management. By integrating multimodal data, such as electronic health records and medical imaging, AI models address limitations in risk prediction, phenotyping, diagnosis, treatment, and prognosis, offering novel insights to improve the quality of life for HF patients. However, several challenges remain before AI can be reliably implemented in clinical practice, including model selection, model generalization, interpretability, and limited reliability in real-world settings. In this review, we systematically summarize recent advances in application of AI in HF management across multiple domains, including inspection, monitoring, treatment, and integration. We further discuss key real-world challenges to implementation, and outline future directions for the development of intelligent HF management. In addition, representative application cases are presented to illustrate how AI technologies can be developed and translated into clinical practice, with the aim of providing practical insights and methodological guidance for researchers.

Background: Glucocorticoids are widely used for managing acute exacerbations of chronic obstructive pulmonary disease (AECOPD); however, limited studies have described the comparative effectiveness of inhaled corticosteroids (ICS), systemic corticosteroids administered orally or intravenously (oral/intra), and a combination of ICS and oral/intra for AECOPD treatment in China. Thus, we aimed to explore the effects of different glucocorticoid administration routes during hospitalization on both short- and long-term patient prognosis in AECOPD. Methods: Data were collected from the Acute Exacerbations of Chronic Obstructive Pulmonary Disease Inpatient Registry study, a nationwide multicenter, prospective, observational study conducted in China from September 2017 to November 2021. The study involved 179 hospitals. The patients were categorized into three groups according to their treatment profiles as follows: (1) ICS alone, (2) ICS combined with oral/intra, and (3) oral/intra. Propensity score-matching was utilized to minimize potential bias, using a caliper value <0.1. Competing risk models were used to calculate the relative risks for short- (30 days) and long-term (12 months) severe exacerbations, COPD-specific readmission, and all-cause readmission. Results: After propensity score matching, each group included 572 patients. In the ICS group, the cumulative incidence of short-term severe exacerbations, COPD-specific readmission, and all-cause readmission was 2.4%, 2.2%, and 2.7%, respectively, which was comparable to that in the ICS + oral/intra group (3.7%, 3.4%, and 4.2%, respectively). However, the incidence in the ICS + oral/intra group was significantly lower than that in the oral/intra group (5.4% for short-term severe exacerbations, 5.2% for COPD-specific readmission, and 5.7% for all-cause readmission). The 12-month incidence did not significantly differ among the groups. Compared with the ICS group, the short- or long-term risks did not differ in the ICS + oral/intra group, whereas the short-term risk was higher in the oral/intra group (severe exacerbations: hazards ratio [HR] = 2.29, 95% confidence interval [CI]: 1.09–4.82; COPD-specific readmission: HR = 2.44, 95% CI: 1.12–5.30; and all-cause readmission: HR = 2.18, 95% CI: 1.07–4.45). Conclusion: The use of systemic corticosteroids alone during hospitalization for AECOPD increases the short-term risk of outcomes but does not affect the long-term prognosis.

Background: Triple-negative breast cancer (TNBC) is a highly aggressive and treatment-resistant subtype of breast cancer, characterized by high rates of metastasis and mortality. This study aimed to identify and evaluate the therapeutic potential of blestriarene C (BC), a novel diphenanthrene compound, in the treatment of TNBC. The study also sought to explore the underlying mechanisms and signaling pathways involved in BC’s antitumor effects. Methods: A multiomics analysis was conducted to identify key genes and pathways involved in TNBC treatment. We performed experiments related to cell viability, ferroptosis, and mitophagy to explore the effects of BC in the treatment of TNBC, utilizing the TNBC cell lines BT-549 and 4T1 cells. The impact of sestrin 2 (SESN2) knockout on BC’s effects was also studied. We also conducted in vivo experiments using the patient-derived xenograft (PDX) model in zebrafish to assess the antitumor effects of BC. Results: The results of RNA sequencing and proteomics showed that ferroptosis and mitophagy may be the main mechanisms of BC acting on TNBC cells. BC could inhibit cell proliferation by modulating the phosphoinositide 3-kinase/protein kinase B/forkhead box O4 and SESN2/mechanistic target of rapamycin signaling pathways, and inducing ferroptosis and mitophagy. SESN2 and microtubule-associated protein 1 light chain 3 beta (MAP1LC3B), as hub genes, participated in regulating the therapeutic effect of BC on TNBC. TNBC tumors in zebrafish treated with BC were smaller and lighter, indicating that BC had antitumor effect. Conclusions: BC emerges as a promising therapeutic agent for TNBC by targeting SESN2 and MAP1LC3B, modulating associated signaling pathways, and inducing ferroptosis and mitophagy. These findings provide the basis for further investigation of BC’s potential as a targeted therapy for TNBC.

