Shulong Jiang

Glioblastoma (GBM) is currently the most lethal type of primary brain tumor, with a median survival time of 15‑20 months despite the use of multimodal therapy. Although radiotherapy (RT) remains a cornerstone of GBM treatment, a subset of patients who initially respond to RT eventually acquire resistance, leading to tumor relapse. The emergence of radioresistance severely impairs the long‑term efficacy of RT, highlighting the importance of understanding its underlying mechanisms. The present review synthesizes emerging evidence that therapy‑induced remodeling of the blood‑brain barrier (BBB), upregulation of ATP‑binding cassette efflux transporters, hypoxia‑driven hypoxia inducible factor‑1α signaling and tumor microtube (TM)‑mediated intercellular communication converge to create a self‑reinforcing resistance network. These interconnected mechanisms collectively drive adaptive radioresistance, rather than acting in isolation. Based on this framework, the present review evaluates therapeutic strategies designed to disrupt distinct nodes of this network, including epigenetic modulators, poly (ADP‑ribose) polymerase inhibitors, BBB‑penetrant agents and TM‑targeting approaches, such as connexin43 peptide inhibitors and high‑linear energy transfer particle therapy. The clinical implications of these findings are discussed, with emphasis on biomarker‑driven patient stratification and combinatorial regimens that concurrently target multiple resistance mechanisms.

Background: Triple-negative breast cancer (TNBC) urgently needs effective therapies due to limited targeted options and unfavorable outcomes. We investigated Trichosanthes kirilowii Maxim formula granules (TKM) using integrated network pharmacology, metabolomics, and molecular pharmacology to clarify potential multi-target mechanisms relevant to TNBC. Methods: Liquid chromatography coupled with mass spectrometry was employed to identify the components of TKM formula granules. Network pharmacology-based prediction was used to uncover potential mechanisms by which TKM counteracts TNBC. Potential targets were identified, and pathway enrichment analysis was performed. Subsequently, TNBC cells and 4T1 tumor-bearing mice were used to verify the molecular mechanisms of TKM. Results: We identified 151 active compounds in TKM. Through network pharmacology analysis, 214 TNBC-related targets were found, with 28 core targets, including cell cycle and apoptosis regulators MYC, TP53, AKT1, CCND1, CASP3, PIK3CA, BCL2L1, and CDC42. The compound-target-pathway-disease network showed that schisandrin binds to many treatment targets with satisfactory docking performance, especially for MYC and AKT1. Experimentally, TKM was found to significantly promote apoptosis and induce G2/M-phase cell-cycle arrest in MDA-MB-231 cells. Western blot analysis showed that TKM suppressed PI3K/AKT and Wnt/β-catenin signaling pathways. Surface plasmon resonance experiment revealed that schisandrin binds to recombinant AKT1 with an equilibrium dissociation constant (K_D) of 1.525 × 10 ⁻⁴ M. According to untargeted metabolomics results, TKM can regulate amino acid, glycine, serine, and threonine metabolism, mineral absorption, protein digestion and absorption, central carbon metabolism, and arginine biosynthesis to exert therapeutic effects on TNBC. All findings were consistent with predicted targets and pathways. Conclusion: This study comprehensively explores the multi-target mechanisms of TKM against TNBC using network pharmacology, molecular pharmacology, and metabolomics approaches. These findings provide a foundation for future mechanistic investigations and may support the further preclinical development of TKM-based strategies for TNBC.

Pancreatic cancer, one of the most lethal malignancies, is characterized by insidious onset, frequent late-stage diagnosis, rapid progression, and limited surgical opportunities. Pancreatic ductal adenocarcinoma (PDAC), accounting for over 90% of pancreatic cancer cases, remains a therapeutic challenge due to the scarcity of effective targeted therapies. In this study, we collected formalin-fixed paraffin-embedded (FFPE) specimens from three patients with moderately to poorly differentiated PDAC, extracted genomic DNA, and performed whole-exome sequencing. Through bioinformatics analysis, we identified 68 high-risk deleterious variants, including the DNMT3A p.R882C mutation. This mutation exhibits low frequency in public databases (e.g., esp6500si, GnomAD) and is consistently predicted as deleterious by multiple algorithms (SIFT, Polyphen, LRT, CADD). To investigate its functional impact, wild-type and mutant DNMT3A constructs were cloned into p3xflag-CMV-10 plasmids and transfected into the pancreatic cancer cell lines PANC-1 and PaTu 8988t. In vitro cellular experiments demonstrated that the DNMT3A p.R882C mutation does not alter DNMT3A expression at mRNA or protein levels but significantly promotes cancer cell proliferation and migration while inhibiting apoptosis. These findings suggest that the DNMT3A p.R882C mutation may play a critical role in PDAC pathogenesis. This study not only provides essential laboratory evidence for elucidating PDAC development but also offers new insights for potential targeted therapeutic strategies in pancreatic cancer.

