Volume 139 · Issue 11 · 2026

Diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease worldwide, characterized by increasing prevalence and limited therapeutic options. This review comprehensively synthesizes recent advances in the molecular mechanisms underlying DKD progression, focusing on key cellular events including podocyte injury, tubular damage, endothelial dysfunction, pericyte loss, and immune-inflammatory responses that drive glomerular and tubulointerstitial fibrosis. We further elaborate on critical pathways such as lipotoxicity, mitochondrial dysfunction and oxidative stress, aberrant autophagy, inflammasome activation, and profibrotic signaling. The review also highlights clinically approved agents including renin-angiotensin-aldosterone system inhibitor, sodium-glucose cotransporter 2 inhibitors, endothelin receptor antagonists, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, and emerging therapeutic targets and agents currently under preclinical and clinical investigation, including anti-inflammatory, anti-fibrotic, and metabolic interventions. By integrating mechanistic insights with translational evidence, this work aims to provide a comprehensive review for the development of DKD.

Adipose tissue is a complex endocrine organ that critically regulates cardiovascular health and disease. Different adipose depots vary in location and function, exerting distinct physiological and pathological effects on the cardiovascular system. This review examines the roles of three key depots: (1) epicardial adipose tissue (EpAT), (2) perivascular adipose tissue (PVAT), and (3) bone marrow adipose tissue (BMAT). We also focus on the functional differentiation of adipose tissue based on its anatomical location to provide a robust understanding of its diverse impacts on cardiovascular diseases (CVDs). We further explore pharmacological interventions targeting adiposity and obesity, including their mechanisms, clinical applications, and therapeutic potential in CVD management. By elucidating the intricate interactions between adipose depot dynamics and cardiovascular pathology, this work highlights emerging research directions and underscores the need for adipose-specific strategies in cardiovascular therapeutics.

RNA interference is an ancient biological defense mechanism against external invasions. Mechanistically, small interfering RNA (siRNA) can specifically bind to any target gene, according to the principle of complementary base pairing, to exert silencing effects. Therefore, siRNA has the potential to serve as an efficient therapeutic agent for various diseases. However, due to their susceptibility to nucleases, off-target effects, and low cellular uptake, the development of siRNA-based drugs remains challenging. Fortunately, with the advancement in chemical modifications and delivery systems, patisiran, the first siRNA therapeutic, was approved for the treatment of hereditary transthyretin amyloidosis by the United States Food and Drug Administration (FDA) in 2018, which represents a crucial milestone in the field of siRNA research. Subsequently, seven other siRNA drugs were introduced to the market. Thus, siRNA drugs are on their way to becoming standard pharmacotherapy tools. This review presents the mechanisms of action, delivery barriers, chemical modifications, and delivery platforms of siRNA. Furthermore, it also summarizes commercialized siRNA drugs and some clinical trials, thereby providing a comprehensive knowledge map of siRNA drug modifications, delivery strategies, action mechanisms, and updated clinical trials.

Background: The "Healthy China 2030" initiative, which aims to achieve a 30% reduction in premature mortality by 2030, recognizes leukemia as the primary cause of cancer-related deaths. Given the limited previous research, providing comprehensive national and subnational estimates and temporal trends of the premature leukemia mortality burden from 2005 to 2020 is crucial. Methods: Using data from various sources acquired through the national surveillance mortality system, estimates were derived and compared across 31 provincial-level administrative regions in the Chinese mainland, revealing the magnitude of mortality rates and years of life lost (YLL) due to leukemia in the Chinese population between 2005 and 2020. Results: In 2020, the estimated number of leukemia-related deaths decreased from 61.93 thousand in 2005 to 54.86 thousand, accompanied by a decline in age-standardized mortality rate (ASMR) from 4.97 per 100,000 population in 2005 to 3.49 per 100,000 population. The burden of premature mortality caused by leukemia exhibited a significant reduction, as indicated by a nationwide decline of -39.37% (from 239.46 to 145.18 per 100,000 population) in the age-standardized YLL rate. Despite a notable decrease (-11.41%) in leukemia mortality, China has the highest burden of leukemia-related deaths due to its large population, primarily driven by population aging (12.76%), which has contributed to an upsurge in leukemia fatalities, followed by population growth (7.67%). Leukemia mortality exhibited distinct variations among different provinces and demonstrated a positive correlation with economic activity, particularly in coastal provinces characterized by higher levels of economic development. Xizang is currently the only province experiencing a significant increase in mortality rate, necessitating urgent government support. Conclusions: Significant disparities in premature mortality attributed to leukemia were observed across diverse regions of China, underscoring the need for targeted interventions aimed at promoting a health-protective lifestyles and expanding timely access to basic medical insurance for diagnosis and cost-effective therapy, particularly among high-risk populations and regions with limited healthcare resources.

