GSDMB (Gasdermin B)

Human astrocytes support productive MPXV infection, resulting in inflammatory gene induction with accompanying GSDMB-mediated pyroptosis. These findings clarify the recently recognized neuropathogenic effects of MPXV in humans while also offering potential therapeutic options.

Furthermore, in vivo activation of Hydra caspases resulted in HyGSDME cleavage to induce pyroptosis, exacerbating injury and restricting bacterial burden, which protects Hydra from pathogen invasion. In conclusion, these results suggest that GSDME-dependent pyroptosis may be an ancient and conserved host defense mechanism, which may contribute to better understanding on the origin and evolution of GSDMs.

In conclusion, the findings of the present study indicated that GSDMB, GSDMD and DFNA5 may be considered promising therapeutic agents and potential biomarkers for patients with ccRCC. Furthermore, GSDMB could act as an independent predictor for the OS of patients with ccRCC.

However, it often plays a dual role in these diseases which is a cause for concern and makes it difficult for clinical translation. This review will focus on the multifaceted roles of pyroptosis in respiratory diseases.

The host relies on GSDMs for pathogen defense, tissue tolerance, and cancerous cell death; however, pro-inflammatory milieu caused by pyroptosis and excessive cytokine release may favor the development and progression of inflammatory bowel disease and cancer. Therefore, a thorough understanding of spatiotemporal mechanisms that control gasdermin expression, activation, and function is essential for the development of future therapeutics for intestinal disorders.

These results on pyroptosis-related genes in ccRCC provide a theoretical basis for understanding molecular heterogeneity and for the development of individualized treatment strategies.

By elucidating the complex roles of GSDMB isoforms, this review aims to deepen the understanding of this multifunctional player and its potential implications in disease pathogenesis and therapeutic interventions. [Figure: see text].

Nonetheless, there are still obscure areas to be clarified on the precise functional involvement of GSDMB translated variants in physiological and pathological conditions. In this viewpoint, we critically discuss the most recent and exciting data on this topic and propose a series of relevant challenges that need to be overcome before GSDMB-driven biomedical applications (as a biomarker of disease risk/progression/outcome or as specific therapeutic target) become a reality in clinical settings.

Notably, GSDMB is found to be elevated in Her2-positive gastric cancer cells, providing a rationale for IBI315's efficacy. IBI315 is supported here as a promising bispecific antibody-based immunotherapy approach for Her2-positive gastric cancer in preclinical studies, broadening the therapeutic landscape of this patient population.

Using paired tumor biopsies, we found that tumor-infiltrating immune cells had a reduced expression of inhibitory immune checkpoints (VISTA, PD-1, PD-L2) and an elevated expression of T-cell activation markers (CTLA-4, OX40L) after elraglusib treatment. These results address a significant gap in knowledge concerning the immunomodulatory mechanisms of GSK-3 inhibitor elraglusib, provide a rationale for the clinical evaluation of elraglusib in combination with immune checkpoint blockade, and are expected to have an impact on additional tumor types, besides CRC.

GSDMB and PYCARD are potential targets and effective prognostic biomarkers for the combination of immunotherapy and pyroptosis-targeted therapy in KIRC.

By contrast, the cleavage of GSDMB isoforms by Neutrophil Elastase or caspases produces short N-terminal fragments with no cytotoxic activity, thus suggesting that these proteases act as inhibitory mechanisms of pyroptosis. Summarizing, our results have important implications for understanding the complex roles of GSDMB isoforms in cancer or other pathologies and for the future design of GSDMB-targeted therapies.

GSDMB1-3 were the most abundant isoforms in the tested tumor cell lines and were similarly induced by interferon-γ and the chemotherapy drug methotrexate...Our study indicates that tumors may block and evade killer cell-triggered pyroptosis by generating noncytotoxic GSDMB isoforms. Therefore, therapeutics that favor the production of cytotoxic GSDMB isoforms by alternative splicing may improve antitumor immunity.

Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses showed that GSDMB and its interacting proteins might affect tumor growth through the serine metabolism pathway. Our current results demonstrate a promising therapeutic strategy targeting GSDMB and provide new insights into GSDMB as an immunological and prognostic biomarker for KIRC.

Taken together, our data indicated that anti-HER2 agents could upregulate the expression of GSDME, and the combination of lapatinib and APG-1252 showed a synergistic antitumor effect against HER2-positive gastric cancer through inducing caspase-3/GSDME mediated apoptosis and pyroptosis.