Morutamins A–L from <i>Morus alba</i> L. Root Bark with Inhibitory Effects on Epidermal Growth Factor Receptor and Toll-Like Receptor-Mediated NF-κB/AP-1 Activation

<i>Morus alba</i> L. root bark (MAR, "Sang-Bai-Pi" in traditional Chinese medicine) has been traditionally used for the treatment of inflammatory disorders. Phytochemical investigation of MAR yielded 11 new flavanones and one new chalcone (<b>1</b>-<b>12</b>, morutamins A-L), along with 27 known compounds (<b>13</b>-<b>39</b>). Their structures and absolute configurations were elucidated by combining HRESIMS and NMR analyses with DP4 and DP4+ probability calculations and ECD data. Among these, morutamin L (<b>12</b>) exhibited potent anti-inflammatory and immunomodulatory activities by inhibiting epidermal growth factor receptor and toll-like receptor agonist-induced NF-κB/AP-1 activation, which were explored through network pharmacology, molecular docking, and experimental verification. SwissADME analysis further indicated that morutamin L possesses favorable oral bioavailability and drug-likeness profiles. These findings highlight <i>M. alba</i> root bark as a promising source of lead compounds for the development of functional food ingredients or nutraceuticals targeting inflammation-related disorders.