In vitro study of the efficacy of mandelic acid attenuates acne inflammation by inhibiting MMP9-mediated PI3K/AKT pathway

Acne is a chronic inflammatory skin disease that is highly prevalent in adolescents, and its recurrent flare-ups can affect facial aesthetics, severely impacting adolescents' mental health and quality of life. Screening for safer, more effective fruit acid molecules for daily acne treatment is crucial. This work examined potential mandelic acid derivatives. In a zebrafish model, mandelic acid showed a 78.17 % rate of inflammatory cell aggregation, outperforming supramolecular salicylic acid (86.96 % aggregation) at the same concentration. In a P. acnes -induced cell model, MMP9 protein expression was significantly upregulated in the model group. After treatment with mandelic acid, MMP9 expression decreased by 72.84 % compared to the model group, a better effect than that of supramolecular salicylic acid (36.78 %). Further mechanistic investigations indicate that mandelic acid may inhibit the PI3K/AKT signaling pathway activated by P. acnes , thereby blocking MAPK signaling and modulating MMP9 protein production, thereby averting the development of NLRP3 inflammatory vesicles. Mandelic acid has a favourable safety profile and notable anti-inflammatory properties, which can be further harnessed to mitigate acne in sensitive skin demographics, offering a novel approach to acne treatment. • The zebrafish model evaluated mandelic acid, which has great anti-inflammatory activity without obvious irritation. • Mandelic acid can inhibit inflammation caused by P. acnes and promote the expression of keratin. • Network pharmacology and molecular docking identify MMP9 as a key regulator of mandelic acid against P. acnes inflammation. • Mandelic acid may inhibit the activation of the PI3K/AKT pathway by targeting the inhibition of MMP9.