Ferrous lactate-loaded hydrogels induce iron-dependent non-canonical ferroptosis in Cutibacterium acnes: a novel therapeutic strategy for acne vulgaris

Acne vulgaris is a common inflammatory skin condition that affects up to 85% of adolescents and is primarily driven by Cutibacterium acnes (anaerobic bacteria, formerly Propionibacterium acnes). With the rise of antibiotic resistance, research on alternative antimicrobial agents that can address anaerobic bacteria resistance is becoming increasingly important, especially for patients who cannot use systemic antimicrobial therapy. In this study, a hyaluronic acid (HA)-based hydrogel incorporating ferrous lactate (FeLac) was developed as a non-antibiotic antimicrobial strategy targeting anaerobic pathogens to evaluate the bactericidal effects of FeLac on C. acnes. FeLac-loaded HA hydrogels exhibited excellent mechanical properties, good biocompatibility, superior storage stability, and robust antibacterial activity through sustained Fe2+ release, suggesting their potential as topical antimicrobial formulations. In a rat model of C. acnes-induced acneiform lesions, topical application of FeLac-loaded hydrogel significantly reduced inflammation and promoted lesion resolution through Fe2+ release, with efficacy comparable to conventional topical antibiotics. Mechanistically, FeLac (200 μM) treatment significantly increased intracellular iron levels, induced iron-dependent non-canonical ferroptosis, disrupted key pathways related to translation, biosynthesis, and cell wall integrity, and induced marked morphological alterations, achieving a bactericidal rate exceeding 99.9% after 3 h of treatment. These findings indicate that the FeLac-loaded hyaluronic acid (HA) hydrogel represents a promising non-antibiotic platform for treating acne and anaerobic bacterial infections via an iron-dependent ferroptosis-mediated pathway, demonstrating significant potential in dermatology and the cosmetics industry.