2026年 · 第139卷第13期

High-salt diet (HSD) has emerged as a prevalent environmental factor that exacerbates chronic inflammation and insulin resistance in obesity-associated type 2 diabetes (T2D) by modulating macrophage polarization, metabolic reprogramming, and epigenetic imprinting. Current evidence demonstrates that HSD activates p38/mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling pathways, by which it drives macrophage polarization toward a proinflammatory M1 phenotype while inducing a glycolysis-dominant metabolic shift, thereby establishing a persistent "metabolic memory". Moreover, HSD orchestrates metabolic memory in macrophages through coordinated epigenetic machinery, including histone modifications (Trimethylation of histone H3 at lysine 4 [H3K4me3] and Acetylation of histone H3 at lysine 27 [H3K27ac]), DNA methylation, and noncoding RNAs (e.g., long non-coding RNA MALAT1 and miR-155), leading to sustained inflammatory phenotypes. In multiple metabolic organs (e.g., adipose tissue, liver, pancreas, and gut), the HSD–macrophage axis aggravates systemic insulin resistance through shared proinflammatory signaling and other tissue-specific mechanisms. Most importantly, therapeutic strategies targeting the NLRP3 inflammasome, metabolic pathways, and epigenetic alterations offer novel approaches for managing metabolic inflammation. Future investigations are encouraged to leverage lineage tracing, single-cell sequencing, and spatial multi-omics technologies to advance the development of precision medicine for macrophage-associated metabolic disorders.

Cellular senescence functions as a pivotal stress response with dual roles; it serves as a barrier against early tumorigenesis while paradoxically driving late-stage tumor progression and the pathogenesis of many other age-related diseases, including cardiovascular, neurodegenerative, metabolic, and fibrotic disorders. This review comprehensively elucidates how the senescent phenotype is orchestrated by a dynamic epigenetic landscape. We detail how dysregulation in chromatin remodeling (e.g., heterochromatin loss), histone modifications, DNA methylation, and the epitranscriptome rewrites genome architecture to govern the initiation and maintenance of the senescent phenotype within these specific disease contexts. Crucially, we highlight the profound heterogeneity of senescence across different pathologies, contrasting its detrimental role in driving tissue degeneration in organs like the lung and kidney against its context-dependent beneficial effects, such as limiting fibrosis in the liver. Furthermore, we evaluate the translational potential of epigenetic drugs—categorized by targets such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), and histone deacetylases (HDACs)—as dual-purpose therapeutics. Unlike genetic mutations, epigenetic alterations are reversible. We discuss strategies to either enforce senescence barriers for cancer suppression (pro-senescence) or reverse epigenetic aging signatures for tissue rejuvenation (anti-senescence). This review proposes a roadmap for leveraging epigenetic plasticity, offering a precision medicine approach to target specific senescent cell populations and extend health span.

Female reproductive health encompasses fertility, safe pregnancy and childbirth, and is vital throughout the entire life of women. Tryptophan, an essential amino acid in humans, is involved in protein synthesis and the generation of bioactive substances related to the health and disorders of multiple systems. An increasing number of studies have shown that tryptophan metabolism is closely related to female reproductive health. Tryptophan metabolism occurs mainly through the kynurenine, serotonin, and indole pathways and yields various bioactive substances. The homeostasis of this metabolism modulates the ovarian function by influencing follicle development and hormone secretion. The regulation of the female reproductive system by tryptophan metabolism may be related to its role in the maternal internal environment and its influence on the reproductive axis systemically. In pregnant women, tryptophan metabolism affects the entire process from embryo implantation to childbirth. Factors involved in tryptophan metabolism may represent new targets for the treatment of female reproductive system-related diseases. Here, we summarize the possible mechanisms by which tryptophan metabolites affect female reproductive health and discuss potential related treatments.

Immunoglobulin G4-related disease (IgG4-RD) is a chronic disease characterized by inflammation and fibrosis within multiple organs. The fundamental immunopathogenic mechanisms of IgG4-RD remain largely unidentified. Advancements in multiple omics technologies have enabled researchers to characterize the cellular heterogeneity of IgG4-RD. The pursuit of understanding the immune dysfunction in IgG4-RD is principally guided by genomic, transcriptomic, and proteomic investigations, encompassing three crucial aspects of the traditional central dogma. Besides, genetic and epigenetic mechanisms, along with alterations in posttranslational modifications (PTMs) and small molecules identified through metabolomics and microbiomics studies, interact to uncover the functional basis of abnormal cellular activities. Here, we systematically review the application of multiple omics technologies to uncover the fundamental mechanisms driving IgG4-RD, organized around the traditional central dogma of molecular biology and its remodeling. We also propose an integrated pathophysiological model of multi-layered immune dysregulation, illustrating a self-sustaining loop of immune activation and tissue remodeling in IgG4-RD. It is believed that adopting a combination of diverse technological advancements to examine a series of cellular processes holds promise for the development of personalized approaches to managing IgG4-RD patients.