Background: There is a growing demand for fertility-sparing treatment among young patients with early-stage endometrial cancer (EC) and endometrial atypical hyperplasia (EAH). This study aims to evaluate the efficacy of a regimen that combines anti-estrogen therapy with treatments targeting glucose, lipid, and calcium metabolism in EC and EAH patients. Methods: We conducted a retrospective analysis of patients with EC and EAH who were treated at Peking University People’s Hospital between January 2018 and November 2023. The study investigated the clinical profiles of the patients and assessed the efficacy of different treatment strategies. Results: A total of 285 patients were enrolled in the study, with 149 receiving anti-estrogen monotherapy and 136 receiving a combination therapy (including metformin, statins, calcium channel blockers [CCBs]). The combination therapy group showed a significantly higher proportion of patients with elevated body mass index, insulin resistance, diabetes, and hypertension compared to anti-estrogen group (P <0.05), and both groups had similar complete response (CR) time and CR rate. Pathological type of EAH and metformin regimen were protective factors for shorter complete response time (P <0.05). Subsequent stratified analysis revealed that combination therapy with metformin significantly benefited patients with insulin resistance (hazard ratio [HR] = 1.888, 95% confidence interval [CI]: 1.313–2.713) and diabetes mellitus (HR = 2.749, 95% CI: 1.046–7.299). Conclusions: Fertility-sparing treatments for patients with metabolic risk factors may have poor efficacy. However, the integration of anti-estrogen therapy with the metabolic-targeting interventions, like metformin, appears to improve the outcomes of fertility-preserving strategies in this patient population.

Background: Psoriasis is a systemic disease that brings enormous mental pressure and economic burden to patients and has a significant impact on patients’ quality of life (QoL). This study aimed to explore factors affecting the dermatology life quality index (DLQI) in patients with psoriasis. Methods: This retrospective cross-sectional study used data sourced from the Psoriasis Diagnosis and Treatment Real-world Database, and 8839 patients with psoriasis (recruited between June 24, 2020 and September 2, 2021) were included. Demographic and clinical characteristics and DLQI scores were retrospectively analyzed, and correlations between DLQI score and age, disease course, psoriasis area and severity index (PASI) score were calculated. Regression analysis was conducted to explore the factors affecting the DLQI scores of patients with psoriasis. Results: The average DLQI scores were significantly higher in young (8.58 ± 7.22) and middle-aged individuals (8.09 ± 6.61) than those in juveniles (6.00 ± 5.79) and older individuals (7.39 ± 6.29) (P = 1.70E-15). The average DLQI scores gradually decreased among individuals whose work status were unemployment (10.4 ± 7.83), part-time (9.02 ± 6.83), full-time (8.43 ± 6.90), retired (7.93 ± 6.07), and students (7.10 ± 6.31) (P = 9.82E-23). Except for those with disease course ≥20 years, DLQI scores increased gradually with prolongation of the disease course (P = 4.72E-22). The higher the severity of psoriasis, the higher the average DLQI score (P = 3.79E-113). The presence of psoriatic lesions at the exposed sites significantly affected DLQI scores (P <0.001). The average DLQI scores were significantly higher among individuals with nail holes, joint pain, and comorbidities than among those without these conditions (P <0.05). Correlation analysis indicated that the PASI scores were positively correlated with the DLQI scores (r = 0.26, P = 4.19E-134). Multinomial logistic regression analysis showed significant influencing factors (excluding comorbidity) with different degrees of impact based on the DLQI score (P <0.05). Conclusion: Physicians should focus on significant factors, such as sex, age, marital status, education, work status, sub-types, disease course, PASI score, joint pain, and nail holes, to improve the QoL of patients with psoriasis.

