Severe acne vulgaris is a prevalent chronic inflammatory skin condition affecting individuals worldwide, with abnormal sebaceous gland function closely linked to its pathogenesis. The 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is an effective and safe treatment for severe acne
however, the mechanisms underlying its effects remain unclear. In this study, we first noted a decrease in lipid production after ALA-PDT in patients with acne, acne-like mouse models, and the human immortalized sebocyte cell line XL-i-20. Through RNA sequencing, we identified significant upregulation of the transcription factor NR4A1 after ALA-PDT. Further confirmation of NR4A1 upregulation and its nuclear translocation under ALA-PDT was obtained in vitro and in vivo. Both the knockdown and overexpression of NR4A1 were shown to reverse or enhance the suppressive effect of ALA-PDT on lipid production. The following findings suggest that ALA-PDT inhibits protein kinase B signaling pathway, resulting in the activation of JunD, which subsequently enhances NR4A1 transcription and facilitates its inhibitory effect on lipid production. Overall, our findings highlight the crucial role of NR4A1 in regulating sebaceous lipids, elucidate the mechanism through which ALA-PDT treats acne, and lay the groundwork for enhancing the clinical applications of ALA-PDT.