Casp4, also known as caspase-4, is an inflammatory caspase that plays a key role in the non-canonical inflammasome pathway. It functions as an innate immune receptor for intracellular lipopolysaccharide (LPS), and its activation can lead to pyroptosis, a lytic form of cell death. Casp4 is also involved in regulating autophagy and is associated with various biological processes and disease conditions [6,4].

In transgenic hACE2 humanized mice, deficiency of Casp11 (the mouse homologue of human Casp4) protected the mice from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced disease development, with increased pulmonary parenchymal area, reduced clinical score, and lower mortality, indicating that Casp4/11 promotes NLRP3 activation and disease pathology in COVID-19 [1]. In brain endothelial cells of mice, Casp11 activation mediates blood-brain barrier (BBB) breakdown in response to circulating LPS or during LPS-induced sepsis. In CASP4-humanized mice, Gram-negative Klebsiella pneumoniae infection disrupts the BBB [2]. In gliomas, high expression of CASP4 is associated with a significantly lower survival rate, and it can influence immune cell infiltration, suggesting it could be a diagnostic biomarker and therapeutic target [3]. In renal cell carcinoma, high expression of CASP4 is associated with higher pathological staging and poorer prognosis, and it is identified as an autophagy-pyroptosis-related gene [5].

In conclusion, Casp4 is crucial in the non-canonical inflammasome pathway, pyroptosis, autophagy, and immune-related processes. Studies using gene knockout (KO) or conditional knockout (CKO) mouse models, such as Casp11-deficient mice, have revealed its role in diseases like COVID-19, central nervous system diseases related to BBB impairment, gliomas, and renal cell carcinoma, providing potential targets for therapeutic interventions.