Background: Autologous chimeric antigen receptor T (CAR-T) cell therapy has demonstrated efficacy in the treatment of acute myeloid leukemia (AML). Nevertheless, the intrinsic characteristics of autologous therapy, such as extended manufacturing timelines and patient-specific limitations, contribute to delays in treatment availability. More critically, relapse due to antigen escape following single-targeted CAR-T therapy constitutes a significant clinical obstacle. To address the dual challenges of delayed treatment accessibility and antigen escape relapse, this study proposes the development of universal tandem CAR-T cells. These cells, engineered to target CD123 and B7-H3 through clustered regularly interspaced short palindromic repeats (CRISPR) gene editing technology, represent an innovative therapeutic strategy for AML. Methods: In this study, an immune phage display nanobody library was developed for the purpose of screening CD123-specific nanobodies. The CRISPR/CRISPR-associated protein 9 (CRISPR/Cas9) gene editing system was utilized to disrupt the T-cell receptor alpha chain (TRAC) and B2M genes present in T cells, resulting in the generation of universal CD123/B7-H3 bispecific universal CAR-T (UCAR-T) cells. The efficacy of these dual-specific UCAR-T cells in combating tumors was subsequently assessed through in vitro and in vivo experiments. Results: Through four rounds of panning against CD123 from an immunized camelid VHH library, we identified 21 antigen-specific nanobodies. Tandem bispecific UCAR-T engineered with these binders demonstrated CAR transduction efficiencies ranging from 82% to 87%. In vitro functional profiling revealed a significantly enhanced cytotoxicity of bispecific UCAR-Ts against CD123+/B7-H3+ AML cell lines when compared to single-target constructs, while effectively regulating the secretion of effector cytokines (IL-2, IFN-γ, TNF-α). In AML xenograft models, treatment with bispecific UCAR-T notably inhibited tumor progression, extended the survival of tumor-bearing mice with recurrence-free persistence throughout the observation period, and did not result in significant body weight loss or cytokine release syndrome. Conclusions: The findings of the study address the issue of tumor antigen evasion in the treatment of AML, circumvent certain constraints associated with autologous CAR-T cell therapy, and offer novel insights and strategies for managing AML.

Background: Glioma is a common malignant brain tumor with poor prognosis. Choline kinase α (CHKA) has been implicated in glioma progression, but its regulatory mechanisms remain unclear. Methods: Single-cell ribonucleic acid (RNA) sequencing was performed to assess the coexpression of CHKA and epidermal growth factor receptor (EGFR) in glioma subpopulations. Public datasets were analyzed to evaluate their clinical relevance, which was verified in a cohort from Ningxia Medical Hospital (November 2019–October 2024). Immunohistochemical staining confirmed their expression and subcellular localization. The interaction between CHKA and EGFR was examined using mass spectrometry, coimmunoprecipitation, polymerase chain reaction, and Western blotting. The effects of the CHKA/EGFR axis on the mitogen-activated protein kinase (MAPK) pathway were explored using polymerase chain reaction and Western blotting. Cell Counting Kit-8 (CCK-8), transwell, and wound-healing assays were conducted in glioma cell lines following CHKA knockdown and EGFR rescue. Finally, a nude mouse xenograft model was established to validate in vivo tumorigenicity and MAPK pathway activation. Results: CHKA was highly coexpressed with EGFR in specific glioma subpopulations, and their expression levels were positively correlated. Both genes were associated with advanced tumor grade and poor prognosis. CHKA interacted with EGFR and promoted its expression and phosphorylation. Silencing CHKA reduced EGFR levels and suppressed MAPK signaling. Functionally, CHKA enhanced glioma cell proliferation, migration, and invasion through EGFR upregulation. Moreover, CHKA knockdown inhibited tumor growth and MAPK activation in vivo, while EGFR overexpression restored tumorigenesis. Conclusions: CHKA drives glioma malignancy by regulating EGFR and activating the MAPK pathway. The CHKA/EGFR/MAPK axis represents a potential therapeutic target for glioma treatment.

