Oral squamous cell carcinoma (OSCC) represents a significant global health challenge, characterized by aggressive progression and poor therapeutic response despite advances in treatment modalities. This review provides a comprehensive analysis of diverse cell death mechanisms in OSCC, encompassing traditional pathways (apoptosis, autophagy, and necrosis), newly characterized mechanisms (ferroptosis, pyroptosis, and necroptosis), and emerging pathways (cuproptosis, anoikis, parthanatos, and entosis). By examining the molecular basis of these pathways, particularly the crucial roles of p53 signaling and miRNA regulation, we highlight how their dysregulation contributes to treatment resistance and tumor progression. The review synthesizes recent evidence demonstrating the complex interplay between these ten distinct cell death mechanisms and their impact on the tumor microenvironment and immune response. We evaluate innovative therapeutic approaches that target these pathways, including novel small molecules, combination strategies, and immunomodulatory treatments that exploit specific cell death mechanisms to enhance therapeutic efficacy. Special attention is given to emerging personalized medicine strategies that consider individual tumor characteristics and cell death pathway profiles. By integrating current challenges with future research directions, this review provides a framework for developing more effective treatments that can leverage multiple cell death pathways to overcome therapy resistance and improve outcomes for oral cancer patients.

In response to cellular perturbations, a multimeric cytosolic protein complex known as the NLRP3 inflammasome assembles. As a result of this assembly, caspase-1 is activated, which encourages inflammatory cell death (pyroptosis) as well as the maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Tumor etiology involves dysregulation of NLRP3 inflammasome activation, but because of conflicting results, its significance in the onset and spread of cancer is still up for debate. New research indicates that long-non coding RNAs (lncRNAs) play a crucial part in controlling the activity of the NLRP3 inflammasome in a number of disorders. Non-coding RNAs longer than 200 nucleotides are known as lncRNAs. Cancer development has been connected to its deregulation in the development of illnesses. Growing data suggests that controlling lncRNAs on the NLRP3 inflammasome plays a crucial role in the emergence and progression of cancer-related challenges. Here, we discuss over how lncRNAs control the NLRP3 inflammasome and how it functions in different types of cancer cells, offering new perspectives on creating new cancer treatment strategies in the future.

Skeletal muscle atrophy is a major comorbidity associated with chronic obstructive pulmonary disease caused by exposure to cigarette smoke (CS). CS-activated macrophages and pyroptosis play an important role in skeletal muscle atrophy, but its specific molecular mechanism remains unclear. This study investigated the role and mechanisms of pyroptosis and activated macrophages in CS-induced skeletal muscle atrophy.

In the in vivo model, mice were exposed to either CS or air for 24 weeks, and in the in vitro model, C2C12 murine skeletal muscle cells were co-cultured with macrophages in Transwell chambers. Western blotting, real-time PCR, ELISA, and other methods were used to detect pyroptosis-related markers to investigate the mechanism of CSE-activated macrophages on skeletal muscle atrophy and pyroptosis.

In vivo, CS-induced atrophy of the mouse gastrocnemius muscle was accompanied by increased expression of pyroptosis-related markers, including NLRP3 inflammasome, cleaved Caspase-1, the GSDMD N-terminal domain, and interleukin (IL)-18. In vitro, CS extract (CSE)-activated macrophages mediates pyroptosis of skeletal muscle cells and induces myotube atrophy. Further studies demonstrated that macrophage-derived TNF-α is the initiating factor of skeletal muscle pyroptosis, and this process appears to be mediated through TNF-α activating the TNFR1/NLRP3/caspase-1/GSDMD signaling pathway.

TNF-α released by CSE-activated macrophages can promote skeletal muscle pyroptosis by activating the TNFR1/NLRP3/Caspase-1/GSDMD signaling pathway, which likely contributes to skeletal muscle atrophy. These findings provide more insight into the mechanisms underlying skeletal muscle atrophy in COPD.

