Adipocyte-derived FABP4 promotes metabolism-associated steatotic liver–induced hepatocellular carcinoma by driving ITGB1-mediated β-catenin activation

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Abstract

Metabolic dysfunction–associated steatotic liver disease–induced (MASLD-induced) hepatocellular carcinoma (HCC) is an emerging malignancy linked to excessive accumulation of adipose tissue and hepatic fat. Understanding the role of adipocytes in the development of MASLD-induced HCC is crucial. In an in vitro coculture system, differentiated adipocytes were found to enhance cancer stemness and drug resistance in HCC through paracrine signaling. Fatty acid–binding protein 4 (FABP4) was preferentially secreted by adipocytes, and recombinant FABP4 further augmented the cancer stem cell (CSC) properties of HCC cells. Notably, Fabp4–/– mice exhibited a marked delay in the progression of MASLD-HCC, which correlated with the increased HCC risk observed in MASLD patients with elevated FABP4 expression. Mass spectrometry analysis identified integrin β 1 (ITGB1) as a binding partner of FABP4. These data, together with a substantial downregulation of the Wnt/β-catenin pathway in Fabp4–/– mouse tumors, revealed that FABP4 augmented liver CSC functions by activating PI3K/AKT/β-catenin signaling via ITGB1. We developed an anti-FABP4 neutralizing antibody that successfully inhibited FABP4-driven CSC functions and suppressed MASLD-induced HCC. In conclusion, our findings indicate that adipocyte-derived FABP4 plays a critical role in the development of MASLD-induced HCC and targeting the ITGB1/PI3K/AKT/β-catenin signaling cascade may offer a promising approach to combat this aggressive disease.

Authors

Carmen Oi Ning Leung, Shilpa Gurung, Katherine Po Sin Chung, Rainbow Wing Hei Leung, Martina Mang Leng Lei, Mandy Sze Man Chan, Gregory Kenneth Muliawan, Shakeel Ahmad Khan, Xue Qian Wu, Jun Yu, Hui Lian Zhu, Yin Ying Lu, Stephanie Ma, Xiaoping Wu, Ruby Lai Chong Hoo, Terence Kin Wah Lee