Background: The objective of this study is to delineate the differential gene expression patterns of neutrophils in bronchoalveolar lavage fluid (BALF) from patients with sepsis and those experiencing progression to sepsis-induced acute respiratory distress syndrome (SI-ARDS). Additionally, we aim to comprehensively profile the transcriptomic landscape of neutrophils in BALF from patients with sepsis and SI-ARDS, particularly focusing on cases caused by specific bacterial pathogens. Methods: Patients with confirmed sepsis (n = 14) or SI-ARDS (n = 11) were recruited. Besides, a control group consisting of patients with unrelated diseases (n = 7) who required bronchoscopy was also included (cohort 1). We collected the neutrophils in BALF from participants in cohort 1. To validate the identified differentially expressed genes (DEGs) and evaluate neutrophil apoptosis, an additional cohort (cohort 2) was recruited, consisting of 5 healthy controls, 10 patients with sepsis, and 10 patients with SI-ARDS. Peripheral blood neutrophils were collected from participants in cohort 2 for further analysis. DEGs between SI-ARDS patients and controls, sepsis patients and controls, as well as SI-ARDS patients and sepsis patients were identified. And, publicly available datasets were downloaded to compare with local results. Additionally, the DEGs were also identified between patients infected with drug-resistant Klebsiella pneumoniae and those infected with other bacterial pathogens. Furthermore, a third cohort (cohort 3) consisting of 57 sepsis patients and 46 SI-ARDS patients was recruited for investigating the prognostic significance of neutrophils in SI-ARDS. Results: In cohort 1, 8/14 of the septic patients and 6/11 of the SI-ARDS patients were affected by drug-resistant Klebsiella pneumonia. There were 9921 DEGs between sepsis patients and controls, 10,252 DEGs between SI-ARDS patients and controls, and 24 DEGs between SI-ARDS and sepsis patients in neutrophils from BALF. Notably, fatty acid-binding protein 4 (FABP4) exhibited significant downregulation in SI-ARDS patients. In cohort 2, peripheral blood analysis confirmed consistent trends, demonstrating that FABP4 expression was decreased, which contributed to the attenuation of neutrophil apoptosis. And FABP4 inhibitor-induced apoptosis resistance was reversed by a phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) inhibitor. Furthermore, survival analysis revealed that SI-ARDS patients with low levels of neutrophil FABP4 expression exhibited poor survival. Additionally, 520 overlapping DEGs were identified between the sepsis and control group comparisons and the SI-ARDS and sepsis group comparisons. Among these overlapping DEGs, 85% were downregulated, predominantly targeting immune-related pathways, whereas a smaller subset was upregulated, mainly associated with metabolism. DEGs in neutrophils in BALF of SI-ARDS and controls notably overlapped with those in neutrophils in peripheral blood. Importantly, DEGs in sepsis/SI-ARDS caused by drug-resistant Klebsiella pneumoniae differed from DEGs in sepsis/SI-ARDS caused by other bacteria. Additionally, FABP4 expression consistently decreased, attenuating neutrophil apoptosis. Conclusions: The downregulation of FABP4 in neutrophils was found to inhibit apoptosis through the activation of the PI3K/AKT signaling pathway. Importantly, the expression level of FABP4 in neutrophil emerged as a prognostic indicator for sepsis and SI-ARDS patients, suggesting its potential utility in clinical decision-making to address the challenges posed by this condition.