2026年 · 第139卷第04期

Breast cancer (BC) is the most prevalent malignancy among women and presents significant challenges, such as drug resistance and relapse, particularly triple-negative breast cancer (TNBC). Mitophagy is the primary process by which damaged mitochondria are degraded via the autophagy–lysosomal pathway to maintain mitochondrial homeostasis. The regulatory mechanisms of mitophagy and its role in BC progression are crucial for the discovery of new biomarkers and therapeutic targets. This review provides a comprehensive summary of the current understanding of mitophagy in BC, highlighting the gaps in knowledge related to reliable biomarkers and personalized treatment strategies. The pathways and mechanisms of mitophagy and their importance in BC are also summarized. Key findings include the dual role of mitophagy in BC development, the association of mitophagy-related genes/proteins with BC pathogenesis, and the potential of mitophagy modulators in enhancing treatment outcomes. This review further discusses the design of biosensors for detecting mitophagy in BC metastasis and explores the potential of mitophagy-related genes as biomarkers and prognostic factors. The unique value of this manuscript lies in its in-depth exploration of the regulatory mechanisms of mitophagy in BC, providing a scientific basis for clinical management and treatment while offering guidance for future research directions.

Lymph node metastasis (LNM) represents a critical dissemination route for many malignancies, profoundly influencing patient prognosis through its role in driving disease progression and recurrence. This metastatic cascade involves tumor cell invasion into lymphatic structures, where the complex interactions within the tumor microenvironment (TME) facilitate further dissemination to distant sites. Among TME components, cancer-associated fibroblasts (CAFs) have emerged as pivotal regulators in disease progression and metastatic spread by orchestrating dynamic crosstalk between malignant cells and stromal networks. Mounting evidence highlights the multifaceted contributions of CAFs to LNM pathogenesis, particularly their capacity to prime metastatic niches and enable tumor cell intravasation into lymphatic vessels. This review systematically examines the molecular and functional mechanisms through which CAFs promote LNM, focusing on their dual roles in establishing pre-metastatic niches and facilitating lymphovascular invasion by tumor cells. By synthesizing recent advances in CAF biology and LNM pathophysiology, this review aims to deepen the mechanistic understanding of metastatic dissemination while identifying potential therapeutic opportunities for clinical translation.

Circulating tumor cells (CTCs), shed from the primary malignancies, are regarded as the "seeds" of tumor metastasis. They employ sophisticated strategies to evade immune detection during blood circulation by engaging with various blood components, ultimately facilitating their colonization in distant organs. Elucidating the mechanisms underlying CTC immune evasion may unlock novel immunotherapeutic strategies to prevent tumor metastasis. Recent advancements in CTC isolation and single-cell sequencing have provided insights into their complex microenvironment and immune evasion mechanisms. Many strategies for targeting either CTCs or their associated blood cells have been explored. Here, we systematically delineated the interaction network between CTCs and the diverse blood cells. By elucidating the microenvironmental and biological characteristics of CTCs, we summarize several potential immune evasion mechanisms, including immune checkpoint modulation, CTC clustering, platelet interactions, etc. Additionally, we highlight recent advances in intervention strategies targeting CTCs and the clinical application of CTCs in cancer liquid biopsy.

Background: The cardiovascular–kidney–metabolic (CKM) syndrome is highly prevalent globally. However, the associations between the CKM syndrome and its various components and all-cause and cause-specific mortality are not well understood. This study aims to clarify these mortality associations and provide insights for preventive strategies. Methods: The China Health Evaluation and Risk Reduction through Nationwide Teamwork was a nationwide and population-based project, which was performed in 353 counties/districts across 31 provincial-level administrative divisions in Chinese mainland. A total of 764,856 eligible residents aged ≥35 years from this cohort were included in the study. CKM was classified into stages 0–4 and further sub-grouped stages 2–4 by the presence of chronic kidney disease (CKD) and CKD risk stratification. CKM stage 2 was further divided into six groups in descending order of clinical risk priority. The main outcomes were all-cause and cause-specific mortality. Cox proportional hazards models were used to evaluate the associations of CKM stages and components with mortality, incorporating competing risks models to account for competing events. Results: We found significant positive associations between CKM stages and mortality risk, particularly for cardiovascular mortality with adjusted hazard ratios and 95% confidence intervals of 2.62 (2.10–3.27), 4.04 (3.22–5.07), and 5.64 (4.51–7.05) for stages 2, 3, and 4, respectively. In comparison of participants with CKD with those without CKD at each CKM stage, CKD was associated with an increased risk of all-cause mortality by 64.29%, 68.62%, and 74.89%, and an increased risk of cardiovascular mortality by 72.58%, 71.55%, and 71.95% for CKM stages 2, 3, and 4, respectively. Notably, even moderate-risk CKD was associated with an increased risk of mortality. Among the various components at CKM stage 2, CKD (both high- and moderate-risk) was the most significant risk factor for mortality, with high-risk CKD showing a higher risk (hazard ratio [95% confidence interval]: 2.83 [2.36–3.39]) than moderate-risk CKD (hazard ratio [95% confidence interval]: 2.16 [1.89–2.47]), followed by the coexistence of diabetes and hypertension (hazard ratio [95% confidence interval]: 1.87 [1.65–2.12]) (all P <0.05). Conclusions: The risk of mortality, primarily by cardiovascular disease, increases with advancing stages of CKM. Sub-staging CKM syndrome by stratifying patients according to the presence and severity of CKD and metabolic risk factors can improve the accuracy of evaluating the mortality risk. Consistent monitoring and early interventions aimed at maintaining renal function may considerably reduce the risk of mortality.

