Background: S-Phase kinase associated protein 2 (SKP2) is a key regulator of the cell cycle and proliferation linked to cancer development. Our recent study has revealed that knocking out Skp2 in a mouse model significantly activates anti-tumor immunity. Although several studies have examined SKP2 in relation to the tumor immune microenvironment using public datasets, a comprehensive pan-cancer evaluation that integrates multi-omics layers and in vivo validation has remained limited.

Methods: In this study, we integrated multi-omics data from diverse public datasets to comprehensively analyze SKP2 expression characteristics and its relationship to tumor immunity across pan-cancer. A multiplex immunofluorescence assay was performed on tumors from Skp2 knockout and Skp2-intact mouse models for validation.

Results: Our findings indicate that SKP2 is overexpressed in various cancer types, leading to poor prognosis. Single-cell transcriptomic analyses further revealed that SKP2 is predominantly expressed in malignant and immune cells. Notably, a multiplex immunofluorescence assay on tumors from Skp2 knockout and Skp2-intact mouse models and pan-cancer data unveiled a correlation between SKP2 and the “immune-cold” microenvironment, which, possibly linked to the weakened antigen presentation, reduced secretion of chemokines in SKP2-overexpressing cancers. Additionally, we observed that SKP2 overexpression predicts worse immunotherapy efficacy.

Conclusion: Our findings provide novel insights into the role of SKP2 in regulating the tumor immune microenvironment, suggesting targeting SKP2 as a promising strategy to enhance immunotherapy efficacy in pan-cancer settings.

Background: Cathelicidin (CAMP), plays important roles in pathogen defense, immune regulation, and epithelial barrier maintenance. While previous studies have highlighted its protective function, the post-translational modifications and downstream immune-metabolic effects of CAMP in the pathogenesis of inflammatory bowel disease remain unclear.

Methods: A dextran sodium sulfate (DSS)-induced colitis mouse model was employed to assess the role of CAMP and its citrullination mediated by peptidyl arginine deiminase 4 (PAD4). Proteomic and metaproteomic analyses were performed to investigate microbiota composition and functional shifts. We generated gene-deficient mouse models, CAMP knockout (KO) and PAD4-KO mice, to dissect molecular mechanisms. Epithelial integrity, inflammatory markers, and immune responses have been evaluated at both the protein and mRNA levels. Bone marrow-derived dendritic cells and primary CD4⁺ T cells were co-cultured to examine the effects of CAMP-related metabolites on antigen presentation and Th17 differentiation. Furthermore, we evaluated the impact of CAMP peptide supplementation and the effects of CAMP-KO mice on DSS-induced colitis.

Results: CAMP citrullination was significantly elevated in DSS-induced colitis mice but restored by PAD4 deletion. Citrullination was found to reduce CAMP protein levels without affecting its transcriptional expression. The absence of CAMP exacerbated intestinal inflammation in DSS-treated mice. Metaproteomic analysis identified 70 differentially expressed proteins and 15 altered microbiota families associated with CAMP deficiency. Elevated levels of arginase-1 and its metabolites, particularly polyamines, enhanced dendritic cell maturation and increased Th17 polarization in CAMP-KO mice.

Conclusions: Our findings highlight that the protein level of CAMP decreased after PAD4-mediated citrullination, thus playing a vital role in regulating taxonomic community structure, restricting arginine metabolism, and regulating dendritic cell-Th17 immune responses in IBD.

Objectives: Inflammatory bowel disease is driven by dysregulated CD4⁺ T cell responses to the intestinal microbiota. While T cells can exacerbate inflammation by producing proinflammatory cytokines, they also produce anti-inflammatory mediators, such as interleukin 10 (IL-10) and IL-22. However, the metabolic programs that regulate IL-10 and IL-22 production remain incompletely defined.

Methods: We used CBir1 transgenic mice and in vitro Th1 polarization assays to investigate how metabolic pathways regulate T cell production of IL-10 and IL-22. A panel of metabolic inhibitors was tested for their effects on cytokine expression. Transcriptional mechanisms were assessed using bulk RNA sequencing, qPCR, Enzyme-linked immunosorbent (ELISA), and CRISPR-Cas9-mediated gene editing. Functional relevance was validated using Citrobacter rodentium infection and T cell suppression assays in vivo and in vitro.

Results: Among tested metabolic inhibitors, dichloroacetate (DCA) significantly enhanced IL-10 and IL-22 production by CD4⁺ T cells. DCA increased maximal oxygen consumption and decreased lactate secretion in T cells. Mechanistically, DCA upregulated aryl hydrocarbon receptor (Ahr) and downregulated Bhlhe40, without affecting Prdm1. Pharmacologic inhibition of Ahr suppressed DCA-induced IL-22, but not IL-10, while Bhlhe40 knockout enhanced IL-10 production, identifying distinct transcriptional regulators for each cytokine. Functionally, DCA-treated Th1 cells suppressed naïve T cell proliferation via IL-10. In an in vivo experiment, DCA treatment protected mice from C. rodentium-induced colitis.

