BCL3 (B-cell CLL/lymphoma 3), initially identified in the t(14;19) chromosomal translocation in B-cell malignancies, is an atypical member of the inhibitor of NF-κB (IκB) protein family. Unlike classical IκB proteins, BCL3 predominantly localizes to the nucleus, where it exerts unique bidirectional transcriptional regulatory functions within the NF-κB signaling pathway. This complex functionality is finely modulated by post-translational modifications, particularly phosphorylation. Under pathological conditions, BCL3 functions as an oncogene, driving abnormal neoplastic cell proliferation, inhibiting apoptosis, and promoting metastasis and chemotherapy resistance in various hematological malignancies and solid neoplasms by activating multiple oncogenic signaling pathways. Conversely, BCL3 also serves as a critical regulatory factor of immune homeostasis, modulating the functions of macrophages, T cells, and dendritic cells (DCs), thereby influencing the pathogenesis of immune-related disorders. Beyond oncology and immunology, BCL3 plays pivotal roles in the nervous, cardiovascular, digestive, and musculoskeletal systems, highlighting its broad physiological and pathological significance. This article systematically reviews the molecular structure, post-translational regulatory mechanisms, and multifaceted roles of BCL3 in neoplastic and non-neoplastic diseases. By consolidating current research, this review aims to provide novel insights into the diagnostic and therapeutic potential of targeting BCL3 in related pathologies.

The lung, a key organ for oxygen exchange, is particularly susceptible to high-altitude hypoxic stress. Hypoxia induces vascular impairment, which is characterized by vascular inflammatory responses and aging-like changes. Lipid metabolism has been shown to be closely associated with cellular homeostasis and membrane balance. However, the alterations in pulmonary lipid metabolism in response to high-altitude hypoxia are not fully characterized. In this study, model mice were subjected to a hypobaric chamber at an altitude of 5500m for 3 days, and pulmonary microvascular endothelial cells (PMVECs) were cultured under 1% oxygen for 18h to simulate the effects of acute severe hypoxia. High-altitude hypoxia significantly disrupted lung sphingolipid metabolism, accompanied by inflammation and aging-like changes in mice. Moreover, C24-Ceramide (Cer) and its synthase (CERS2) were significantly increased in PMVECs. C24-Cer was identified to bind to voltage-dependent anion channel 1 (VDAC1) (a mitochondrial outer membrane protein), which promoted mitochondrial DNA (mtDNA) release and subsequently induced the inflammation and aging-like changes by activating the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway. Inhibition of C24-Cer or VDAC1 oligomerization by si-Cers2 or VBIT-4 could significantly reduce mtDNA release and alleviate inflammation and aging-like changes in the PMVECs and lung tissue under hypoxia. Our present work provides a novel and potential therapeutic target for high-altitude hypoxia-related vascular diseases.

Immunotherapy has drawn attention in the current era; CAR T cells and STING agonists are emerging as novel approaches for cancer treatment. Advances in STING agonist development are ongoing, and many remain in the preclinical stage. At the same time, it is now clear that dysregulated or chronic activation of the cGAS-STING pathway contributes to a broad spectrum of human pathological conditions. Classically, cGAS, as a sensor of dsDNA, recognizes the cytoplasmic dsDNA and, due to the enzymatic activity, generates a di-nucleotide molecule as the 2'3' cGAMP. 2'3' cGAMP behaves as the natural activator of STING and further facilitates the downstream pathway via TBK1 to IRF-3 and NF-κB. Conventionally, this pathway is explored in the context of the antiviral immune response. The agonists of STING have a distinct role in immunotherapy, but the cGAS-STING pathway is also associated with other molecular mechanisms that deviate from its canonical pathway and activate its non-canonical pathway, which leads to different molecular patterns, and this is associated with many diseases and cancer survival. Here, we discussed the various pathways that regulate the cGAS-STING activation in chronic and non-canonical ways. Chronic and non-canonical pathways associated with human disease and cancer. We also discussed the therapeutic opportunities.

