Caffeoylglucaric and Caffeoylquinic Acids from <i>Inula japonica</i> Leaves and Their Anti-Skin Aging Effects in TNF-α-Induced Normal Human Fibroblast Damage

This study investigated the secondary metabolites of <i>Inula japonica</i> leaves and determined their corresponding anti-skin aging properties. LC-MS-based molecular networking and compound isolation identified caffeoylglucaric and caffeoylquinic acids as the principal components of the 30% ethanolic extract of <i>I. japonica</i> leaves (IJE). The chemical structures of three previously unreported caffeoylglucaric acids, namely, inulajaponic acids A-C (<b>1</b>, <b>2</b>, and <b>4</b>), were determined. IJE and its compounds exhibited significant inhibitory effects against ROS and MMP-1 production in TNF-α-induced NHDF cells. In particular, compound <b>4</b> suppressed ROS, MMP-1, IL-6, and IL-8 production, while promoting the production of procollagen type I α1. Mechanistic studies revealed that <b>4</b> attenuates the phosphorylation of ERK, JNK, NF-κB, and c-Jun, suggesting that it regulates inflammatory cytokines and prevents collagen degradation via MAPK-NF-κB/AP-1 signaling pathways. Furthermore, <b>4</b> downregulated iNOS and COX-2 expression and upregulated HO-1 expression, demonstrating its ability to reduce the inflammatory responses associated with skin aging.