The designability and high reactivity of nanotechnology provide strategies for antitumor therapy by regulating the redox state in tumor cells. Here, we synthesize a kind of vanadium dioxide nanoparticle encapsulated in bovine serum albumin and containing disulfide bonds (VSB NPs) for photothermal-enhanced ferroptosis and pyroptosis effects. Mechanism studies show that disulfide bonds can effectively consume overexpressed glutathione (GSH) in the tumor microenvironment, leading to a decrease in glutathione peroxidase 4 (GPX4) activity. Simultaneously, tetravalent vanadium can induce a catalytic reaction of overexpressed H2O2, producing plenty of toxic hydroxyl radicals (·OH) and singlet oxygen (1O2), leading to tumor cell ferroptosis. In addition, the consumption of disulfide bonds can also lead to the degradation of nanoparticles into high-valent vanadates, activating thermal protein domain-associated protein 3 (NLRP3) inflammasomes and causing tumor cell pyroptosis. It is worth mentioning that VSB NPs can not only ablate tumor cells under near-infrared light irradiation but also further disrupt the redox homeostasis of the tumor microenvironment, thereby enhancing the ferroptosis and pyroptosis of tumor cells induced by biodegradable vanadium-based nanomaterials. This strategy, based on the biological effects of vanadium to regulate the redox state in tumor cells, provides possibilities for cancer treatment.

Ulcerative colitis (UC) can cause severe oxidative stress in the colon, which can lead to tissue damage and an imbalance in the normal gut microbiota. Ellagic acid (EA) is one of the main types of plant polyphenols with improved pharmacological effects such as antioxidant, anti-inflammatory, and antibacterial properties. However, currently, the studies on the impact of EA on the gut microbiota and its potential to alleviate UC in mice through the ROS/NLRP3 pathway are limited. In this study, dextran sodium sulfate (DSS) was used to construct a UC mouse model, which was then treated with EA as an intervention for UC. The results revealed that EA alleviated the trend of liver, spleen, and weight changes in UC mice and improved colon oxidative stress, inflammation, and pathological damage. Mechanistically, DSS-induced UC indicated a significant increase in ROS/NLRP3 pathway-related factors, whereas EA intervention activated the Nrf2 pathway to reduce these factors. Furthermore, the DSS group had a reduced abundance of Firmicutes (59.02%) and an increased abundance of Bacteroides and Proteobacterium by 1.8 times and 10.16%; however, EA intervention reversed these changes, thus alleviating UC. The findings of this study revealed that EA could significantly enhance the composition of gut microbiota in UC and reduce the inflammatory response, colonic damage as well as oxidative stress caused by DSS by regulating the ROS/NLRP3 pathway. These results provide novel perspectives on the prevention and treatment strategies of UC and highlight the therapeutic benefits of EA in managing colitis.

Inflammation assumes a vital role in the pathogenesis of depression and in antidepressant treatment. Paeoniflorin (PF), a monoterpene glycoside analog possessing anti-inflammatory attributes, exhibits therapeutic efficacy on depression-like behavior in mice. The objective of this study was to evaluate the antidepressant effects of PF on depression elicited by the chronic unpredictable mild stress (CUMS) model and the precise neural sequence associated with the inflammatory process. In this study, we established an in vivo mouse model induced by CUMS and an in vitro BV2 cell model induced by LPS+ATP. The mechanism of PF for depression was assessed by the SIRT1 selective inhibitor EX-527. The findings demonstrated that PF significantly alleviated the damage of BV2 cells treated with LPS and ATP, inhibited the generation of ROS, up-regulated the expression of SIRT1 mRNA, and down-regulated the expression of nuclear NF-κB, p65, NLRP3, Caspase-1 and GSDMD-N in vitro. In vivo, PF mitigated the depressive-like behavior induced by CUMS, reduced the number of neurons, and decreased the secretion of pro-inflammatory factors IL-1β, IL-6, and TNF-α in the hippocampus. Immunohistochemical results indicated that PF attenuated CUMS-induced hyperactivation of microglia. Moreover, the expression level of SIRT1 in the hippocampus was augmented, while the protein levels of NF-κB, p65, NLRP3, Caspase-1, IL-1β and GSDMD-N were diminished after PF treatment. Additionally, the selective inhibition of SIRT1 attenuated the therapeutic effect of PF on depression. These results imply that PF possesses antidepressant properties that rely on SIRT1 signaling to regulate NLRP3 inflammasome inactivation.

