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Zhouxun Chen,1,* Jiahao Lin,2,* Shuyi Feng,2,* Xuxu Chen,2 Hanzhang Huang,3 Chen Wang,3 Yujun Yu,3 Yu He,3 Shaoliang Han,3 Linfeng Zheng,4 Guoyu Huang3 1Department of Colorectal and Anal Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; 2School of The First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China; 3Department of Gastrointestinal Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; 4Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China *These authors contributed equally to this work Background: SIRT4, a protein localized in the mitochondria, is one of the least characteristic members of the sirtuin family. It is known that SIRT4 has deacetylase activity and plays a role in energy metabolism, but little is known about its possible role in carcinogenesis. Recently, several studies have suggested that SIRT4 may function as either a tumor oncogene or a tumor suppressor gene. However, its relationship with thyroid cancer remains unclear. Methods: We stably overexpressed SIRT4 or silenced its expression in the human thyroid cancer cell line BCPAP by means of lentiviral vectors. We conducted a variety of tests, such as CCK-8, wound healing, migration, and invasion assays, to investigate the role of SIRT4 in the proliferation, migration, and invasion abilities of thyroid cancer cells. We also investigated the effects of SIRT4 overexpression on cell cycle progression and apoptosis of BCPAP cells and studied the role of glutamine metabolism in the effects of SIRT4 on BCPAP cell migration and invasion. Finally, we analyzed SIRT4 expression levels in thyroid cancer specimens by immunohistochemistry and investigated their association with clinicopathological features. Results: Overexpression of SIRT4 inhibited the proliferation, migration, and invasion abilities of BCPAP thyroid cancer cells, blocked the cell cycle in the G0/G1 phase, and induced apoptosis. Mechanistically, SIRT4 inhibited BCPAP migration and invasion by inhibiting glutamine metabolism. Moreover, we found that SIRT4 protein levels in thyroid cancer tissues were markedly lower than in their non-neoplastic tissue counterparts (P