Lysine-specific demethylase 1 (LSD1) stabilizes hypoxia-inducible factor 1α (HIF1α) to advance tumor progression, while HIF1α functions as a transcription factor to increase the expression of microRNA-146a (miR-146a).We aim to investigate whether LSD1 affects the development of papillary thyroid carcinoma (PTC) via HIF1α and miR-146a.The in vitro assays were performed with Nthy-ori 3-1, BHP5-16, BCPAP, K1 and BHP2-7. Besides, in vivo assays were conducted with established xenograft tumor in nude mice.This study was conducted at our lab.Nthy-ori 3-1, BHP5-16, BCPAP, K1 and BHP2-7 as well as fifty male BALB/c nude mice were selected.Cells were transfected with sh-LSD1, sh-GABPA, oe-LSD1, oe-HIF1α, miR-146a mimic, miR-146a inhibitor. Besides, K1 cells expressing lv-oe-LSD1, lv-miR-146a inhibitor, lv-oe-LSD1 or miR-146a inhibitor were injected into the right side of the mice.LSD1, HIF1α, miR-146a and GABPA expression as well as their effect on PTC.LSD1 was highly expressed in clinical PTC tissues. LSD1 stabilized HIF1α and inhibited the degradation of its ubiquitin proteasome. HIF1α was enriched in the promoter region of miR-146a, an up-regulated miRNA in PTC. HIF1α increased miR-146a expression to promote PTC progression in vitro, which was achieved by inhibiting GABPA, a target gene of miR-146a. LSD1 up-regulated miR-146a to enhance the development and metastasis of PTC in nude mice.Taken together, LSD1 functions as an oncogene in PTC by up-regulating HIF1α and miR-146a, which contributes to understanding of undefined mechanisms associated with tumor progression in PTC.