Pyroptosis plays an important role in lung adenocarcinoma (LUAD). In this study, we aimed to explore the pyroptosis-related gene (PRG) expression pattern and to identify promising pyroptosis-related biomarkers to improve the prognosis of LUAD. The gene expression profiles and clinical information of LUAD patients were downloaded from the Cancer Genome Atlas (TCGA), and validation cohort information was extracted from the Gene Expression Omnibus database. Gene expression data were analyzed using the limma package and visualized using the ggplot2 package as well as the pheatmap package in R software. Functional enrichment analysis was also performed for the 44 differentially expressed PRGs (DEPRGs). Then, consensus clustering revealed pyroptosis-related tumor subtypes, and differentially expressed genes (DEGs) were screened according to the subtypes. Next, univariate Cox and multivariate Cox regression analyses were used to identify independent prognostic PRGs. After overlapping DEGs and the Lasso regression analysis-based prognostic genes, the predictive risk model was established and validated. Correlation analysis between PRGs and clinicopathological variables was also explored. Finally, the TIMER and TISIDB databases were used to further explore the correlation analysis between immune cell infiltration levels, the risk score, and clinicopathological variables in the predictive risk model. A total of 52 genes from the PubMed were identified as PRGs, and 44 of the 52 genes were pooled as DEPRGs. The most significant GO term was "collagen trimer" (P = 2.46E-13), and KEGG analysis results indicated that 44 DEPRGs were significantly enriched in Salmonella infection (P < 0.001). Then, consensus clustering analysis divided LUAD patients into two clusters, and a total of 79 DEGs were identified according to these cluster subtypes. Subsequently, univariate and multivariate Cox regression analyses were used to identify 12 genes that could serve as independent prognostic indicators and we also performed Lasso regression analysis and screened 23 DEGs. After overlapping 23 DEGs and 12 genes, only 4 (KLRG2, MAPK4, C6 and SFRP5) of 12 genes were selected for the further exploration of the prognostic pattern. Survival analysis results indicated that this risk model effectively predicted the prognosis (P < 0.001). Combined with the correlation analysis results between the 4 genes and clinicopathological variables, C6 and KLRG2 were screened as prognostic genes. In this study, we constructed a predictive risk model and identified two pyroptosis subtype-related gene expression patterns to improve the prognosis of LUAD. Understanding the subtypes of LUAD is helpful for accurately characterizing the LUAD and developing personalized treatment.

Myelodysplastic syndrome (MDS) holds a unique position among blood cancers, encompassing a spectrum of blood-related disorders marked by impaired maturation of blood cell precursors, bone marrow abnormalities, genetic instability, and a higher likelihood of progressing to acute myeloid leukemia. MicroRNAs (miRNAs), short non-coding RNA molecules typically 18-24 nucleotides in length, are known to regulate gene expression and contribute to various biological processes, including cellular differentiation and programmed cell death. Additionally, miRNAs are involved in many aspects of cancer development, influencing cell growth, transformation, and apoptosis. In this study, we explore the impact of microRNAs on cellular apoptosis in MDS.

Gallbladder polypoid lesions (GPLs) refer to any elevated lesion of the mucosal surface of the gallbladder wall, and the prevalence is estimated to be between 0.9% and 12.1%. GPLs include benign polyps and malignant polyps. Benign polyps are further classified as non-neoplastic polyps and neoplastic polyps. Cholesterol polyps are the most common benign polyps and adenocarcinoma is the main type of malignant polyp. Hepatitis B virus infection, liver function abnormalities, dyslipidemia, and obesity are the main risk factors for GPLs. Studies of biological mechanisms have focused on malignant gallbladder polyps, the development of which is regulated by hormone levels in vivo , gut microbiota, inflammation, oxidative stress, Salmonella typhimurium , and related molecules. Diagnostic modalities include chemical examination and imaging examination, with imaging examination currently being the mainstay. Treatment of patients with GPLs is based on the presence or absence of symptoms, age, size of the polyps, tendency of the polyp to increase, and risk factors for symptomatic malignancy to determine whether surgery should be performed.

