Lavender essential oil coordinates epidermal GABA shunt and nucleotide turnover to rescue cortisol-induced stress damage

Sustained elevation of cortisol levels induces epidermal metabolic disorders, triggering cutaneous stress and inflammatory responses. Although “Taikong Blue” lavender essential oil (TLEO) counteracts this damage, how cortisol drives epidermal metabolic network collapse and the precise cell-intrinsic molecular mechanisms of TLEO remain to be elucidated. Here, an epidermal stress model was established using cortisol-stimulated human keratinocytes (HaCaT) to systematically evaluate the cytoprotective effects of TLEO. TLEO intervention effectively inhibited cortisol-induced stress markers (H2AX, Loricrin, G6PDH), significantly reducing reactive oxygen species accumulation, lipid peroxidation (MDA), and inflammation-related markers, including COX-2, IL-8 and IL-17. Transcriptomic PPI network and validation analyses identified core hub targets spanning xenobiotic detoxification ( CYP1A1 ), the Nrf2-ARE pathway ( NQO1 , GCLC , AKR1C1 ), and chemokines ( CCL2 ). Integrated transcriptomic and untargeted metabolomic analyses further revealed coordinated changes in ABAT, ALDH5A1, and GLUL expression together with altered succinate abundance, consistent with modulation of GABA-shunt-related metabolism. Concurrently, TLEO coordinated nucleotide metabolic regulation by altering the expression of ADSL , ADSS2 , and TYMS ; the concomitant changes in intracellular AMP and dTMP abundance and H2AX expression were associated with altered nucleotide metabolism and attenuation of the DNA-damage-associated response In conclusion, TLEO alleviated cortisol-induced epidermal stress in HaCaT cells and was associated with coordinated changes in GABA-related and nucleotide metabolic processes.This approach provides a multi-omic framework for evaluating volatile natural complexes as potential candidates for alleviating stress-induced cellular dysfunction in keratinocytes.