Conclusions: Our findings demonstrate that DCA enhances IL-22 and IL-10 production in Th1 cells through Ahr and Bhlhe40, respectively. These results identify a novel metabolic mechanism by which DCA promotes mucosal immune regulation and highlight its potential as a therapeutic strategy for inflammatory bowel disease.

Background: The clinical benefit of T-DXd in advanced breast cancer with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-ultralow tumors in the DESTINY-Breast06 trial has drawn attention to this subtype.

Methods: We re-evaluated 473 pathological specimens from 302 HER2-negative breast cancer patients in our next generation sequencing database, classifying HER2-negative status into HER2-ultralow, IHC 0 without membrane staining (MS−) and HER2-low. Clinicopathologic characteristics and genomic profiles were analyzed by HER2 status.

Results: Overall, 35.5% of primary and 49.0% of metastatic HER2-IHC 0 tumors were reclassified as ultralow. Subtype analysis based on HR status showed no distinct clinicopathological characteristics in the HER2-ultralow subgroup. Upon metastasis, 40% of HER2-ultralow primary tumors converted to IHC 0 (MS−) and 46.7% to HER2-low. In the metastatic tumors, 60% of HER2-IHC 0 (MS−) and 50% of HER2-ultralow translated to other HER2 statuses in re-obtained samples. HER2-ultralow status was associated with worse disease-free survival than HER2-IHC 0 (MS−) and HER2-low status in HR-negative breast cancer, but no differences of overall survival were observed. The median progression-free survival for first-line chemotherapy was 7.2 months in HR+ HER2-low, 6.8 months in ultralow, and 8.8 months in IHC 0 (MS−) patients (P= 0.06). PIK3CA mutations were more common in the HER2-low subtype than in HER2-ultralow tumors in the HR− subtype.

Conclusion: In conclusion, HER2-ultralow status is not associated with distinct clinicopathologic or genomic characteristics. HER2-IHC 0 (MS−) and ultralow statuses often coexist within the same patient.

Background: Relapsed soft tissue sarcomas (STS) have poor prognosis and limited treatment options. However, the molecular mechanism underlying recurrence and the prognostic predictor for STS are unclear.

Methods: We enrolled 35 extremity and trunk STS patients. Tumor specimens of 20 relapsed and 15 primary STS underwent sequencing to detect DNA mutation, RNA expression, and DNA methylation. Moreover, 206 STS cases from The Cancer Genome Atlas (TCGA) were utilized to construct the relapse-associated risk score model (RRSM), validated using three Gene Expression Omnibus datasets. Key model genes, COL6A3, FZD7, ITPKA, and PRKAG1, were validated in formalin-fixed paraffin-embedded tissue sections from primary and relapsed STS patients, confirming their potential involvement in STS recurrence.

Results: The primary STS exhibited an immune-enriched tumor microenvironment, whereas the tumor microenvironment of relapsed STS had features that promote tumor recurrence or metastasis. The RRSM could predict relapse-free survival in TCGA STS and performed well in the validation cohort. Multivariate analysis revealed that RRSM was an independent prognostic factor. Moreover, the nomogram developed had excellent predictive ability.

Conclusions: This study revealed different multi-omic profiles between relapsed and primary STS. RRSM is a potential prognostic predictor for STS and lays a foundation for early intervention of high-risk STS patients. The expression of genes FZD7, ITPKA, and PRKAG1 may guide STS treatment decisions.

Cancer is becoming one of the leading causes of death among patients with diabetes. Hyperglycemia and obesity, two key characteristics of type 2 diabetes, modify the risks of cancer in patients with type 2 diabetes. However, recent studies suggested that glycemic control and weight loss mediated by anti-diabetic medications might not be sufficient to lower the risks of cancer in patients with type 2 diabetes. Thus, there is a need to explore the association between anti-diabetic medications and cancer beyond glycemic and body weight control. This review has summarized the preclinical and clinical evidence between various anti-diabetic drugs and cancer. More importantly, this review focused on the underlying links between anti-diabetic medications and cancer beyond glycemic and body weight control, including modified cell proliferation, altered levels of some hormones, inflammation and oxidative stimuli, autophagy and apoptosis, intestinal flora shift, and angiogenesis and epithelial-mesenchymal transition. This review may provide insights for future clinical and mechanistic studies to further elucidate the association between anti-diabetic medications and cancer.

