Curcumin and Resveratrol vs. Ferrocene-Modified Polyphenols: Role in Enhancing Protective Properties in Human Keratinocytes

<b>Background/Objectives</b>: Resveratrol (RSV) and curcumin (CRC) have antioxidant, anti-inflammatory, photoprotective, and cell-repairing properties. We selected them to investigate the potential role involved in human keratinocyte protection. Additionally, we tried to overcome the limitations of their application due to poor pharmacokinetics by introducing ferrocene into their structure. <b>Methods</b>: The multiple cellular endpoints-viability (determined by MTT and Trypan Blue method), ROS (reactive oxygen species) formation (evaluated by fluorescence intensity measurement), apoptosis and autophagy (assessed using flow cytometry) of <i>trans</i>-3,5,4'-tri(4-ferrocenylbutanoyloxy)-stilbene (RF) and (<i>E</i>)-5-(4-hydroxy-3-methoxyphenyl)-1-ferrocenylpent-4-ene-1,3-dione (CF), as well as of RSV and CRC, were evaluated in the HaCaT cell line. <b>Results</b>: RF and CF showed significantly lower antiproliferative activity, and cell survival was markedly pronounced compared to RSV or CRC-treated cells. CRC exerted the highest cytotoxicity, and cell viability was almost completely impaired at >50 µM. All compounds showed a beneficial effect on the reduction of ROS induced by <i>t</i>BHP (<i>tert</i>-butyl hydroperoxide), while in UV (ultraviolet) experiments, results were inconclusive (variable depending on dose). CRC and CF had the most prominent antioxidant capacity. Cytofluorimetry showed that CRC has a diverse range of targets in HaCaT cells, including cell proliferation arrest, apoptosis, and autophagy induction. RF at the lowest dose (5 µM) slightly induced autophagy, while treatment with CF even led to a decrease in the autophagy induction ratio. <b>Conclusions</b>: Based on the results, introducing ferrocene into natural compounds is an appropriate approach to protect skin cells, considering the low cytotoxicity of ferrocene-modified polyphenols and their retained antioxidant ability. However, caution should be exercised with CRC at ≥20 µM as it significantly impairs cell viability and induces cell death.