OBJECTIVE To investigate the mechanism by which Viaminate treats hyperkeratosis of ear acne epidermis in rats. METHODS Thirty male SD rats were randomly divided into three groups: control group, model group, and viaminate-treated group. The formation of ear acne was induced by combining Propionibacterium acnes with a sebum smear. After successful modeling, viaminate was administered orally every 12 h for 30 d. Acne tissues were collected from the rats after the treatment, and immunohistochemical, Masson, and hematoxylin-eosin staining were performed to assess histopathology. Transcriptomic sequencing and molecular docking were conducted to analyze the target of viaminate. The effect of viaminate on the selected protein was confirmed using western blotting. Retinol binding protein 4 (RBP4) was silenced in HaCat cells to verify the targeting relationship between viaminate and RBP4. RESULTS After 30 days of treatment with viaminate, significant improvements were observed in the symptoms of rat ear swelling, epidermal thickening, and inflammation. Additionally, the expression of the keratinization-related proteins, vimentin and keratin 6 (KRT6), was inhibited. Transcriptomic analysis revealed that viaminate had a notable regulatory effect on the keratinization pathway. Molecular docking results suggested that RBP4 may be a critical target of viaminate. Western blotting results demonstrated that viaminate could upregulate the expression of RBP4/retinoic acid receptor γ (RARγ) protein in rats with acne. In addition, viaminate significantly inhibits abnormal proliferation and the expression of vimentin and KRT6 in HaCat cells induced by P. acnes. It also downregulates the phosphorylation of Akt. However, after transfection with RBP4 siRNA, the regulatory effects of viaminate on the aforementioned phenomena are significantly reversed. CONCLUSION Viaminate improves acne by reducing excessive keratinization in rat epidermis via activation of RBP4/RARγ and downregulation of Akt phosphorylation. It also inhibits the proliferation and keratinization of human epidermal keratinocytes induced by P. acnes in vitro.