Prognostic biomarker and clinical significance of PLOD gene family in clear cell renal cell carcinoma

Xuan Shang^1,2,3Liu Liu^1,2,3Zhenwei Yang^1,2Min Yan^1,2Ruimin Ren⁴Kexin Guo^1,2Jie Wang^1,2Wei Zhang⁵Jiasong Chang^1,2,3Jia-Lei Li^1,2Jimin Cao^1,2,3Guang Li^6,7*Lijuan Gao^1,2,3*

• ¹Department of Cardiology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China
• ²Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi Province, China
• ³Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi Province, China
• ⁴Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, Shanxi Province, China
• ⁵Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China
• ⁶Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
• ⁷Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Medicine, Southwestern Medical University, Luzhou, Sichuan Province, China

Background: The PLOD gene family, involved in extracellular matrix (ECM) remodeling, plays a role in tumor progression, but its comprehensive role and clinical significance in clear cell renal cell carcinoma (ccRCC) remains unclear. Methods: We integrated multi-omics bioinformatics analyses from public databases (TCGA, GEO) with experimental validation using RT-qPCR, western blotting, and functional assays to systematically evaluate the expression patterns, prognostic value, immune microenvironment associations and drug resistance of PLOD genes in ccRCC. Computational approaches, including the comparative toxicogenomics database and molecular docking, were further employed to identify potential chemical modulators. Results: PLOD1, PLOD2, and PLOD3 were consistently overexpressed at both mRNA and protein levels in ccRCC tissues and cell lines. High PLOD expression was significantly correlated with reduced overall survival, and poor-free survival. Functional enrichment analysis revealed involvement in collagen biosynthesis, ECM-receptor interaction, and lysine degradation pathways. PLOD expression was also linked to an immunosuppressive microenvironment and resistance to conventional therapeutics. Through toxicogenomics screening and molecular docking, acetaminophen was identified as a potential regulator of all three PLOD proteins. Conclusions: This study underscores the pivotal role of the PLOD family in ccRCC pathogenesis through ECM remodeling, immune modulation, and therapy resistance. Our results support their utility as diagnostic and prognostic biomarkers, and acetaminophen may serve as a candidate for targeting PLOD-mediated pathways, providing a foundation for future preclinical and therapeutic investigations.