Background: Role impairment due to health problems is a public health issue. China Mental Health Survey (CMHS) is a national epidemiological study in China, providing plenty of information on mental disorders and physical diseases.This study focused on the association between mental disorders and physical diseases with role impairment. Methods: This study was based on CMHS, a cross-sectional study in a large-scale nationally representative sample across China from 2012 to 2015. Trained interviewers carried out face-to-face interviews with 28,140 respondents using the Composite International Diagnostic Interview-3.0 (CIDI-3.0). The prevalence of mental disorders and physical diseases was assessed. In addition, each respondent reported information about the number of days in the past month being totally and partially unable to work or carry out their other normal daily activities because of problems with either mental disorders or physical diseases. Associations of role impairment with physical diseases and mental disorders were analyzed by multiple regression. Results: Overall, the weighted rate of role impairment was 3.68% in patients with any mental disorders and 8.75% in those with any physical diseases. Chronic pain (β = 0.07, P <0.001) became the main physical disease associated with role impairment, while depressive disorder (β = 0.12, P <0.001) became the main mental disorder associated with role impairment. Patients with more mental disorders or physical diseases experienced more days with role impairment. Conclusions: Common mental disorders and physical diseases account for a large proportion of the number of days out of role. It should be addressed to substantially increase the level of mental health in China.

Background: It is a common challenge in clinical decision-making to optimize and select maintenance therapy (MT) regimens that balance efficacy and toxicity. This study compares the efficacy and toxicity of immune checkpoint inhibitors (ICIs) monotherapy vs. ICIs plus pemetrexed as MT following initial immunotherapy in non-small cell lung cancer (NSCLC) patients. Methods: We performed a multicenter retrospective real-world study that included non-squamous NSCLC (nqNSCLC) patients who received 4-6 cycles of ICIs plus pemetrexed as the first-line treatment and continued ICIs monotherapy or ICIs plus pemetrexed as MT between April 1, 2018, and June 30, 2023. Progression-free survival (PFS) and overall survival (OS) were reported using the Kaplan-Meier method. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: Out of 1060 recorded patients, 328 met the inclusion criteria for the analysis: 235 received ICIs plus pemetrexed, and 93 received ICIs monotherapy as MT. Demographic characteristics were comparable between the two groups. No significant difference was observed in median PFS (15.0 vs. 14.6 months; P = 0.756) between the two groups, regardless of programmed death-ligand 1 (PD-L1) stratification. Similarly, median OS did not differ significantly (28.3 vs. 38.9 months; P = 0.799). Anemia incidence was higher in the ICIs plus pemetrexed MT group (48.5 vs. 32.3%). Patients who were rechallenged with ICIs as second-line therapy experienced improved OS compared to those who received non-ICI therapy (not reached vs. 20.4 months; P = 0.009). Conclusion: The absence of statistically significant survival difference and increased toxicity in the ICIs plus pemetrexed cohort suggest that chemotherapy may not be crucial in MT. Moreover, the significant benefits of ICIs-based therapy as a second-line treatment reinforce its value, offering confidence to both patients and physicians in making informed decisions regarding MT strategies and subsequent systemic therapies.

Background: Although monocyte-to-macrophage differentiation is essential for innate immune defense, its dysregulation can drive excessive inflammation in sepsis. Reticulocalbin 3 (RCN3) is an endoplasmic reticulum chaperone in the secretory pathway implicated in alveolar epithelial maturation and lung injury repair. This study aimed to investigate the effect of RCN3 on monocyte-to-macrophage differentiation in pneumonia-associated sepsis. Methods: Patients with pneumonic sepsis (n = 10) and age- and sex-matched healthy volunteers (n = 8) were enrolled from Beijing Chao-Yang Hospital. Peripheral blood was collected within 12 h after diagnosis; peripheral blood mononuclear cells (PBMCs) were isolated and monocytes were purified for transcriptional analyses of RCN3 and macrophage markers. For in vivo validation, myeloid-specific Rcn3 knockout mice received intratracheal lipopolysaccharide (10 mg/kg) or saline, and were assessed 16 h later (n = 3-6 per group). Mechanistic studies in THP1 cells, human primary circulating monocytes and mouse bone marrow-derived monocytes used RCN3 knockdown and overexpression to evaluate differentiation markers, intracellular oxidative stress, and phagocytosis assays and autophagy flux evaluation. Results: In patients with pneumonic sepsis, RCN3 was significantly increased in circulating monocytes, but not lymphocytes, and its expression correlated with the macrophage marker CD68. RCN3 was also upregulated during monocyte-to-macrophage differentiation in both human and mouse monocytes. Furthermore, RCN3 knockdown attenuated differentiation, phagocytosis, and the lipopolysaccharide (LPS)-induced inflammatory response, whereas RCN3 overexpression had opposite effects. In vivo, myeloid-specific Rcn3 deletion decreased lung interstitial macrophage accumulation after intratracheal LPS instillation and alleviated acute lung injury. Mechanistically, the blunted differentiation caused by RCN3 deficiency was associated with reduced autophagy, due to impaired autophagosome formation. Conclusions: The upregulation of RCN3 in sepsis facilitates monocyte-to-macrophage differentiation by modulating autophagy. These findings also suggest that RCN3 in circulating monocytes presents a potential therapeutic target for sepsis.

