FABP4 in macrophages facilitates obesity-associated pancreatic cancer progression via the NLRP3/IL-1β axis

Obesity is an essential risk factor for pancreatic Cancer (PC). Macrophage-induced inflammation plays a pivotal role in obesity-associated carcinogenesis and disease progression; however, the underlying molecular mechanisms remain unclear. In this study, we found that fatty acid-binding protein 4 (FABP4) overexpressed in serum of obese patients and was associated with poor overall survival. In vivo and in vitro experiments have revealed that FABP4 induces macrophage-related inflammation to promote Cancer cell migration, invasion and metastasis under obese condition. Mechanistically, FABP4 participates in transferring saturated fatty acid to induce macrophages Pyroptosis in a Caspase-1/GSDMD-dependent manner and mediates NOD-like Receptor thermal protein domain associated protein 3 (NLRP3)/IL-1β axis in macrophages, which further regulates epithelial-mesenchymal transition signals to promote the migration, invasion, and metastasis of PC cells. Our results suggest that FABP4 in macrophages is a crucial regulator of the NLRP3/IL-1β axis to promote the progression of PC under obese conditions, which could act as a promising molecular target for treating of PC patients with obesity.

FABP4; Inflammation; Macrophage; Obesity; Pancreatic cancer; Pyroptosis.