Gingival epithelial cells (GECs) are physical and immunological barriers against outward pathogens while coping with a plethora of non-pathogenic commensal bacteria. GECs express several members of Toll-like receptors (TLRs) and control subsequent innate immune responses. TLR4 senses lipopolysaccharide (LPS) while TLR7/8 recognizes single-strand RNA (ssRNA) playing important roles against viral infection. However, their distinct roles in GECs have not been fully demonstrated. Here, we analyzed biological responses of GECs to  LPS and CL075, a TLR7/8 agonist. GE1, a mouse gingival epithelial cell line, constitutively express TLR4 and TLR7, but not TLR8, like primary skin keratinocytes. Stimulation of GE1 cells with CL075 induced cytokine, chemokine, and antimicrobial peptide  expressions, the pattern of which is rather different from that with LPS: higher mRNA levels of interferon (IFN) β, CXCL10, and β-defensin (BD) 14 (mouse homolog of human BD3); lower levels of tumor necrosis factor (TNF), CCL5, CCL11, CCL20, CXCL2, and CX3CL1. As for the intracellular signal transduction of GE1 cells, CL075 rapidly induced significant AKT phosphorylation but failed to activate IKKα/β-NFκB pathway, whereas LPS induced marked IKKα/β-NFκB activation without significant AKT phosphorylation. In contrast, both CL075 and LPS induced rapid IKKα/β-NFκB activation and AKT phosphorylation in a macrophage cell line. Furthermore, specific inhibition of AKT activity abrogated CL075-induced IFNβ, CXCL10, and BD14 mRNA expression in GE1 cells. Thus, TLR4/7 ligands appear to induce rather different host-defense responses of GECs through distinct intracellular signaling mechanisms.

We aimed to screen novel gene signatures for ovarian cancer (OC) and explore the role of biomarkers in OC via regulating pyroptosis using bioinformatics analysis.

Differentially expressed genes (DEGs) of OC were screened from GSE12470 and GSE16709 datasets. Hub genes were determined from protein-protein interaction networks after bioinformatics analysis. The role of Centromeric protein M (CENPM) in OC was assessed by subcutaneous tumor experiment using hematoxylin-eosin and immunohistochemical staining. Tumor metastasis was evaluated by detecting epithelial-mesenchymal transition-related proteins. The proliferation, migration, and invasion were determined using cell counting kit and transwell assay. Enzyme-linked immunosorbent assay was applied to measure inflammatory factors. The mRNA and protein expression were detected using real-time quantitative PCR and western blot.

We determined 9 hub genes (KIFC1, PCLAF, CDCA5, KNTC1, MCM3, OIP5, CENPM, KIF15, and ASF1B) with high prediction value for OC. In SKOV3 and A2780 cells, the expression levels of hub genes were significantly up-regulated, compared with normal ovarian cells. CENPM was selected as a key gene. Knockdown of CENPM suppressed proliferation, migration, and invasion of OC cells. Subcutaneous tumor experiment revealed that CENPM knockdown significantly suppressed tumor growth and metastasis. Additionally, pyroptosis was promoted in OC cells and xenograft tumors after CENPM knockdown. Furthermore, CENPM knockdown activated cGAS-STING pathway and the pathway inhibitor reversed the inhibitory effect of CENPM knockdown on viability, migration, and invasion of OC cells.

CENPM was a novel biomarker of OC, and knockdown of CENPM inhibited OC progression by promoting pyroptosis and activating cGAS-STING pathway.

The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.

Duodenogastric reflux (DGR) has been linked to the onset of gastric cancer (GC), although the precise mechanism is yet obscure. Herein, we aimed to investigate how refluxed bile acids (BAs) and macrophages are involved in gastric carcinogenesis. In both active human bile reflux gastritis and the murine DGR model, ubiquitin specific protease 50 (USP50) was dramatically raised, and macrophages were the principal leukocyte subset that upregulated USP50 expression. Enhancing USP50 expression amplified bile acid-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and subsequent high-mobility group box protein 1 (HMGB1) release, while USP50 deficiency resulted in the reversed alteration. Mechanistically, USP50 interacted with and deubiquitinated apoptosis-associated speck-like protein containing CARD (ASC) to activate NLRP3 inflammasome. The release of HMGB1 contributes to gastric tumorigenesis by PI3K/AKT and MAPK/ERK pathways. These results may provide new insights into bile reflux-related gastric carcinogenesis and options for the prevention of DGR-associated GC.