Poly (ADP‒ribose) polymerase inhibitors (PARPis) are widely used in maintenance therapy for various platinum-sensitive cancers regardless of the occurrence of BRCA mutations. However, the mechanisms of action and treatment resistance associated with the use of PARPis for maintenance therapy in pancreatic cancer remain unclear. In this study, in addition to the induction of apoptosis, the use of PARPis (olaparib and niraparib) as maintenance therapies inhibited cell proliferation by causing cellular senescence to exert potent anticancer effects on Capan-1 (BRCA mutated) and PANC-1 (BRCA wild-type) cells. Mechanistically, the cellular senescence caused by PARPis relies on the Chk2‒p21 pathway but not in a p53-dependent manner. Interestingly, in addition to directly causing DNA damage, PARPis also exacerbate DNA damage through the generation of ROS via the positive feedback pathway, thereby inducing cellular senescence. Unfortunately, PARPis therapy-induced senescence is a reversible anticancer mechanism in which senescent cancer cells lose their senescence-like phenotype and continue proliferating upon drug withdrawal. This potentially explains the requirement for sustained PARPi therapy in the clinic. Furthermore, the expression of Bcl-2 was increased in PARPi-induced senescent cancer cells, providing a window for opportunistic elimination via synergistic senolytic drugs. The inhibition of Bcl-2 through the sequence-dependent combination of navitoclax enhanced the anticancer effects of PARPis by removing senescent cells. Collectively, data from our study demonstrate that the clinical application of PARPis as maintenance therapy could be achieved through the induction of cellular senescence. Furthermore, sequence-dependent combination with senescence-targeting drugs can potentiate pancreatic cancer treatment effects of PARPis regardless of the BRCA status.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease marked by irreversible deposition of the extracellular matrix (ECM) and subsequent disruption of pulmonary architecture. Although current pharmacological interventions, such as Pirfenidone and Nintedanib, are available, they merely decelerate the progression of the disease. Notably, the monocyte count in peripheral blood is strongly correlated with the prognosis and mortality associated with IPF. An elevated monocyte count is observable in the early stages of IPF, with monocyte accumulation in lung tissue persisting throughout the disease's progression. Monocytes are recruited to the lung tissue in response to chemoattractant signals, where they differentiate into macrophages, dendritic cells, and fibrocytes. These differentiated cells are integral to the pathology of IPF, with macrophages, in particular, being identified as pivotal contributors to disease progression. This review aims to elucidate the primary pathways involved in monocyte recruitment to the lungs during IPF and to investigate the crucial roles that monocytes play in the disease's pathogenesis. This review aims to establish a foundation for novel therapeutic strategies targeting monocytes, thereby facilitating early detection and intervention in IPF.

Traditional chemotherapeutic agents are indispensable in cancer treatment. However, their therapeutic efficacy is frequently constrained by associated toxicities and adverse effects. Among these adverse effects, cardiotoxicity has emerged as a major clinical concern due to the increasing incidence. Emerging evidence suggests that oxidative stress, programmed cell death pathways, oxidative stress, and inflammatory cascades predominantly mediate the pathogenesis of cardiotoxicity induced by chemotherapeutic agents. Current strategies for monitoring and prevention rely on potential biomarkers, including markers of myocardial injury (e.g., troponins and natriuretic peptides), inflammatory mediators (e.g., myeloperoxidase, interleukin-6, C-reactive protein, and tumor necrosis factor-alpha), and exosomal contents (e.g., microRNAs, proteins, and metabolites). Clinical trials and case reports have demonstrated that patients with chemotherapy-induced cardiotoxicity may benefit from therapeutic interventions such as angiotensin-converting enzyme inhibitors, dexrazoxane, and β-blockers. However, limitations associated with these potential biomarkers and therapeutic agents warrant further discussion because of the lack of solid evidence from large-scale, prospective clinical studies. In summary, further research is imperative to enhance the understanding, monitoring, and therapeutic management of cardiotoxicity associated with traditional chemotherapeutic agents.

The core pathological mechanism of diabetes mellitus and its complications is rooted in the interactive regulation between immunometabolic dysregulation and inflammatory programmed cell death, with PANoptosis serving as a critical hub in this process. PANoptosis is a distinct innate immune-mediated inflammatory lytic cell death pathway initiated by pattern-recognition receptors and propagated via the PANoptosome complex, which plays a critical hub role in the interactive regulation between immunometabolic dysregulation and inflammatory programmed cell death in diabetes. Under diabetic conditions, metabolic stressors, including chronic hyperglycemia and lipotoxicity, directly promote PANoptosome assembly by disrupting cellular energy balance, inducing mitochondrial dysfunction, and accumulating reactive oxygen species. Meanwhile, the activation of immune signaling pathways such as TLR/NLR further amplifies the PANoptotic effect, leading to pancreatic β-cell loss, exacerbated adipose tissue inflammation, and vascular endothelial damage, ultimately driving the progression of complications such as nephropathy, retinopathy, and neuropathy. There exists a bidirectional regulation between PANoptosis and immunometabolism: metabolic intermediates such as succinate and lactate can enhance the expression of PANoptosis-related molecules by activating the SUCNR1-NF-κB pathway or regulating histone lactylation; in turn, DAMPs released by PANoptosis, such as HMGB1 and IAPP, reshape the metabolic phenotype of immune cells by activating TLR/RAGE signaling. This review systematically synthesizes the immunometabolic regulatory mechanisms of PANoptosis in diabetes and its complications, clarifies its cell-specific roles in β-cells, immune cells, and vascular tissues, and evaluates therapeutic strategies targeting the metabolic-immune crosstalk axis and core PANoptotic components, providing new theoretical basis and potential targets for precision intervention in diabetes and its complications.

