One of the hottest topics in biomedical research is to decipher the functional implications of the Gasdermin (GSDM) protein family in human pathologies. These proteins are the key effectors of a lytic and pro-inflammatory cell death type termed pyroptosis (also known as “Gasdermin-mediated programmed cell death”). However, ever-growing evidence showed that GSDMs can play multiple and complex roles in a context-dependent manner. In this sense, Gasdermin-B (GSDMB; the only GSDM gene absent in mice and rats) has been implicated in antibacterial defense, numerous inflammatory pathologies (e.g., asthma, ulcerative colitis) and cancer, but both cell death-dependent and independent functions have been reported in these diseases, fueling the debate on whether GSDMB has genuine pyroptotic capacity. Recently, a series of seminal papers cast light on the GSDMB multitasking capacity by showing that different GSDMB transcriptional isoforms have distinct biological activities. 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.

中文翻译：

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Gasdermin-B (GSDMB) 在抗菌防御、炎症性疾病和癌症方面占据中心地位

生物医学研究中最热门的话题之一是破译 Gasdermin (GSDM) 蛋白家族在人类病理学中的功能意义。这些蛋白质是称为细胞焦亡（也称为“Gasdermin 介导的程序性细胞死亡”）的溶解性和促炎性细胞死亡类型的关键效应物。然而，越来越多的证据表明，GSDM 可以根据具体情况发挥多种复杂的作用。从这个意义上说，Gasdermin-B（GSDMB；小鼠和大鼠中唯一缺失的 GSDM 基因）与抗菌防御、多种炎症病理（例如哮喘、溃疡性结肠炎）和癌症有关，但其功能既依赖于细胞死亡，也具有独立功能在这些疾病中已有报道，引发了关于 GSDMB 是否具有真正的焦亡能力的争论。最近，一系列开创性论文通过表明不同的 GSDMB 转录异构体具有不同的生物活性，揭示了 GSDMB 的多任务处理能力。尽管如此，关于 GSDMB 翻译变体在生理和病理条件下的精确功能参与，仍有一些模糊的领域需要澄清。从这个角度来看，我们批判性地讨论了有关该主题的最新且令人兴奋的数据，并提出了在 GSDMB 驱动的生物医学应用之前需要克服的一系列相关挑战（作为疾病风险/进展/结果的生物标志物或作为特定的治疗目标） ）在临床环境中成为现实。