Hepatocellular carcinoma (HCC) remains a critical global health concern, particularly in regions with high endemicity of hepatitis B, hepatitis C, and non-alcoholic fatty liver disease. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a promising therapeutic strategy for advanced HCC. Despite encouraging results, primary and acquired resistance to ICIs continues to pose significant challenges in clinical practice. Recent research has identified tumor-associated macrophages (TAMs) as key contributors to immune evasion and ICI resistance in HCC, primarily through polarization to the M2 phenotype. M2-polarized TAMs secrete a range of immunosuppressive cytokines that inhibit T cell activation and promote tumor progression through processes such as angiogenesis and epithelial-mesenchymal transition. These mechanisms compromise the efficacy of ICIs and facilitate tumor expansion and metastasis. This review summarizes the role of TAM-related signaling pathways in driving immune evasion and ICI resistance in HCC, with particular emphasis on the contribution of TAM surface receptors and chemokines in immune suppression. Additionally, the review highlights emerging insights into TAM metabolic reprogramming and transcriptional regulation, which have been closely linked to ICI resistance. Furthermore, we explore promising therapeutic strategies targeting TAMs and their associated signaling pathways to enhance ICI efficacy in HCC. Integrating these novel approaches could potentially overcome TAM-driven immune evasion and ICI resistance, boosting the efficacy of immunotherapy and improving patient prognosis in HCC.

Neglected Tropical Diseases (NTDs) and malaria, as tropical diseases, have long been major global public health challenges, particularly in low-income countries. Although the burden of NTDs and malaria has declined in recent years, significant health inequalities persist across regions. In the future, climate change may further exacerbate the burden of NTDs and malaria, with these burdens likely to disproportionately concentrate in low-income countries. This study aims to describe the global trends in the burden of NTDs and malaria, reveal health inequalities, and forecast future disease burdens. This study utilizes the latest data from the Global Burden of Disease Study (GBD) 2021 to assess the global trends and spatial distribution of NTDs and malaria burden from 1990 to 2021. Inequality analyses and frontier analysis were employed to evaluate disparities in disease burden and governance potential across countries, and the interactive effects between environmental risks and socio-economic factors on the burden of NTDs and malaria were explored in depth. Furthermore, the Bayes Age-Prior-Cohort model was used to forecast changes in disease burden from 2022 to 2041. From 1990 to 2021, the age-standardized DALY rate for NTDs and malaria declined from 1506.54 to 1020.27 per 100,000. Western Sub-Saharan Africa remains the most affected, contributing 51.18% of the global burden. Males have lower incidence but higher mortality rates compared to females. Despite improvements in global inequality, regional disparities persist. Environmental and socio-economic factors interact significantly, exacerbating the burden in vulnerable regions. The NTDs and malaria burden is projected to increase over the next 20 years, particularly in Middle and Low-middle Socio-Demographic Index (SDI) regions. Despite a global decline in the burden of NTDs and malaria, low-income countries, particularly in Western Sub-Saharan Africa, continue to experience significant health inequalities. Global climate change may exacerbate this burden, and these burdens will be disproportionately concentrated in tropical, poverty-stricken countries.

The tumor microenvironment (TME) is characterized by distinct metabolic adaptations that not only drive tumor progression but also profoundly influence immune responses. Among these adaptations, lactate, a key metabolic byproduct of aerobic glycolysis, accumulates in the TME and plays a pivotal role in regulating cellular metabolism and immune cell function. Tumor-associated macrophages (TAMs), known for their remarkable functional plasticity, serve as critical regulators of the immune microenvironment and tumor progression. Lactate modulates TAM polarization by influencing the M1/M2 phenotypic balance through diverse signaling pathways, while simultaneously driving metabolic reprogramming. Furthermore, lactate-mediated histone and protein lactylation reshapes TAM gene expression, reinforcing their immunosuppressive properties. From a therapeutic perspective, targeting lactate metabolism has shown promise in reprogramming TAMs and enhancing anti-tumor immunity. Combining these metabolic interventions with immunotherapies may further augment treatment efficacy. This review underscores the crucial role of lactate in TAM regulation and tumor progression, highlighting its potential as a promising therapeutic target in cancer treatment.

Purpose: This study aimed to investigate the pharmacological mechanisms of Shugan Jianpi Formula (SGJPF) in treating TNBC using network pharmacology and molecular biology approaches. Methods: HPLC/MS identified the key compounds in SGJPF. In vitro assays were performed on norepinephrine (NE)-stimulated MDA-MB-231 and SUM159PT cells to mimic triple-negative breast cancer (TNBC) under chronic psychological stress (CPS) and evaluate SGJPF’s effects on cell proliferation, apoptosis, cell cycle, migration, and invasion. A TNBC mouse model exposed to CPS was used to assess SGJPF’s influence on tumor growth. SGJPF’s mechanisms were explored via network pharmacology and molecular docking, with target validation through Western blotting, immunohistochemistry, and immunofluorescence. Results: HPLC/MS analysis identified 806 compounds in SGJPF, including flavonoids, polyphenols, saponins, polysaccharides, alkaloids, terpenoids, coumarins, organic acids, and glycosides. Network pharmacology and molecular docking analyses identified SRC, ERK (MAPK1), and STAT3 as pivotal targets underlying the anti-tumor effects of SGJPF in TNBC. Both in vitro and in vivo experiments confirmed that SGJPF exerts its therapeutic effects through the modulation of the SRC/ERK/STAT3 signaling axis. In vitro, SGJPF effectively inhibited TNBC cell proliferation, migration, and invasion, while promoting apoptosis in NE-stimulated cells. In a CPS-induced TNBC mouse model, SGJPF significantly alleviated tumor progression, further corroborating its potential as a novel therapeutic strategy for TNBC. Conclusion: This study highlights the potential of SGJPF as a therapeutic strategy for TNBC through its modulation of the SRC/ERK/STAT3 signaling axis, offering a robust foundation for further investigation into its clinical application.