Jiaxin Bei,1,2,* Zihao Sun,1,2,* Rongdang Fu,3,* Xinkun Huang,4 Jiabai Huang,4 Yongyou Luo,5 Yihu Li,6 Ye Chen,4 Zhisheng Wei7 

1Department of Immuno-Oncology, First School of Clinical Medicine, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510080, People’s Republic of China; 2Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Therapy, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510080, People’s Republic of China; 3Department of Hepatic Surgery, the First People’ S Hospital of FoShan, Guangdong, 528000, People’s Republic of China; 4Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, People’s Republic of China; 5Department of Pathology, First School of Clinical Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510080, People’s Republic of China; 6Department of Hepatobiliary Surgery, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, People’s Republic of China; 7Department of Neurology, Neurological Research Institute of Integrated Traditional Chinese and Western Medicine, First School of Clinical Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510080, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Ye Chen, Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, People’s Republic of China, Email onenine@126.com Zhisheng Wei, Department of Neurology, Neurological Research Institute of Integrated Traditional Chinese and Western Medicine, First School of Clinical Medicine, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510080, People’s Republic of China, Email weizs084@gdpu.edu.cn

Purpose: Hepatocellular Carcinoma (HCC) features a complex pathophysiology and unpredictable immunosuppressive microenvironment, which limit the effectiveness of traditional therapies and lead to poor patient outcomes. Understanding the immune characteristics of HCC is essential for elucidating the immune microenvironment and developing more effective treatments. This study investigates the role of Peptidyl-prolyl isomerase H (PPIH) in HCC by analyzing its expression, prognosis, methylation levels, and relationship with immune cell infiltration.
Methods: We utilized bulk sequencing and clinical data from UCSC Xena and the GTEx database for preprocessing and subsequent differential expression analysis of PPIH in tumor and adjacent normal tissues, evaluating prognostic parameters like overall survival and disease-free interval between low and high PPIH expression groups. Immune infiltration was analyzed via CIBERSORT and ssGSEA, while DNA methylation and somatic mutation analyses were performed using MExpress and “maftools”, respectively, alongside in vitro and in vivo experiments to assess PPIH’s functional roles.
Results: Our findings indicated that PPIH is significantly upregulated in various cancer types, correlating with poor patient prognosis, increased somatic mutations, and altered gene methylation patterns. High PPIH levels were linked to enhanced T regulatory (Treg) cell infiltration and a decline in Th17 cell populations, impacting vital pathways related to DNA damage repair and tumor proliferation. Furthermore, PPIH knockdown in vitro led to reduced cell viability, proliferation, and invasion while promoting apoptosis. In vivo, PPIH knockdown repressed tumor growth and modified the immune microenvironment by attenuating Th17 cell infiltration and potentially increasing Treg cell accumulation.
Conclusion: This study emphasizes PPIH’s critical role in HCC progression by facilitating tumor growth and survival while modulating the immune landscape, thereby positioning PPIH as a potential therapeutic target for HCC management.

Keywords: hepatocellular carcinoma, PPIH, bioinformatics analysis, immune infiltration, Th17/Treg cell