Background: Sepsis is a global health challenge associated with high morbidity and mortality rates. Early diagnosis and treatment are challenging because of the limited understanding of its underlying mechanisms. This study aimed to identify effective biomarkers for diagnosing and treating sepsis through an integrated multi-method approach. Methods: Publicly available single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq datasets were analyzed for naive CD4+ T cell-specific genes. Based on these hub genes, Mendelian randomization (MR) analysis, followed by the MR-Bayesian model averaging (MR-BMA) algorithm, was implemented to explore the causality between these genes and sepsis. In addition, single-cell-type expression analysis, cell–cell communication detection, metabonomic evaluation, clinical samples, and both in vivo and in vitro studies were conducted to unveil the underlying mechanisms of potential therapeutic targets. Results: scRNA-seq revealed significant depletion of naive CD4+ T cells in sepsis, identifying 33 key genes. Both MR and MR-BMA analyses confirmed that elevated proportion of naive CD4+ T cell in total CD4+ T cells were related to sepsis occurrence (odds ratio [OR] = 0.90, 95% confidence interval [CI], 0.83–0.97, P = 0.007) and 28-day mortality associated with sepsis (OR = 0.75, 95% CI, 0.64–0.88, P <0.001). Notably, among the 33 hub genes, PC-esterase domain containing 1B (PCED1B) exhibited a strong causal association with 28-day mortality in patients with sepsis (OR = 0.64, 95% CI, 0.51-0.81, P <0.001), which was further validated by bulk RNA-seq analysis. PCED1B mediated the impact of proportion of naive CD4+ T cell in CD4+ T cell on sepsis-related mortality. In addition, clinical samples and both in vivo and in vitro experiments validated the elevated expression of PCED1B in naive CD4+ T cells derived from sepsis patients and mice. Mechanistic investigations revealed PCED1B+ CD4+ T cells may interact with monocytes/dendritic cells through the macrophage migration inhibitory factor (MIF)–(CD74+CD44) axis, concurrently engaging with B cells/plasmablasts through the MIF–(CD74+CXCR4) axis, thereby regulating multiple metabolic alterations in sepsis. Conclusion: The interplay between PCED1B and naive CD4+ T cells, as revealed by this study, is instrumental in developing immunotherapeutic strategies for sepsis.

Background: Evidence of an association between physical activity (PA) and mortality has mainly focused on leisure-time physical activity (LTPA) and moderate-to-vigorous-intensity physical activity (MVPA). We aimed to assess the associations of total, domain-specific, and intensity-specific PA with all-cause and cause-specific mortality. Methods: We used baseline PA data from the China Kadoorie Biobank, including 482,067 participants aged 30–79 years from 10 areas in China. PA via self-report was quantified as a metabolic equivalent of task hours per day. Total PA was calculated by summing occupational, commuting, household, and leisure-time PA, and domain- and intensity-specific PAs were also calculated. Cox regression was used to estimate the associations of quintiles of different types of PA with all-cause and cause-specific mortality and adjust for potential confounders. Cause-specific mortalities were also examined in a competing risk analysis. Results: During a median follow-up of 12.1 years, 47,281 deaths occurred. Total PA was inversely associated with the risk of all-cause mortality, with a hazard ratio (HR) (95% confidence interval [95% CI]) of 0.69 (0.67–0.71) in the highest quintile as compared with the lowest quintile. Similar associations were observed for disease-specific mortality risks from cardiovascular disease, cancer, respiratory disease, diabetes, and nervous system disease, with HR (95% CI) for top vs. bottom quintile of PA of 0.68 (0.64–0.71), 0.80 (0.76–0.83), 0.39 (0.35–0.44), 0.44 (0.35–0.55), and 0.52 (0.38–0.73), respectively. In addition, the risk of all-cause mortality was lowered by 34%, 13%, 17%, and 30% for occupational PA, non-occupational PA, low-intensity PA, and MVPA, respectively, when comparing the highest quintile with the lowest quintile. Conclusions: PA was inversely associated with the risk of all-cause and cause-specific mortality, regardless of domain and intensity. Any PA can bring long-term beneficial health effects.

