Nonresolving
inflammation in the intestine predisposes individuals to the development of
colitis-associated cancer (CAC).
Inflammasomes are thought to mediate intestinal homeostasis, and their dysregulation contributes to
inflammatory bowel diseases and CAC. However, few agents have been reported to reduce CAC by targeting
inflammasomes. Here we show that the small molecule
andrographolide (Andro) protects mice against
azoxymethane/
dextran sulfate sodium-induced colon
carcinogenesis through inhibiting the NLRP3
inflammasome. Administration of Andro significantly attenuated
colitis progression and
tumor burden. Andro also inhibited NLRP3
inflammasome activation in macrophages both in vivo and in vitro, as indicated by reduced expression of cleaved CASP1, disruption of NLRP3-PYCARD-CASP1 complex assembly, and lower IL1B secretion. Importantly, Andro was found to trigger mitophagy in macrophages, leading to a reversed mitochondrial membrane potential collapse, which in turn inactivated the NLRP3
inflammasome. Moreover, downregulation of the PIK3CA-AKT1-MTOR-RPS6KB1 pathway accounted for Andro-induced autophagy. Finally, Andro-driven inhibition of the NLRP3
inflammasome and amelioration of murine models for
colitis and CAC were significantly blocked by BECN1 knockdown, or by various autophagy inhibitors. Taken together, our findings demonstrate that mitophagy-mediated NLRP3
inflammasome inhibition by Andro is responsible for the prevention of CAC. Our data may help guide decisions regarding the use of Andro in patients with
inflammatory bowel diseases, which ultimately reduces the risk of CAC.