The activation of the pyrin inflammasome is a critical mechanism employed by the innate immune system to combat pathogenic agents. Pyrin, a protein encoded by the *MEFV* gene, plays a central role in various autoinflammatory diseases (AIDs), including familial Mediterranean fever (FMF). The activation of the pyrin inflammasome is dependent on molecular processes that alter homeostasis, primarily involving the disruption of RhoA GTPases by pathogen toxins. Key regulatory pathways include the phosphorylation of specific pyrin residues by kinases PKN1/2 and the binding of the chaperone 14-3-3. The cytoskeleton and gasdermin D also play crucial roles in pyrin activation, with gasdermin D forming pores in the context of pyroptosis. Recent evidence highlights the involvement of steroid hormone catabolites and alarmins S100A8/A9 and S100A12 in pyrin-dependent inflammation. This review provides a comprehensive overview of the molecular pathways and clinical manifestations associated with the pyrin inflammasome, focusing on the correlation between these pathways and AIDs. The *MEFV* gene, located on chromosome 16p13.3, encodes the pyrin protein, which is composed of four main functional domains: the N-terminal pyrin domain (PYD), the zinc finger domain (B-box), the α-helical coiled-coil domain (CC), and the C-terminal domain (B30.2/SPRY). Each domain has specific roles in the activation and regulation of the pyrin inflammasome. The review also discusses the importance of the cytoskeleton and actin filaments in pyrin regulation, as well as the role of pyroptosis, gasdermin D, and alarmins in pyrin activation. Finally, the clinical features and management of pyrin-related inflammasomopathies, such as FMF, pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND), and mevalonate kinase-related disorders (MKD and porokeratosis), are discussed.The activation of the pyrin inflammasome is a critical mechanism employed by the innate immune system to combat pathogenic agents. Pyrin, a protein encoded by the *MEFV* gene, plays a central role in various autoinflammatory diseases (AIDs), including familial Mediterranean fever (FMF). The activation of the pyrin inflammasome is dependent on molecular processes that alter homeostasis, primarily involving the disruption of RhoA GTPases by pathogen toxins. Key regulatory pathways include the phosphorylation of specific pyrin residues by kinases PKN1/2 and the binding of the chaperone 14-3-3. The cytoskeleton and gasdermin D also play crucial roles in pyrin activation, with gasdermin D forming pores in the context of pyroptosis. Recent evidence highlights the involvement of steroid hormone catabolites and alarmins S100A8/A9 and S100A12 in pyrin-dependent inflammation. This review provides a comprehensive overview of the molecular pathways and clinical manifestations associated with the pyrin inflammasome, focusing on the correlation between these pathways and AIDs. The *MEFV* gene, located on chromosome 16p13.3, encodes the pyrin protein, which is composed of four main functional domains: the N-terminal pyrin domain (PYD), the zinc finger domain (B-box), the α-helical coiled-coil domain (CC), and the C-terminal domain (B30.2/SPRY). Each domain has specific roles in the activation and regulation of the pyrin inflammasome. The review also discusses the importance of the cytoskeleton and actin filaments in pyrin regulation, as well as the role of pyroptosis, gasdermin D, and alarmins in pyrin activation. Finally, the clinical features and management of pyrin-related inflammasomopathies, such as FMF, pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND), and mevalonate kinase-related disorders (MKD and porokeratosis), are discussed.