Novel Anti-inflammatory Lignans Identified in <i>Piper nigrum</i> L. Leaves via Bioactivity-Guided Isolation

<i>Piper nigrum</i> L. is widely cultivated in Hainan, China, and its abundant leaves represent an underutilized resource. This study aims to investigate its phytochemical constituents and anti-inflammatory potential. Through anti-inflammatory activity-guided phytochemical isolation, thirty-one compounds were isolated from <i>P. nigrum</i> leaves, including three novel lignans (<b>1-3</b>) and twenty-eight known compounds (<b>4</b>-<b>31</b>). Notably, 24 components are identified in <i>P. nigrum</i> for the first time. All isolated compounds were assessed for anti-inflammatory activity in LPS-induced BV-2 cells, of which <b>4</b> showed potent inhibitory activity of NO production (IC₅₀ = 2.7 μM) and dose-dependently reduced the levels of TNF-α, IL-6, and IL-1β. In addition, a validated UPLC-TQ-ESI-MS/MS method was developed to quantify eight representative compounds (<b>4</b>, <b>6</b>, <b>9</b>, <b>14</b>, <b>16</b>, <b>17</b>, <b>29</b>, and <b>30</b>). These findings enrich the phytochemical profile of <i>P. nigrum</i> and identify promising anti-inflammatory candidates, exploring the potential for developing natural anti-inflammatory agents and herbal supplements from agricultural waste.