| Summary: | To look in-depth into the phytochemical and pharmacological properties of Taiwan juniper, this study investigated the chemical profiles and anti-lymphangiogenic activity of <i>Juniperus chinensis</i> var. <i>tsukusiensis</i>. In this study, four new sesquiterpenes, 12-acetoxywiddrol (<b>1</b>), cedrol-13-al (<b>2</b>), α-corocalen-15-oic acid (<b>3</b>), 1,3,5-bisaoltrien-10-hydroperoxy-11-ol (<b>4</b>), one new diterpene, 1β,2β-epoxy-9α-hydroxy-8(14),11-totaradiene-3,13-dione (<b>5</b>), and thirty-three known terpenoids were successfully isolated from the heartwood of <i>J. chinensis</i> var. <i>tsukusiensis</i>. The structures of all isolates were determined through the analysis of physical data (including appearance, UV, IR, and optical rotation) and spectroscopic data (including 1D, 2D NMR, and HRESIMS). Thirty-four compounds were evaluated for their anti-lymphangiogenic effects in human lymphatic endothelial cells (LECs). Among them, totarolone (<b>6</b>) displayed the most potent anti-lymphangiogenic activity by suppressing cell growth (IC<sub>50</sub> = 6 ± 1 µM) of LECs. Moreover, 3β-hydroxytotarol (<b>7</b>), 7-oxototarol (<b>8</b>), and 1-oxo-3β-hydroxytotarol (<b>9</b>) showed moderate growth-inhibitory effects on LECs with IC<sub>50</sub> values of 29 ± 1, 28 ± 1, and 45 ± 2 µM, respectively. Totarolone (<b>6</b>) also induced a significant concentration-dependent inhibition of LEC tube formation (IC<sub>50</sub> = 9.3 ± 2.5 µM) without cytotoxicity. The structure–activity relationship discussion of aromatic totarane-type diterpenes against lymphangiogenesis of LECs is also included in this study. Altogether, our findings unveiled the promising potential of <i>J. chinensis</i> var. <i>tsukusiensis</i> in developing therapeutics targeting tumor lymphangiogenesis.
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