Zinc finger DHHC-type containing 2 emerges as a novel therapeutic target in osteoarthritis pathogenesis: genome-wide data analysis in European populations

Abstract

BACKGROUND: Studies have suggested that palmitoylation-mediated regulation offers distinct advantages in osteoarthritis. Therefore, it is essential to utilize whole-genome data to explore novel key drug-targetable tissue-constructing hubs of palmitoylation regulation in osteoarthritis from a genetic perspective. OBJECTIVE: To explore novel key drug targets involved in palmitoylation-mediated regulation of osteoarthritis pathogenesis through Mendelian randomization analysis, thereby providing valuable insights for developing targeted therapeutic strategies against osteoarthritis. METHODS: We identified 31 palmitylation-related genes from three independent studies and cross-referenced them with 15 695 druggable genes from the eQTLGen Consortium database (which is publicly available and aims to better understand diseases at the plasma proteome gene level, containing multiple druggable gene targets). This yielded 22 potential palmitoylation drug targets. Using drug-target Mendelian randomization, sensitivity analysis, and colocalization analysis, we identified novel drug targets for palmitoylation-regulated osteoarthritis (from GWAS Catalog database, established by the National Human Genome Research Institute, summarizing data from published genome-wide association studies). GeneMANIA and STRING interaction network analyses were performed to explore potential interacting proteins of the novel drug target. After further validation with osteoarthritis validation genes (also from GWAS Catalog), we determined the interacting proteins of the novel drug target. RESULTS AND CONCLUSION: (1) After matching 31 palmitoylation genes, 22 potential palmitoylation drug targets were obtained. Through Mendelian randomization, sensitivity analysis, and colocalization analysis, zinc finger DHHC-type containing 2 (ZDHHC2) was identified as a novel drug target for palmitoylation-regulated osteoarthritis. GeneMANIA and STRING analyses revealed 7 potential interacting proteins, and validation with osteoarthritis genes suggested a strong interaction between ZDHHC3 and ZDHHC2. These results indicate that ZDHHC2 is a novel key drug target in palmitoylation-regulated osteoarthritis pathogenesis, and ZDHHC3, as an interacting protein, may exert synergistic effects, facilitating future construction of efficient and safe drug prevention and treatment chains for osteoarthritis patients through palmitoylation regulation. (2) The use of international databases and European populations provides important reference for Chinese biomedical and clinical research, offering clues for osteoarthritis research in the Chinese population from a genetic perspective. This approach can also be used to screen drug gene targets in Chinese populations, target palmitoylation regulation, and promote personalized and precise medication for osteoarthritis prevention and treatment.

1. Introduction

Osteoarthritis is a chronic disease characterized primarily by degenerative changes in articular cartilage, with clinical manifestations including joint pain, stiffness, limited mobility, and joint swelling [1-2]. Globally, approximately 300 million people suffer from osteoarthritis, with a prevalence exceeding 10% in those over 60 years old [3]. Patients often experience pain that affects daily life, and severe cases may lead to joint deformity and dysfunction [4]. The pathogenesis of osteoarthritis involves multiple mechanisms, including mechanical load, inflammatory responses, oxidative stress, and apoptosis [5-6]. Current drug treatments for osteoarthritis are suboptimal; intra-articular injections such as sodium hyaluronate and corticosteroids can improve joint function to some extent but may cause adverse reactions like synovial atrophy [7-8]. In recent years, with the aging of the Chinese population, the incidence of osteoarthritis is expected to rise further [9]. Therefore, it is necessary to explore novel therapeutic targets with minimal side effects that can target key pathological processes of osteoarthritis, delve into its pathogenesis, and facilitate targeted therapy, early prevention, and prevention before disease onset, thereby improving the quality of life for osteoarthritis patients.