Background: The nucleotide-binding oligomerization domain [NOD-], leucine-rich repeats [LRR-], and Pyrin domain-containing protein 3 (NLRP3) inflammasome plays an essential role in hypertension-related atrial fibrillation (AF). p300 is involved in cardiovascular inflammation. In this study, we aimed to investigate the role of p300 in NLRP3 inflammasome activation and its subsequent impact on the Ikur current in angiotensin II (Ang II)-induced HL-1 cells and Ang II-infused mice. Methods: Expression levels of p300, Kv1.5, and NLRP3 in left atrial appendage (LAA) tissues from AF and participants with sinus rhythm (SR) were detected by Western blot. A hypertension mouse model was established in p300 knockout (p300-KO) mice via Ang II infusion, and AF incidence was assessed by electrocardiogram (ECG) after rapid atrial pacing. In vitro, the expression level of p300 in HL-1 cells was modulated by adenoviral overexpression, curcumin (an inhibitor of p300) treatment, and small interfering RNA (siRNA) knockdown. NLRP3 inflammasome activation was evaluated by Western blot and enzyme-linked immunosorbent assay, and electrophysiological properties of HL-1 cells were analyzed using whole-cell patch-clamp recordings. Co-immunoprecipitation assays were performed to investigate the interaction between p300 and nuclear factor kappa B (NF-κB). Results: The expression levels of p300, Kv1.5, and NLRP3 were found to be significantly higher in the LAA tissue of AF patients compared to SR patients. p300-KO decreased AF incidence in Ang II-infused mice by impairing NLRP3 inflammasome activation. p300-OE facilitated NLRP3 inflammasome activation, which subsequently increased the Ikur density and shortened the action potential duration of HL-1 cells. Both curcumin and p300-siRNA treatments reversed Ang II-induced atrial electrical remodeling and NLRP3 inflammasome activation. Moreover, co-immunoprecipitation showed that p300 interacts with NF-κB to promote NLRP3 inflammasome activation. Conclusions: p300 participates in hypertension-induced AF susceptibility by interacting with NF-κB to activate the NLRP3 inflammasome, which subsequently upregulates the transmembrane current of Ikur in atrial cardiomyocytes.

Background: The isatuximab, pomalidomide, and dexamethasone (Isa-Pd) regimen has shown survival benefits for relapsed and/or refractory multiple myeloma (RRMM) in several trials, while evidence of effectiveness and safety among Chinese patients is limited. This study aimed to provide real-world evidence of Isa-Pd in Chinese patients with RRMM. Methods: In a prospective observational real-world study (IsaFiRsT), we enrolled Chinese RRMM patients who had received ≥2 prior therapies, including lenalidomide and proteasome inhibitors, and received the Isa-Pd regimen at Shanghai Jiaotong University School of Medicine, Ruijin-Hainan Hospital. A historical cohort of patients with RRMM who had received >1 additional line of treatment after ≥2 prior therapies was retrospectively included. The primary endpoint of the Isa-Pd cohort was the overall response rate (ORR). Inverse probability treatment weighting (IPTW) was used to balance confounding factors between the Isa-Pd cohort and historical cohort. Results: The Isa-Pd cohort comprised 24 patients with RRMM and reported an ORR of 82.6% (19/23, 95% confidence interval [CI]: 61.2% to 95.0%), a very good partial response or better rate of 73.9% (17/23) and a complete response or better rate of 43.5% (10/23). The median time to first response was 1.2 months (range: 0.9, 3.1 months). The median duration of response, progression-free survival (PFS), and overall survival (OS) were not reached, with a median follow-up of 8.4 months. The 6-month PFS and OS rates were 87.0% and 91.3%, respectively. The IPTW-adjusted ORR in the Isa-Pd cohort was 85.1% compared to 33.4% in the historical cohort, with a risk ratio of 2.55 (95% CI: 1.73 to 4.12). The most common grade >3 treatment-emergent adverse events in the Isa-Pd cohort were neutrophil count decreased (75.0%, 18/24), white blood cell count decreased (54.2%, 13/24), and anemia (45.8%, 11/24). Conclusion: The IsaFiRsT study reported that Isa-Pd provided a high rate of deep and rapid response in heavily pretreated Chinese RRMM patients, with an acceptable safety profile in a real-world setting, consistent with Isa-Pd trials.