Background: Severe acute pancreatitis (SAP) often leads to life-threatening multiorgan dysfunction, with intestinal barrier failure being a key driver of systemic inflammation. Although Rhein shows efficacy in SAP, its mechanism for protecting against pancreatitis-associated intestinal injury remains unclear. This study aimed to elucidate the mechanism of Rhein in pancreatitis-associated intestinal injury (PAII), with a focus on intestinal macrophage polarization and peroxisome proliferator-activated receptor γ (PPARγ) signaling. Methods: SAP was induced in male C57BL/6J mice by intraperitoneal injections of cerulein and lipopolysaccharide (LPS). Pancreatic and intestinal histopathology were assessed by hematoxylin and eosin staining using both paraffin and frozen sections. The expression of PPARγ, NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome components, and macrophage polarization markers was examined by real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting, and immunofluorescence. RT-qPCR was also used to quantify the messenger RNA (mRNA) levels of pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, tumor necrosis factor [TNF]-α, monocyte chemoattractant protein-1 [MCP-1]) and the anti-inflammatory cytokine IL-10 in colonic tissues. Reactive oxygen species (ROS) levels in colonic tissues were detected by dihydroethidium staining. Serum levels of lipopolysaccharide were measured by enzyme-linked immunosorbent assay (ELISA). For in vitro mechanistic studies, primary bone marrow-derived macrophages isolated from C57BL/6J mice were stimulated with LPS and interferon-γ to induce M1 macrophage polarization, with or without Rhein treatment. Results: SAP-induced intestinal injury was characterized by downregulated PPARγ, NLRP3 inflammasome hyperactivation, and dominant M1 macrophage polarization. Rhein restored PPARγ, suppressed NLRP3, and reduced secretion of key M1-sustaining cytokines (IL-6, IL-1β, and TNF-α). This attenuated the proinflammatory milieu, indirectly facilitating an M1-to-M2 phenotypic shift. All benefits were abolished by PPARγ antagonism. Conclusion: Rhein alleviates pancreatitis-associated intestinal injury by activating PPARγ, which suppresses the NLRP3 inflammasome and downstream proinflammatory cytokine cascade, thereby modulating macrophage polarization. The PPARγ-NLRP3 axis is a crucial regulatory pathway and potential therapeutic target in SAP.

Background: The development of thoracic aortic dissection (TAD) is closely associated with the loss of vascular smooth muscle cells (VSMCs). Androgen receptor (AR) signaling has increasingly been recognized as an important regulator of cell death in prostate cancer. However, the role of AR signaling in the development of TAD in men remains unknown. Methods: The expression of AR was analyzed in clinical specimens obtained from TAD patients undergoing surgical aortic replacement and control subjects receiving heart transplantation. Using β-aminopropionitrile (BAPN)-induced aortic dissection mouse models, we systematically investigated the protective role of AR through multiple approaches. Histopathological evaluation was performed using immunohistochemistry and immunofluorescence. Primary vascular smooth muscle cells were isolated for functional studies including AR knockdown, ferroptosis assessment, and metabolic profiling. Mechanistic insights were gained through chromatin immunoprecipitation, luciferase reporter assays, and RNA stability tests. Seahorse extracellular flux analysis and targeted metabolomics were employed to characterize metabolic alterations. Results: The expression of AR in VSMCs was downregulated in both clinical samples and animal models of TAD. Using in vitro and in vivo models, we demonstrated a novel function of AR that inhibited ferroptosis in VSMC by promoting excessive lipid peroxidation. Mechanistically, we showed that AR counter-regulated the expression levels of acyl-CoA synthetases ACSL3 and ACSL4 in VSMCs. AR acted as a transcriptional regulator to promote the transcription of ACSL3 gene while inhibiting the transcription of the ACSL4 gene, both of which inhibited lipid peroxidation and ferroptosis. Importantly, activating AR signaling was beneficial in preventing TAD from developing and progressing in the animal model. Conclusions: Our results reveal a previously unrecognized role of AR in TAD pathogenesis and uncover the opposite yet complementary regulation of ACSL3/ACSL4 levels involved in lipid peroxidation-driven ferroptosis in VSMCs.