Anti-Photoaging Activity of a Structurally Optimized Curcumin Analogue (THHGV-5) in UV-B-Irradiated Human Dermal Fibroblasts: An Integrated In Silico and In Vitro Study.

Ultraviolet-B (UV-B) radiation is a major extrinsic factor driving skin photoaging through excessive oxidative stress, matrix metalloproteinases (MMPs) activation, extracellular matrix degradation, and premature cellular senescence. Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid 2–related factor 2 (NRF2) signaling serves as an upstream regulator of redox homeostasis and has been associated with modulation of ROS-driven MMP-1 and MMP-3 expression during photoaging. The anti-photoaging potential of tetrahydrohexagamavunon-5 (THHGV-5), a hydrogenated curcumin analogue, was evaluated using integrated in silico and in vitro approaches. Skin-relevant ADMET properties were predicted using SwissADME and ADMETlab 3.0, while molecular docking was performed against KEAP1, MMP-1, and MMP-3. UV-B–irradiated human dermal fibroblasts were used to assess cytoprotection, ROS generation, MMP expression, and cellular senescence. In silico analysis predicted dermally compatible physicochemical properties, low skin sensitization and reactivity, and limited systemic exposure for THHGV-5 compared with curcumin. Comparative docking indicated structurally relevant interactions within the catalytic domains of MMP-1 and MMP-3, whereas interaction within the KEAP1 binding interface was comparatively limited. Consistently, THHGV-5 reduced UV-B–induced ROS accumulation, suppressed MMP-1 and MMP-3 expression at transcriptional and protein levels, improved fibroblast viability, and markedly inhibited cellular senescence. These findings suggest that THHGV-5 attenuates UV-B–induced photoaging–related cellular changes, potentially through attenuation of oxidative stress and suppression of matrix-degrading enzymes, while exhibiting a skin-compatible in silico predicted ADMET profile, supporting its further development as a topical anti-photoaging candidate.