Background/Objectives: 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. Methods: 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 trans-3,5,4′-tri(4-ferrocenylbutanoyloxy)-stilbene (RF) and (E)-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. Results: 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 tBHP (tert-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. Conclusions: 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.

Polychlorinated biphenyls (PCBs) can induce neurotoxicity, immunotoxicity, reproductive toxicity, genotoxicity, and carcinogenicity (IARC group 1 Carcinogens). Scientific data suggest that resveratrol possesses the ability to attenuate ortho-PCB-induced toxicity. Recently, a novel ferrocene-containing triacyl derivative of resveratrol (RF) was synthesized and in this study, its potential to protect CHO-K1 cells from selected PCB congeners (75 µM) was evaluated. Cell viability/proliferation was observed by Trypan Blue (TB), Neutral Red (NR), Kenacid Blue (KB), and MTT bioassays, ROS formation by fluorescent probes, and the extent of apoptosis by flow cytometry. All applied bioassays confirmed that RF (2.5–100 μM) remarkably improves viability in PCB 153-treated cells with an increase in cell survival almost up to control levels. This effect was not determined after PCB 77 exposure, although ROS formation was decreased at RF ≥ 50 µM. Apoptosis was significant (p < 0.05) for both congeners. In PCB 77-treated cells, RF did not suppress the induction of cell death. The intended protective effect of RF was evident when cells were treated with PCB 153, and this correlates with results obtained for cell viability. Compared to resveratrol, the novel RF showed promising results in terms of improved biological activity and cell protection against PCB 153 toxicity at all concentrations tested.