Bakuchiol Ferulate: A Novel Functional Retinol Analog With Enhanced Photostability and Reduced Phototoxicity for Cosmetic Applications

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ABSTRACT Background Retinol (ROL) is essential in dermatology for antiaging; however, its clinical utility is frequently limited by inherent chemical instability and significant cutaneous irritation. Objective This study describes the development of bakuchiol ferulate (BF), a novel molecular hybrid synthesized from bakuchiol and a ferulic acid (FA) analog. The study aimed to evaluate BF as a stable, well‐tolerated, and efficacious alternative to ROL. Methods The performance of BF was compared against ROL, bakuchiol (BKU), and FA. Stability was assessed using HPLC‐based degradation assays and electron paramagnetic resonance (EPR) spectroscopy. Cytotoxicity was evaluated via CCK‐8 assays in HaCaT and 3T3 cell lines. Phototoxicity was determined using the 3T3‐NRU assay (OECD 432) and singlet oxygen/superoxide ions generation analysis. A 14‐day human cumulative irritation patch test was conducted to compare the dermal compatibility and Mean Cumulative Irritancy Index (MCII) of varying concentrations of BF and ROL. Finally, ROL‐like activity and molecular mechanisms were characterized through transcriptome profiling in human dermal fibroblasts. Results BF demonstrated superior thermal and photostability compared to both ROL and BKU. In phototoxicity testing, BF exhibited the lowest photo‐reactivity and UV‐triggered ROS induction, maintaining a non‐phototoxic profile. Clinical results showed that all concentrations of BF remained nonirritating with negligible MCII scores, demonstrating significantly higher dermal tolerance in human subjects. Transcriptomic analysis revealed that BF's gene expression profile highly correlates with that of ROL, specifically upregulating pathways involved in the cell cycle and DNA repair. Crucially, BF achieved these effects while avoiding the pro‐apoptotic and inflammatory signatures typically associated with ROL treatment. Conclusion BF functions as a potent functional ROL analog that successfully merges structural stability with minimized phototoxicity. These findings suggest that BF offers a stable, efficacious, and safer alternative for advanced cosmetic and dermatological applications.

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