Bioactive compounds in European ferns: inhibition of pro-inflammatory enzymes and cytotoxic effects on cancer cells

BACKGROUND: Ferns, among the oldest vascular plants, have been widely used in traditional medicine worldwide. While pharmacological studies predominantly focus on tropical and subtropical species, European ferns remain underexplored despite their potential to yield novel bioactive compounds. Given the limitations and side effects of existing anti-inflammatory and anticancer agents, European ferns represent a promising source of safer, naturally derived therapeutic options. METHODS: This study investigated the anti-inflammatory and anticancer properties of methanol extracts from 16 European fern species. The extracts were tested for their ability to inhibit pro-inflammatory enzymes of the arachidonic acid cascade, specifically cyclooxygenases (COX-1, COX-2) and 5-lipoxygenase (5-LOX). Cytotoxicity assays on SW480 human colon cancer cells, HeLa cervical cancer cells, CCD 841 CoN colorectal epithelial cells, and HepaRG liver cancer/non-cancer cells were performed to evaluate anticancer activity and toxicity. Flavonoid content analysis was conducted for selected species using LC/MS. RESULTS: Most fern extracts at low concentration of 10 µg/mL effectively inhibited COX-1, with Dryopteris cambrensis and Athyrium distentifolium achieving inhibition comparable to Ibuprofen (92% and 91%, respectively). Moderate inhibition of 5-LOX (over 50%) was observed across many species, while only a few, including Blechnum spicant, Dryopteris expansa, and D. aemula, moderately inhibited COX-2. Cytotoxicity screening identified five species, notably D. aemula and D. borreri, with significant activity against SW480 cells (IC50 = 79 and 115 µg/mL). A. distentifolium exhibited notable activity against HeLa cells. Despite cytotoxicity of active species toward non-cancerous CCD 841 CoN cells, HepaRG cell assays suggested a more favorable toxicity profile for most active species. CONCLUSIONS: This study reveals the significant anti-inflammatory and anticancer potential of European ferns, particularly their selective cytotoxicity in HepaRG cancer cells. These findings highlight European ferns as promising sources of therapeutic agents and encourage further exploration of their bioactive compounds for drug development.