Phosphatidylserine liposomes containing metformin mitigate experimental atopic dermatitis: evidence for Akt/mTOR pathway involvement.

BACKGROUND

Atopic dermatitis (AD) is driven by dysregulated cytokine signaling, oxidative stress, and eicosanoid-mediated inflammation, with current therapies offering incomplete control and safety concerns during long-term use. Metformin has recognized antioxidant and immunomodulatory actions, but its limited ability to traverse the skin barrier constrains topical application. Phosphatidylserine formulations may overcome this limitation by facilitating delivery and regulating inflammatory signaling cascades.

OBJECTIVE

To assess the therapeutic efficacy of phosphatidylserine-based metformin formulations (PS-Met) in an oxazolone-induced murine model.

METHODS

AD was induced in sixty-four female mice through topical oxazolone sensitization and challenge. Animals received 14 days of topical treatment with PS-Met at 0.5%, 1%, or 2%, phosphatidylserine alone, betamethasone, or saline. Clinical scores, pruritus-related behaviors, histopathology, cytokine and oxidative stress markers, cyclooxygenase-1/2 expression, and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway were evaluated.

RESULTS

PS-Met produced dose-dependent therapeutic effects, with the 1% and 2% formulations showing pronounced responses. These treatments reduced macroscopic dermatitis scores, epidermal thickening, collagen deposition, and pruritus-related behaviors. Serum immunoglobulin E and malondialdehyde were decreased, while superoxide dismutase and interleukin-10 levels were restored. PS-Met also lowered interleukin-1β, interleukin-12, and interleukin-31, reduced nitroblue tetrazolium activity, selectively suppressed cyclooxygenase-2, and downregulated Akt/mTOR signaling, with the 1% and 2% formulations achieving effects comparable to or exceeding those of betamethasone.

CONCLUSION

Topical PS-Met provides multi-targeted improvement in AD by attenuating inflammation, oxidative stress, and key signaling pathways, particularly at 1% and 2% concentrations. While promising, these preclinical findings require validation in chronic models and clinical studies to establish translational relevance.