Background: Physical activity (PA) is a key modifiable factor for elevated blood pressure (EBP). We aimed to clarify the evolving relationships between PA and EBP in childhood or adolescence by examining multilevel factors within an ecological model. Methods: National data were extracted from 2010, 2014, and 2019 cycles of the Chinese National Survey on Students’ Constitution and Health, using a multistage stratified cluster sampling design. We defined EBP by the updated Chinese reference standards and obesity by sex- and age-specific body mass index (BMI) cutoffs. Inadequate PA was defined as <1 h/day; ecological factors at society-, school-, and individual-level were collected through a questionnaire. Multilevel logistic regression, interaction analyses, and population-attributable fractions were used to evaluate associations between multilevel ecological factors related to PA and EBP. Results: We included 642,386 participants (7–18 years). The EBP prevalence increased from 13.6% to 17.9% alongside increasing obesity, while inadequate PA decreased in prevalence. Inadequate PA was associated with EBP in 2010, with the odds ratio (OR) of 1.17 (95% confidence interval [CI]: 1.04, 1.21) but attenuated during 2010–2019. The multilevel factors related to PA displayed interactions to reduce EBP risk (P for interaction <0.05). At the societal-level, urban residence was protective against EBP, whereas a lack of exercise facilities increases the odds. At the school-level, inadequate physical education and sports competitions, coupled with unhealthy dietary lifestyles at the individual-level, contributed to EBP (P <0.05). The contributions of individual-level ecological factors related to PA decreased but of societal- and school-level increased on EBP, independent of obesity. Conclusions: A rise in EBP burdens during 2010–2019 contrasted with an increase in PA. PA-related ecological factors across society-, school-, and individual-level exhibited complex interactions on EBP. Although the impact of individual-level lifestyles on EBP was waning and obesity remained a primary concern, there was increased recognition of societal- and school-level’s ecological factors related to PA during 2010–2019. Promoting PA requires a comprehensive approach that addresses both facilitating and inhibiting factors, which is crucial for healthy blood pressure (BP).

Background: Age plays a crucial role in the incidence and prognosis of esophageal cancer. In China, the age distribution of patients with esophageal cancer remains unclear, and comprehensive large-scale studies on its prognostic impact are lacking. Methods: Using a cohort of 294,523 patients with esophageal cancer, we compared onset age distributions across clinicopathological characteristics (χ2 test). Trends in the proportion of patients diagnosed under 60 years were analyzed using linear regression. Survival differences by age were assessed via Kaplan–Meier analysis and Cox regression (univariate and multivariate). Directed acyclic graphs defined causal relationships. Robustness was evaluated using multiple imputation and sensitivity analyses. Subgroup and propensity score matching analyses addressed confounding. Restricted cubic spline models explored nonlinear relationships between age and surgery rates, overall mortality risk, and perioperative mortality. Results: The proportion diagnosed under age 60 years significantly declined over time (P <0.05, R2 = 0.96), with this younger demographic being more prevalent among males, high-incidence area, smokers, alcohol consumers, and those with family history (all P <0.001). Surgical rates decreased sharply beyond age 62 years. Advanced age was an independent predictor of poorer survival, with surgery offering the best prognosis compared with radiochemotherapy and untreated, supported by subgroup and post-propensity score matching survival analyses. Mortality risk increased most rapidly with age in untreated patients (inflection at 65 years), followed by radiochemotherapy (63 years) and surgery (60 years), while perioperative mortality rose steeply beyond age 60 years. Conclusions: Male, residence in high-incidence area, smoking, alcohol intake, and positive family history were associated with earlier onset age of esophageal cancer; the proportion of patients under 60 years old declined significantly over time. While advanced age independently predicted poorer survival, it should not absolutely contraindicate surgery. A precise perioperative risk assessment system is crucial to balance surgical benefits and risks in the elderly.

