NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.

Background: Qishen granules (QSG) has been applied to treat heart failure (HF) for decades. Our previous transcriptomics study has suggested that Qishen granules (QSG) could regulate the pathways of cardiac energy metabolism in HF, but the specific regulatory mechanism has not yet been clarified. This study was to investigate the potential mechanism of QSG in regulating myocardial fatty acid (FA) and glucose metabolism in a rat model of HF. Methods: The model of HF was induced by left anterior descending coronary artery ligation. Cardiac structure and function were assessed by cine magnetic resonance imaging (MRI) and echocardiography. Level of glucose metabolism was non-invasively evaluated by ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT). Blood lipid levels were determined by enzymatic analysis. The mitochondrial ultrastructure was observed with a transmission electron microscope. The critical proteins related to FA metabolism, glucose metabolism and mitochondrial function were measured by western blotting. The ANOVA followed by a Fisher’s LSD test was used for within-group comparisons. Results: QSG ameliorated cardiac functions and attenuated myocardial remodeling in HF model. The levels of serum TC, TG and LDL-C were significantly reduced by QSG. The proteins mediating FA uptake, transportation into mitochondria and β-oxidation (FAT/CD36, CPT1A, ACADL, ACADM, ACAA2 and SCP2) as well as the upstreaming transcriptional regulators of FA metabolism (PPARα, RXRα, RXRβ and RXRγ) were up-regulated by QSG. As to glucose metabolism, QSG inhibited glycolytic activity by decreasing LDHA, while stimulated glucose oxidation by decreasing PDK4. Furthermore, QSG could facilitate tricarboxylic acid cycle, promote the transportation of ATP from mitochondria to cytoplasm and restore the mitochondrial function by increasing SUCLA2, CKMT2 and PGC-1α and decreasing UCP2 simultaneously. Conclusion: QSG improved myocardial energy metabolism through increasing FA metabolism,inhibiting uncoupling of glycolysis from glucose oxidation.

Targeting of DNA repair pathway is the main therapeutic approach for BRCA1 and BRCA2 associated tumors, including breast cancer. BRCA1/2 genes play a pivotal role in HRR pathway. Mutations in BRCA1/2 leads to DDR deficiency, which cause the increasing of genome instability, thus rendering cancer cells vulnerable to inhibition of DNA repair related proteins, such as PARP1. Pre-clinical studies has demonstrated that cancer cells with BRCA1/2 deficient are sensitive to PARPi, which are an emerging class of small molecule drug. Several clinical trials demonstrated the promising efficacy of PARP inhibitors for BRCA1/2 mutated breast cancer patient through selectively induce synthetic lethality cancer cells. Currently, four PARP inhibitors had been approved by FDA for clinical use. PARPi demonstrated to improve progression-free survival, while resistance to PARPi is inevitable. In this review article, we highlighted the advances in the PARPi clinical trials, resistance mechanism and coping strategies in breast cancer patients. We also summarized the international guideline and recommendations on PARP inhibitor usage in breast cancer.

Peritoneal metastasis (PM) is the major cause of recurrence in patients with gastric cancer (GC) and is associated with poor prognosis. The oncogenic role of Nicotinamide N‐methyltransferase (NNMT) in GC has been reported, but the role of secreted NNMT that is transported by exosomes remains unknown. In this study, exosomes were isolated from GC patients with or without PM and from GC cell line, including GC‐114, GC‐026, MKN45, and SNU‐16 cells. The contents of NNMT were significantly enhanced in exosomes isolated from GC patients with PM compared with those from GC patients without PM. Furthermore, the levels of NNMT were significantly enhanced in exosomes from GC cell lines relative to those from normal human gastric epithelial cell line GES‐1 cells. These data indicate that NNMT may be involved in intercellular communication for peritoneal dissemination. Moreover, colocalization of GC‐derived exosomal NNMT was found in human peritoneal mesothelial cell line HMrSV5 cells. Additionally, relative to GES‐1 exosomes, SNU‐16 exosomes significantly activated TGF‐β/smad2 signaling in HMrSV5 cells. However, when NNMT was silenced, the activation of TGF‐β/smad2 by SNU‐16 exosomes was abolished in HMrSV5 cells. We propose that NNMT‐containing exosomes derived from GC cells could promote peritoneal metastasis via TGF‐β/smad2 signaling.

BrMs represent a significant clinical challenge due to its high incidence, complex biology, and poor prognosis. Astrocytes, the predominant glial cells in the central nervous system, are increasingly recognized for their central role in shaping the brain microenvironment and driving the progression of brain metastases. This review highlights the multifaceted contributions of astrocytes to the metastatic cascade, including their involvement in tumor cell invasion, modulation of the blood–brain barrier, and establishment of a pro-metastatic niche. Astrocytes interact with tumor cells through various mechanisms, such as forming gap junctions, secreting factors that enhance tumor survival, and supporting immune evasion. These interactions promote tumor growth and protect metastatic cells from chemotherapy and radiotherapy, complicating current treatment strategies. Furthermore, astrocytes help reshape the brain microenvironment to support tumor adaptation and expansion, making them critical players in both the early and late stages of metastasis. Emerging therapeutic approaches are focused on disrupting astrocyte-tumor interactions, with strategies targeting astrocyte-driven communication pathways, immune modulation, and metabolic support systems. Nanotechnology and precision medicine also offer novel opportunities to improve drug delivery across BBB and directly target the astrocyte-tumor axis. This review underscores the importance of further research to fully understand the role of astrocytes in brain metastasis and develop therapies that leverage this knowledge to improve patient outcomes. Graphical Abstract