Region-Specific Lipid Alterations Around the 28-Year Transition as Early Indicators of Skin Aging

<b>Background</b>: Early molecular changes on the facial skin surface during early adulthood remain insufficiently characterized. We integrated biophysical readouts with untargeted skin surface lipid (SSL) profiling to identify region-dependent, age-associated features in women with combination skin. <b>Methods</b>: Eighty healthy Chinese women were stratified into 22-28 years (<i>n</i> = 40) and 29-35 years (<i>n</i> = 40). Sebum was measured on the cheek and forehead; cheek elasticity, hydration (CM), transepidermal water loss (TEWL), pH, and tone indices were assessed under standardized conditions. SSLs from both regions were profiled by UPLC-QTOF-MS. Differential features were prioritized using OPLS-DA (VIP > 1) with univariate screening (<i>p</i> < 0.05; fold change > 2 or <0.5). <b>Results</b>: TEWL, CM, and pH were comparable between age groups, whereas the older group showed lower cheek elasticity and reduced sebum. Lipidomics revealed clearer remodeling on the cheek than the forehead: 30 and 59 differential SSL features were identified in the cheek and forehead, respectively. Cheek changes in the older group were characterized by lower ceramides (including acylceramides), TG/DG and long-chain fatty acids, alongside relatively higher cholesteryl esters. <b>Conclusions</b>: Conventional barrier indices remained largely stable across this age window, while cheek SSL profiles captured earlier molecular shifts, providing candidates for targeted validation and longitudinal follow-up.