Background: Adjuvant chemotherapy is the standard management approach for patients with stage II/III colon cancer; however, the effectiveness in older patients is still unclear. This study aimed to explore the efficacy of adjuvant chemotherapy and whether oxaliplatin-based chemotherapy has better oncological outcomes than capecitabine monotherapy in older patients with stage III or high-risk stage II colon cancer. Methods: We analyzed and compared oxaliplatin-based adjuvant chemotherapy with capecitabine monotherapy and non-adjuvant chemotherapy in 468 patients aged ≥70 years with stage III and high-risk stage II colon cancer, and a propensity score-matched analysis was conducted. The endpoints were overall survival (OS), cancer-specific survival (CSS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS). Results: Multivariate analysis shows that adjuvant-treated stage III or high-risk stage II patients experienced a highly significant increase in OS (hazard ratio [HR]: 0.34, 95% confidence interval [CI]: 0.20–0.59, P <0.001) and CSS (HR: 0.39, 95% CI: 0.20–0.75, P = 0.005) compared with the control group without adjuvant chemotherapy. By contrast, no statistically significant difference was observed in either LRFS or DMFS (all P >0.05). The subgroup analysis suggested that no statistically significant benefits were observed between oxaliplatin-based adjuvant chemotherapy and capecitabine monotherapy, and no significant differences in oncological outcomes were detected with ≥6 months of therapy compared with 3–6 months (excluding 6 months) of therapy. Conclusion: Older patients with stage III or high-risk stage II colon cancer can benefit from adjuvant chemotherapy, and capecitabine monotherapy has non-inferior oncological outcomes compared with oxaliplatin-based regimens.

Background: Iron imbalance, including iron deficiency and overload, is associated with increased cardiovascular morbidity and mortality. However, the iron status and its association with postoperative adverse outcomes in pediatric patients with congenital heart disease (CHD) is unclear. This study aimed to investigate the preoperative iron status and its correlation with adverse outcomes in pediatric patients with CHD. Methods: This is a single-center retrospective study. A total of 8065 pediatric patients (aged 1 month to 5 years) who underwent surgical treatment at Fuwai Hospital’s Pediatric Cardiac Surgery Center between 2017 and 2022 were consecutively included. All patients had undergone comprehensive preoperative laboratory tests, including iron-related hematology and biochemistry examinations. The association between ferritin and adverse outcomes was examined using restricted cubic splines. A multivariable logistic regression model was used to determine the associations between preoperative iron status and postoperative adverse outcomes. Results: Iron deficiency, anemia, and iron deficiency anemia were observed in 23.0% (1856/8065), 12.0% (969/8065), and 7.0% (564/8065) of patients, respectively. Patients with cyanotic CHD had a higher prevalence of iron deficiency but a lower incidence of anemia compared with patients with acyanotic CHD. A right-skewed U-shaped relationship was observed between ferritin and death and composite adverse events. Multivariable logistic regression analysis demonstrated that patients with high ferritin levels (ferritin ≥100 µg/L) had a significantly higher risk of in-hospital death (odds ratio [OR]: 8.20, 95% confidence interval [CI]: 1.61–41.86]) and composite adverse events (OR: 4.21 [95%CI: 2.65–6.68]) compared with patients with iron repletion (ferritin levels of ≥15 and <33 µg/L). In addition, patients with iron deficiency (OR: 1.80 [95%CI: 1.18–2.73]) and intermediate ferritin levels (ferritin levels of ≥33 and <100 µg/L; OR: 1.64 [95%CI: 1.11–2.44]) had a higher incidence of composite adverse events compared with those with iron repletion. Conclusions: Iron deficiency and anemia are common concern in children with CHD. Preoperative iron imbalance, including both iron deficiency and high iron load, was significantly associated with postoperative adverse outcomes in pediatric patients with CHD. Assessment of preoperative iron status might facilitate early identification of high-risk patients, and correcting iron imbalance could potentially mitigate adverse outcomes.

Background: Cardiac lymphatics play an important role in myocardial edema and inflammation, however, the heterogeneity of cardiac lymphatic endothelial cells (LECs) and their biological functions have rarely been investigated. Methods: This study integrated single-cell sequencing data and spatial transcriptome data from mouse heart tissue at different time points post-myocardial infarction (MI), and then revealed LECs heterogeneity and biological functions by clustering, spatial localization, cell trajectory, and Cell-Chat analyses. Results: Four transcriptionally distinct subtypes of LECs were identified and localized in space. Cardiac LEC subgroups were found to be localized in different zones of infarcted heart related to different functions. LEC capillary III (LEC CaIII) may be involved in the direct regulation of myocardial injuries in an infarcted zone (IZ) from the perspective of metabolic stress, while LEC CaII may be related to the rapid immune inflammatory responses of the border zone (BZ) in the early stage of MI. LEC CaI, as well as LEC collection mainly participate in the regulation of myocardial tissue edema resolution in the middle and late stages post-MI. Cell trajectory and Cell-Chat analyses further identified that LECs may regulate myocardial edema through Aquaporin 1, and might affect the infiltration of macrophages through the galectin-9 (Gal-9)-CD44 pathway. Conclusion: This study revealed the dynamic transcriptional heterogeneity distribution of LECs in different regions of the infarcted heart, and these LECs formed different functional subgroups that might exhibit different bioeffects in myocardial tissue post-MI.