Xuanzhi Yan,1,* Jiaxing Fan,1,* Wanying Qin,1,* Minjun Liao,1,2,* Siming Li,1 Liya Suo,1 Yujin Xie,1 Xin Jiang,3 Dengfeng Zou,4 Weijia Liao1 

1Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China; 2Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, Beijing, 100044, People’s Republic of China; 3Guangxi Key Laboratory of Drug Discovery and Optimization, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China; 4Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, Guangxi, 541199, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Weijia Liao, Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China, Email liaoweijia288@163.com Dengfeng Zou, Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, Guangxi, 541199, People’s Republic of China, Email zdf1226@163.com

Background: In recent years, photodynamic therapy (PDT) has gradually attracted the attention of researchers due to its therapeutic potential for treating malignant tumors. Hypericin (HC) is anticipated to enhance the therapeutic effect on tumors as an efficient photosensitizer (PS) for PDT. However, the role and mechanism of PDT in hepatocellular carcinoma (HCC) remain unclear.
Methods: In this study, we investigated the efficacy of hypericin nanoparticles (HC-NPs)-associated PDT (HC-NPs-PDT) on HCC to explore its anti-HCC mechanism both in vitro and in vivo. Cellular molecular experiments, as well as HCC mouse tumor models, were utilized to validate the impact of HC-NPs-PDT on HCC. Additionally, molecular docking and related experiments were employed to investigate its potential mechanism.
Results: Our findings demonstrated that HC-NPs-PDT effectively inhibits the viability, migration, and invasion abilities of HCC cells, as well as suppresses the growth of subcutaneous HCC tumors in BALB/C-nu nude mice. SERPINE1 (also known as PAI, PAI-1, PAI1, PLANH1) may be a key target of HC, as its mRNA and protein levels were significantly up-regulated following HC-NPs-PDT. This upregulation led to a decrease in mitochondrial membrane potential and promoted apoptosis of HCC cells. Additionally, inhibition of SERPINE1 partially restored changes in mitochondrial membrane potential.
Conclusion: These results suggest that HC-NPs-PDT may regulate the biological behavior of HCC by upregulating SERPINE1 expression, offering a new perspective for treating HCC.

Keywords: hepatocellular carcinoma, photodynamic therapy, hypericin, SERPINE1, biological behavior