Pyroptosis is a type of programmed necrosis triggered by the detection of pathogens or endogenous danger signals in the cytosol. Pyroptotic cells exhibit a swollen, enlarged morphology and ultimately Show more
Pyroptosis is a type of programmed necrosis triggered by the detection of pathogens or endogenous danger signals in the cytosol. Pyroptotic cells exhibit a swollen, enlarged morphology and ultimately undergo lysis, releasing their cytosolic contents - such as proteins, metabolites, and nucleic acids - into the extracellular space. These molecules can function as danger-associated molecular patterns (DAMPs), triggering inflammation when detected by neighboring cells. Mechanistically, pyroptosis is initiated by members of the gasdermin protein family, which were identified a decade ago as pore-forming executors of cell death. Mammalian gasdermins consist of a cytotoxic N-terminal domain, a flexible linker, and a C-terminal regulatory domain that binds to and inhibits the N-terminus. Proteolytic cleavage within the linker releases the N-terminal domain, enabling it to target various cellular membranes, including nuclear, mitochondrial, and plasma membranes, where it forms large transmembrane pores. Gasdermin pores in the plasma membrane disrupt the electrochemical gradient, leading to water influx and cell swelling. Their formation also activates the membrane protein ninjurin-1 (NINJ1), which oligomerizes to drive complete plasma membrane rupture and the release of large DAMPs. Since their discovery as pore-forming proteins, gasdermins have been linked to pyroptosis not only in host defense but also in various pathological conditions. This review explores the history of pyroptosis, recent insights into gasdermin activation, the cellular consequences of pore formation, and the physiological roles of pyroptosis. Show less
Non‑small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite sig Show more
Non‑small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite significant advances in targeted therapy and immunotherapy, the overall prognosis of patients with NSCLC remains poor. Hypoxia is a critical driving factor in tumor progression, influencing the biological behavior of tumor cells through complex molecular mechanisms. The present review systematically examined the role of the hypoxic microenvironment in NSCLC, demonstrating its crucial role in promoting tumor cell growth, invasion and metastasis. Additionally, it has been previously reported that the hypoxic microenvironment enhances tumor cell resistance by activating hypoxia‑inducible factor and regulating exosome secretion. The hypoxic microenvironment also enables tumor cells to adapt to low oxygen and nutrient‑deficient conditions by enhancing metabolic reprogramming, such as through upregulating glycolysis. Further studies have shown that the hypoxic microenvironment facilitates immune escape by modulating tumor‑associated immune cells and suppressing the antitumor response of the immune system. Moreover, the hypoxic microenvironment increases tumor resistance to radiotherapy, chemotherapy and other types of targeted therapy through various pathways, significantly reducing the therapeutic efficacy of these treatments. Therefore, it could be suggested that early detection of cellular hypoxia and targeted therapy based on hypoxia may offer new therapeutic approaches for patients with NSCLC. The present review not only deepened the current understanding of the mechanisms of action and role of the hypoxic microenvironment in NSCLC but also provided a solid theoretical basis for the future development of precision treatments for patients with NSCLC. Show less