Theacrine enhances autophagy and inhibits inflammation via regulating SIRT3/FOXO3a/Parkin pathway

Abstract Background Psoriasis, a common chronic inflammatory skin condition, impacts around 2%–3% of the global population. Theacrine is recognized for its potential anti‐inflammatory and antioxidant properties. However, the role of theacrine in psoriasis remains unclear. Purposes To investigate the effects of theacrine on psoriasis and explore the underlying signaling pathways. Methods For imiquimod (IMQ)‐induced Psoriasis‐like mice, the psoriatic inflammation was monitored using Psoriasis Area and Severity Index (PASI). The skin damage was observed using Hematoxylin and Eosin staining. The KI67 and CD4 in skin tissues were assessed using Immunohistochemistry analysis. Western blots were performed to evaluate the expression of Keratin 1 (KRT1), KRT6, LC3, P62, Beclin1, T‐bet, GATA3, RAR‐related orphan receptor (ROR)‐γt, Sirtuin‐3 (SIRT3), Forkhead Box O3a (FOXO3a) and Parkin. Additionally, LC3B expression was analyzed using an immunofluorescent assay, while flow cytometry was performed to analyze the percentage of Th17, Th1, and Th2 positive cells in skin‐draining lymph node. Results Theacrine improved skin condition by reducing hyperkeratosis and acanthosis, lowering PASI scores, and decreasing KI67‐positive cells. Theacrine also modulated keratin expression, elevating KRT1 while reducing KRT6 levels. Theacrine enhanced autophagy indicated by an increased LC3‐II/LC3‐I ratio and Beclin1, while reduced P62 levels. Additionally, Theacrine reduced CD4‐positive cells and suppressed Th17 and Th1 cell activation. Theacrine activated the FOXO3a/Parkin pathway by upregulating SIRT3 expression, and down‐regulation of SIRT3 counteracted theacrine's effects in psoriasis‐like mice. Conclusion Theacrine inhibits skin damage, promotes autophagy, and mediates inflammation in IMQ‐induced psoriasis mice via upregulating SIRT3 to activate FOXO3a/Parkin pathway, positioning theacrine as a candidate for psoriasis treatment.