The involvement of gut microbiota in metabolic disorders, including gallstones, has been increasingly reported, mainly focusing on the study of gut bacteria. However, as a relatively small proportion of intestinal microorganisms, the homeostasis of fungi still plays an important role in maintaining the health of the body. Our study showed that compared with healthy volunteers, patients with gallstones showed intestinal fungal dysregulation, which was marked by increased fungal biodiversity and changes in composition. At the same time, patients with gallstones also showed changes in fungal-bacterial interactions. In order to determine the role of intestinal fungal dysbiosis in gallstone formation, we administered fluconazole (a broad-spectrum antifungal drug) to C57 mice on a lithogenic diet and found that the formation of gallstones in mice treated with fluconazole was reduced. We then gavaged mice with Rhodotorula mucilaginosa and discovered that it can promote gallstone formation. Further analysis, including liver metabolism determination, liver immunohistochemistry and immunofluorescence, revealed that intestinal fungi promoted liver neutrophil infiltration and neutrophil extracellular trap formation to aggravate gallstone formation. In addition, through liver transcriptome sequencing, we found that the effect of fluconazole on intestinal fungi may hinder the formation of gallstones by regulating multiple targets related to gallstones. In summary, our study determined the role of intestinal fungal disorders in promoting gallstone formation, and fluconazole can effectively inhibit gallstone formation.

Flap transplantation is a widely used for wound reconstruction but continues to carry a substantial risk of postoperative necrosis. We evaluated the therapeutic effect of phillyrin for improving flap survival and elucidated its underlying pharmacological mechanisms. In vivo, a McFarlane flap model was established on the dorsal skin of rats. Animals were assigned to four groups: control, low-dose (17.5mg/kg/day, intraperitoneal [i.p.]), medium-dose (35mg/kg/day, i.p.), and high-dose (70mg/kg/day, i.p.) phillyrin. At 7 days postoperatively, we evaluated flap survival, blood perfusion, oxidative stress, cytokine expression, toll-like receptor 4/nuclear factor κB/NOD-like receptor protein 3 (TLR4/NF-κB/NLRP3) axis activity, and pyroptosis. In vitro, human umbilical vein endothelial cells were treated with hypoxia/reoxygenation or lipopolysaccharide/nigericin models, to investigate the protective effects of phillyrin against inflammation-related pyroptotic injury. Phillyrin improved flap survival, significantly enhanced local blood perfusion, reduced neutrophil infiltration, and mitigated oxidative stress. Its mechanism of action is closely associated with the inhibition of the TLR4/NF-κB/NLRP3 axis: phillyrin significantly downregulated pathway activity, reduced cytokines secretion, and decreased the expression of pyroptosis-related effector proteins. In vitro, phillyrin demonstrated anti-inflammatory and anti-pyroptotic cytoprotective effects in H/R and inflammatory injury models by modulating the TLR4/NF-κB/NLRP3 axis. Phillyrin improves flap survival by inhibiting the TLR4/NF-κB/NLRP3 signaling pathway, suppressing excessive inflammation and alleviating ischemia-reperfusion injury.

Despite the crucial role of antigen presentation in immune checkpoint inhibitor (ICI) efficacy, its contribution and the mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear, representing a key knowledge gap in overcoming immune escape in its immunotherapy. This study explores how tumor antigen presentation and intercellular interactions in the tumor microenvironment (TME) drive ICI resistance using single-cell RNA sequencing (scRNA-seq). Publicly available scRNA-seq data from 24 ESCC patients treated with chemotherapy and ICIs were analyzed. Cell clustering, transcription factor regulation, cell-cell communication analysis, and KEGG/GO enrichment analyses were used to examine malignant cell heterogeneity, the relationship between antigen-presenting cells and ICI responses, and cell-cell interactions influencing anti-tumor response. Spatial relationships were validated through multiplex immunofluorescence. Malignant cells were classified by enrichment analyses into cNMF_1, cNMF_2, cNMF_3, and cNMF_4, with cNMF_4 showing antigen-presenting traits. Based on ICI response groups, cell-cell communication analysis revealed that in poor responders, the antigen presentation ability of tumors induced by treatment was enhanced, and mainly enriched in the MHC-I pathway. The crosstalk between Progenitor CD8+ Tex and hyper-Treg in the TME drove ICI resistance. Hyper-Treg likely regulated CD8+ T activation through the CLEC2C-KLRB1 axis, forming an inhibitory cell interaction network dominated by hyper-Treg, resulting in an overall strong immune suppression state of the TME in this population. The antigen-presenting malignant epithelial cells of ESCC exhibit significant interactions with various T cells in the TME. ICI resistance is closely associated with the crosstalk between progenitor CD8+ Tex and hyper-Treg, representing a promising target for personalized ESCC therapy.