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

Jian Yang; Shujie Liu; Yongzheng Li; Zhiyao Fan; Yufan Meng; Bin Zhou; Guangyong Zhang; Hanxiang Zhan

doi:10.1016/j.canlet.2023.216403

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

Cancer Lett. 2023 Oct 28:575:216403. doi: 10.1016/j.canlet.2023.216403. Epub 2023 Sep 21.

Authors

Jian Yang¹, Shujie Liu¹, Yongzheng Li¹, Zhiyao Fan¹, Yufan Meng¹, Bin Zhou², Guangyong Zhang³, Hanxiang Zhan⁴

Affiliations

¹ Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, China.
² Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China.
³ Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, China. Electronic address: guangyongzhang@hotmail.com.
⁴ Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, China. Electronic address: zhanhanxiang@hotmail.com.

PMID: 37741433
DOI: 10.1016/j.canlet.2023.216403

Abstract

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 conditions. 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.

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