Yuhang Wang, Sivakumar Lingappa, Zizhen Kang
The NLRC4 inflammasome is a cytosolic immune sensor that detects bacterial virulence structures and rapidly initiates inflammatory responses. While tightly regulated NLRC4 activation is essential for host defense, genetic mutations that enhance NLRC4 signaling can drive severe autoinflammatory disease. Studies in patients and genetically engineered mouse models have begun to reveal how dysregulated NLRC4 activation disrupts intestinal and systemic immune homeostasis. This review summarizes current insights into NLRC4-associated autoinflammatory diseases, with particular emphasis on the mechanisms underlying autoinflammation with infantile enterocolitis, and highlights emerging concepts related to disease heterogeneity and therapeutic targeting. This mini-review summarizes how dysregulated NLRC4 inflammasome activation disrupts immune homeostasis, driving autoinflammation with enterocolitis, and discusses disease mechanisms, variability, and therapeutic approaches.