Aging is a risk factor for disease via increased susceptibility to infection, decreased ability to maintain homeostasis, inefficiency in combating stress, and decreased regenerative capacity. Multiple diseases, including urinary tract infection (UTI), are more prevalent with age; however, the mechanisms underlying the impact of aging on the urinary tract mucosa and the correlation between aging and disease remain poorly understood. Here, we show that, relative to young (8-12 weeks) mice, the urothelium of aged (18-24 months) female mice accumulates large lysosomes with reduced acid phosphatase activity and decreased overall autophagic flux in the aged urothelium, indicative of compromised cellular homeostasis. Aged bladders also exhibit basal accumulation of reactive oxygen species (ROS) and a dampened redox response, implying heightened oxidative stress. Furthermore, we identify a canonical senescence-associated secretory phenotype (SASP) in the aged urothelium, along with continuous NLRP3-inflammasome- and Gasdermin-D-dependent pyroptotic cell death. Consequently, aged mice chronically exfoliate urothelial cells, further exacerbating age-related urothelial dysfunction. Upon infection with uropathogenic E. coli, aged mice harbor increased bacterial reservoirs and are more prone to spontaneous recurrent UTI. Finally, we discover that treatment with D-mannose, a natural bioactive monosaccharide, rescues autophagy flux, reverses the SASP, and mitigates ROS and NLRP3/Gasdermin/interleukin (IL)-1β-driven pyroptotic epithelial cell shedding in aged mice. Collectively, our results demonstrate that normal aging affects bladder physiology, with aging alone increasing baseline cellular stress and susceptibility to infection, and suggest that mannose supplementation could serve as a senotherapeutic to counter age-associated urothelial dysfunction.

Immunotherapy is a promising and safer alternative to conventional cancer therapies. It involves adaptive T-cell therapy, cancer vaccines, monoclonal antibodies, immune checkpoint blockade (ICB), and chimeric antigen receptor (CAR) based therapies. However, most of these modalities encounter restrictions in solid tumours owing to a dense, highly hypoxic and immune-suppressive microenvironment as well as the heterogeneity of tumour antigens. The elevated intra-tumoural pressure and mutational rates within fastgrowing solid tumours present challenges in efficient drug targeting and delivery. The tumour microenvironment is a dynamic niche infiltrated by a variety of immune cells, most of which are macrophages. Since they form a part of the innate immune system, targeting macrophages has become a plausible immunotherapeutic approach. In this review, we discuss several versatile approaches (both at pre-clinical and clinical stages) such as the direct killing of tumour-associated macrophages, reprogramming pro-tumour macrophages to anti-tumour phenotypes, inhibition of macrophage recruitment into the tumour microenvironment, novel CAR macrophages, and genetically engineered macrophages that have been devised thus far. These strategies comprise a strong and adaptable macrophage-toolkit in the ongoing fight against cancer and by understanding their significance, we may unlock the full potential of these immune cells in cancer therapy.

The NLRP3 inflammasome is an intracellular sensor and an essential component of the innate immune system involved in danger recognition. An important hallmark of inflammasome activation is the formation of a single supramolecular punctum, known as a speck, per cell, which is the site where the pro-inflammatory cytokines IL-1β and IL-18 are converted into their bioactive form. Speck also provides the platform for gasdermin D protein activation, whose N-terminus domain perforates the plasma membrane, allowing the release of mature cytokines alongside with a highly inflammatory form of cell death, namely pyroptosis. Although controlled NLRP3 inflammasome-pyroptosis pathway activation preserves mucosal immunity homeostasis and contributes to host defense, a prolonged trigger is deleterious and could lead, in genetically predisposed subjects, to the onset of inflammatory bowel disease, including Crohn's disease and ulcerative colitis, as well as to gastrointestinal cancer. Experimental evidence shows that the NLRP3 inflammasome has both protective and pathogenic abilities. In this review we highlight the impact of the NLRP3-pyroptosis axis on the pathophysiology of the gastrointestinal tract at molecular level, focusing on newly discovered features bearing pro- and anti-inflammatory and neoplastic activity, and on targeted therapies tested in preclinical and clinical trials.

The symbiotic bacteria that live in the human gut and the metabolites they produce have long influenced local and systemic physiological and pathological processes of the host. The gut microbiota are increasingly being recognized for its impact on a range of human diseases, including cancer, it may play a key role in the occurrence, progression, treatment, and prognosis of many types of cancer. Understanding the functional role of the gut microbiota in cancer is crucial for the development of the era of personalized medicine. Here, we review recent advances in research and summarize the important associations and clear experimental evidence for the role of the gut microbiota in a variety of human cancers, focus on the application and possible challenges associated with the gut microbiota in antitumor therapy. In conclusion, our research demonstrated the multifaceted mechanisms of gut microbiota affecting human cancer and provides directions and ideas for future clinical research.