Background: Immune cells critically influence pituitary neuroendocrine tumor (PitNET) progression and therapeutic responses. However, their composition and functional dynamics remain unclear. This study aimed to delineate the immune heterogeneity and intercellular communication networks within PitNETs. Methods: This study conducted single-cell RNA sequencing (scRNA-seq) on 22 fresh PitNET samples obtained from surgical patients at Beijing Tiantan Hospital between September 2023 and January 2024, with classification based on the expression of key transcription factors: pituitary-specific transcription factor 1 (PIT1), steroidogenic factor 1 (SF1), and T-box transcription factor 19 (TPIT). Following cell type identification, cell–cell communication analysis revealed specific intercellular interactions, which were validated by multiplex immunohistochemistry (mIHC), flow cytometry, and in vitro co-culture assays. Results: The scRNA-seq analysis revealed significant cellular heterogeneity and a lineage-specific immune landscape, including cancer-associated fibroblasts (CAFs), neutrophils, T cells, natural killer cells, and myeloid cells. Specifically, CAF subset distribution was highly lineage-dependent. Collagen-expressing CAF3 was significantly enriched in the PIT1 lineage compared to both TPIT and SF1 lineages. In contrast, inflammatory CAF5 was predominantly found in the TPIT lineage relative to the PIT1 and SF1 lineages. Furthermore, CD4+ regulatory T (Treg) and T follicular helper (Tfh) cells were significantly enriched in the PIT1 lineage relative to the TPIT and SF1 lineages, as validated by both flow cytometry and mIHC data. Cellular communication analysis revealed notable interactions between Treg/Tfh cells and macrophages/microglia that were mediated by the cytotoxic T-lymphocyte-associated protein 4 (CTLA4)–CD86 pathway. Subsequent mIHC assays confirmed spatial colocalization of Treg cells with macrophages/microglia. Complementing these findings, in vitro co-culture assays demonstrated functional CTLA4–CD86 signaling specifically between Treg cells and macrophages, providing deeper insights into the complex cellular crosstalk within the PitNET tumor microenvironment (TME). Conclusions: The three major PitNET lineages exhibited distinct immune cell frequencies, with the PIT1 lineage notably enriched in Treg and Tfh cells, as well as collagen-producing CAF3. Furthermore, a novel immunosuppressive interaction between Treg cells and macrophages, mediated by the CTLA4–CD86 pathway, was identified, suggesting its potential regulatory role within the TME.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unknown etiology. The absence of reliable biochemical and imaging markers often delays diagnosis and limits treatment effectiveness. As metabolic reprogramming is increasingly recognized as a hallmark of ALS, a comprehensive untargeted metabolomics analysis was employed to identify critical metabolic perturbations in ALS and explore novel candidate biomarkers with potential utility in clinical diagnosis. Methods: Plasma from two independent cohorts comprising 399 participants (170 ALS patients, 200 healthy controls, and 29 ALS-unrelated neurological disease controls) was included. Cohort 1 was recruited from Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital (April 2020–September 2022), and cohort 2 from Sichuan Academy of Sciences-Sichuan Provincial Hospital, Ruijin Hospital, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, and The First Affiliated Hospital of Dalian Medical University (October 2022–February 2023). Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approaches were used to identify metabolic alterations and potential diagnostic biomarkers for ALS. Complementary multivariable and univariable statistical approaches were applied to characterize disease-specific metabolic reprogramming in ALS. In addition, the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of differential metabolites, and binary logistic regression analysis was used to construct a multivariate biomarker model. Results: Metabolic changes of ALS were mainly observed in amino acids, fatty acyls, and purines. Inosine and hypoxanthine were found to be the most significantly and critically dysregulated metabolites in ALS. Aminoacyl-transfer ribonucleic acid (tRNA) biosynthesis and amino acid metabolism were regarded as the most significantly perturbed pathways. Across both cohorts, 26 metabolites were consistently changed. Notably, a biomarker panel comprising hypoxanthine, inosine, and trigonelline was constructed using binary logistic regression, achieving excellent diagnostic performance in distinguishing ALS from controls, with an area under the ROC curve of 0.982 in cohort 1 (sensitivity 0.970, specificity 0.940) and 0.934 in cohort 2 (sensitivity 0.942, specificity 0.791). Conclusion: The disturbed pathways and biomarker candidates identified in this study may provide novel insights into ALS pathogenesis and improve diagnostic strategies.