Multi-omics profiling reveals epigenetic alterations and a candidate SIRT1-β-catenin axis in bakuchiol ferulate-mediated photoaging protection

Skin photoaging, driven primarily by ultraviolet A (UVA) exposure, involves extracellular matrix degradation, aberrant inflammation, and multilayered epigenetic dysregulation. Bakuchiol ferulate (BF), a novel ester conjugate of bakuchiol (BAK) and a ferulic acid (FA) analog, was synthesized to combine the beneficial properties of BAK and FA. However, its anti-photoaging efficacy and mechanisms of action remain unexplored. Here, we evaluated BF in a UVA-induced nude mouse model using integrated transcriptomic, DNA methylomic, and miRNA profiling, with BAK, FA, and retinol (ROL) included as comparators. BF dose-dependently attenuated UVA-induced photoaging phenotypes and produced greater improvements than BAK or FA across the endpoints examined. Relative to 0.01% ROL, 0.1% BF showed comparable efficacy, whereas 0.4% BF yielded larger improvements in epidermal thickness, dermal collagen content, and inflammatory markers. These phenotypic effects were accompanied by coordinated epigenetic changes, including alterations in miRNA expression and DNA methylation. Integrative network analysis revealed an association between the SIRT1-β-catenin signaling pathway and BF’s anti-photoaging effects. These network-level predictions were in line with molecular observations of β-catenin nuclear accumulation and elevated Cyclin D1 expression, together with reduced miR-34a-5p and miR-450b-3p expression associated with increased SIRT1 and β-catenin protein levels, respectively. Molecular docking further suggested potential binding of BF to SIRT1. Collectively, these findings characterize the multi-layered molecular response to BF in photoaged skin and associate its protective effects with potential engagement of the SIRT1-β-catenin axis. These findings underscore molecular grafting as a rational strategy for engineering phytochemical derivatives with enhanced anti-photoaging profiles, expanding the chemical space of natural product-based skin protective agents.