Heteronemin Attenuates LPS-Induced Oxidative Stress and Inflammatory Responses in RAW264.7 Macrophages

Marine-derived natural products have attracted considerable attention as potential anti-inflammatory agents. Although the anticancer and pro-oxidative effects of heteronemin, a marine sponge-derived scalarane-type sesterterpenoid, have been reported, its direct regulatory effects on inflammatory mediator production in activated macrophages remain unclear. In this study, we aimed to investigate the anti-inflammatory effects of heteronemin in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Heteronemin significantly suppressed LPS-induced nitric oxide production at concentrations up to 10 μM with minimal effects on cell viability. In addition, heteronemin reduced the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), attenuated intracellular reactive oxygen species (ROS) accumulation, and downregulated pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Furthermore, heteronemin treatment was associated with reduced phosphorylation of mitogen-activated protein kinases (MAPKs), including p38, JNK, and ERK, following prolonged LPS stimulation. In contrast to its previously reported ROS-inducing activity in cancer cells, heteronemin reduced inflammation-associated ROS accumulation and was associated with decreased MAPK phosphorylation in LPS-stimulated macrophages, suggesting that its effects on cellular redox responses may depend on the experimental context. Collectively, these findings suggest the therapeutic potential of heteronemin as a promising marine-derived lead compound for inflammatory diseases.