Abstract
ATP citrate lyase (ACLY) is pivotal in de novo fatty acid synthesis. It emerges as a core metabolic enzyme implicated in malignant tumor progression, especially in Endometrial Cancer (EC). The present investigation revealed that Xanthohumol (XN), a naturally prenylated flavonoid, is a novel inactivator of ACLY. XN demonstrates a significant reduction in de novo fatty acid synthesis and concurrent inhibition of cell proliferation in EC. Moreover, XN directly inhibits ACLY enzyme activity and facilitates Smurf1-mediated ACLY ubiquitination and degradation. The research revealed that the knockdown of ACLY reduced fatty acid synthesis, proliferation, and colony formation in EC cells. Conversely, contrasting results were observed upon ACLY overexpression. Additionally, treatment with XN inhibited fatty acid synthesis, cell proliferation, and colony formation, inducing non-apoptotic cell death and G0/G1 cycle arrest by downregulating ACLY expression. The crucial involvement of Smurf1-mediated ACLY ubiquitination in the XN-induced downregulation of ACLY was also highlighted. Notably, the role of the E3 ubiquitin ligase Smurf1 in mediating the ubiquitination of ACLY is reported here for the first time. Furthermore, these findings indicated the potential of ACLY as a prospective drug target for EC. Considering the inhibitory effect of XN on ACLY, it presents encouraging prospects for treating EC.