Background: Shenzhuo Formula (SZF), a modified Didang Tang, is used for diabetic kidney disease (DKD), though high-quality evidence is limited.

Methods: In a randomized, double-blind, double-dummy, active-controlled, multicenter trial, irbesartan (IRB) was the control. A Bayesian model assessed efficacy. Mechanistic studies included Olink inflammation proteomics, single-cell RNA sequencing (scRNA-seq) of KK-Ay mouse kidneys, and in vivo experiments.

Results: A total of 120 DKD patients with macroalbuminuria were randomized (SZF n = 57, IRB n = 63). At 24 weeks, 24 h urinary total protein change was −0.03 (−0.24 to 0.18) g/24 h in the SZF group and 0.08 (−0.30 to 0.14) g/24 h in the IRB group (P = 0.61). Estimated glomerular filtration rate improved with SZF by 5.91 (1.80 to 10.01) mL/min/1.73m² but declined with IRB by −1.67 (−5.18 to 1.84) mL/min/1.73m² (P < 0.01). Serum creatinine decreased with SZF by −5.15 (−9.73 to −0.56) μmol/L but increased with IRB by 3.39 (−0.84 to 7.61) μmol/L (P < 0.01). Traditional Chinese medicine syndrome response was higher with SZF (89.47% vs. 63.49%, P < 0.01). Safety and metabolic parameters were comparable. Bayesian analysis favored SZF for renal benefit. Mechanistically, SZF downregulated CX3CL1 in endothelial cells and MCP-1 in mesangial and tubular cells, suggesting anti-inflammatory effects restoring endothelial function and attenuating fibrosis.

Conclusions: SZF matched IRB in proteinuria reduction but was superior in preserving renal function and improving traditional Chinese medicine symptoms in DKD, with good safety. Benefits may involve suppression of CX3CL1/MCP-1-mediated inflammation.

Hepatoblastoma (HB) is the most common malignant liver tumor in children. Early diagnosis and effective treatment are crucial for improving the prognosis of children with HB. In recent years, microRNAs (miRNAs), an important class of noncoding RNA molecules, have been increasingly recognized for their key regulatory roles in the occurrence, development, and treatment of HB. This review systematically reviews the expression characteristics, molecular mechanisms, and potential application value of miRNAs in the diagnosis and treatment of HB. Research indicates that the interaction network between miRNAs and long noncoding RNAs and circular RNAs has a significant effect on the development of HBs. miRNAs regulate signaling pathways, such as the Wnt/β-catenin, mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B, and Janus kinase 2/signal transducer and activator of transcription 3 pathways, and also play critical roles in the biological behavior of HBs. Furthermore, the progress of preclinical research on miRNAs as biomarkers and therapeutic targets provides new ideas and directions for precision medicine in HB. Finally, this article looks forward to the future development directions of miRNAs in precision medicine for HBs, emphasizing their important potential in improving diagnostic accuracy and treatment efficacy.

RNA modifications encompass a series of dynamic chemical changes and editing events on RNA molecules, playing a pivotal role in essential physiological processes such as embryonic development, immune response, and the maintenance of cell homeostasis. By influencing RNA stability, splicing, translation, and intermolecular interactions, RNA modifications serve as crucial mechanisms regulating gene expression at the post-transcriptional level. Dysregulation of the modification machineries or aberrant modification patterns is closely associated with the onset and progression of various diseases, including tumors, metabolic disorders, cardiovascular diseases, and neurological and immune conditions, making them potential biomarkers for disease diagnosis, prognosis, and treatment. In this review, we summarize the molecular mechanisms of major RNA modifications, emphasize their functions in health and disease, and discuss their diagnostic and therapeutic value in pathological contexts.

More than 500 million Chinese adults suffered from overweight or obesity in 2023. The pandemic of obesity consumes healthcare and economic resources by imposing enormous burden from its complications such as cardiovascular, kidney and metabolic diseases. In response, China launched a series of important policy changes including “Weight Management Year”, facilitating the engagement of public health, clinical practitioners, industry and stakeholders in different fields. The shift triggered rapid evolution of technologies in obesity care including both treatment and prevention, which added great opportunities for all stakeholders. Nevertheless, challenges exist, including misdiagnosis of obesity secondary to other diseases, population disparity, indirect evidence supported by trials conducted in other ethnic groups, health inequalities and the collaboration across stakeholders with diverse backgrounds. Traditional Chinese diets such as Jiangnan Diet and activities such as Tai Chi represent tradition-based lifestyle interventions that provide Chinese people with cultural benefits. The evolution of technologies, especially digital healthcare and novel medications, will play critical roles in future obesity care in China. Policy makers and clinical and public health practitioners must make every effort to address the urgent crisis posed by obesity pandemic in China.