Acne vulgaris is one of the most prevalent dermatological conditions worldwide, which is characterized by androgen-induced excessive sebum secretion, abnormal hyperkeratinization of the pilosebaceous duct, combined with consequent overgrowth of skin commensal bacteria and an intense inflammatory response (Liu et al., 2015). Propionibacterium acnes which mainly resides on human skin as part of the normal flora is widely recognized as a crucial pathogenic factor in the acne development (Kumar et al., 2016). It is known that the major cytoderm components of P. acnes such as Lipoteichoic acid (LTA) and peptidoglycan are involved in the initiation and prolongation of inflammation via stimulation of toll-like receptor 2 (TLR2) and the subsequent activation of the MAPK and NF-kB signaling pathways (Jin et al., 2023). P. acnes also secretes proteases, lipases, and hyaluronidases which play a key role in the progression of inflammation (Jin et al., 2023). In addition, P. acnes can reportedly activate keratinocytes, causing reactive oxygen species (ROS) production and inflammation development (Grange et al., 2009). Therefore, P. acnes killing combined with the pathogen-related inflammation suppression would lead to the amelioration of disease symptoms. Currently, the recommended topical treatments for acne vulgaris include retinoids, benzoyl peroxide, azelaic acid, and antibiotics. However, these therapeutic agents are often associated with mild to severe side effects. For example, antibiotics is one of the most common strategies to treat acne vulgaris so far. However, its long-term application leads to high incidence of P. acnes with antibiotic resistance (Jiang et al., 2022). Furthermore, antibiotics lack the ability to neutralize bacterial components such as lipopolysaccharide (LPS) and LTA, which can promote pathogen-related inflammation. Similarly, benzoyl peroxide, another widely used treatment, can cause adverse effects such as erythema, scaling and skin irritation (Brammann and Müller-Goymann, 2020; Tripathi et al., 2013). Therefore, there is an emergent and urgent clinical need for new and effective therapeutic for acne vulgaris.

Natural products represent a significant and valuable source of substances for drug development, and numerous studies have successfully identified and explored medicinal molecules derived from natural resources for the treatment of acne vulgaris (Cristani and Micale, 2024; Lee et al., 2014; Ryu et al., 2015; Wu et al., 2021a; Yang et al., 2019; Ye et al., 2020). Antimicrobial peptides (AMPs) have also emerged as promising candidates for antibiotic alternatives, owing to their multifaceted roles in host defense mechanisms against invasive pathogens and their reduced probability to induce microbial resistance (Erdem Büyükkiraz and Kesmen, 2022). Moreover, the increased levels of AMPs found in skin biopsies from patients with acne vulgaris suggest a role in acne pathogenesis (Borovaya et al., 2014; Harder et al., 2013). AMPs are considered as important mediators to dampen clinical symptoms of acne and many exogenous AMPs are reported to have positive effect against acne vulgaris development but induction of endogenous AMPs might worsen the clinical symptoms of acne due to their inflammatory properties (Harder et al., 2013). As of now, many AMPs are reported to have treatment effect on acne vulgaris. For example, Esc-1GN, Cath-MH, Melittin, P5, and C16-KWKW can treat acne vulgaris in in vitro and in vivo assays due to their anti-P. acnes and anti-inflammatory properties (Lee et al., 2014; Ryu et al., 2015; Wu et al., 2021a; Yang et al., 2019; Ye et al., 2020). Thus, AMPs are ideal candidates for drug development against acne vulgaris, and the discovery of new AMPs with anti-acne activities is an essential step towards acne treatment improvement. Cath-HG (GKCNLLCKVKNKIKNKVKAILQKL) from the skin of the frog Hylarana guentheri displays antimicrobial, anti-inflammatory, protease-regulating, LPS-binding, and platelet glycoprotein VI (GPVI) inhibition activities at a concentration that does not trigger hemolytic or cytotoxic effects (Chai et al., 2024; Li et al., 2025; Xiong et al., 2024). Given its multiple pharmacological actions, we hypothesized that Cath-HG could be an effective treatment for acne vulgaris. To evaluate this, we tested its therapeutic activity in vitro and in vivo and investigated the underlying mechanisms mediating its action against acne vulgaris development.