Disulfidptosis-related Protein RPN1 may be a Novel Anti-osteoporosis Target of Kaempferol

Author:

Pan Chengzhen1ORCID,Zhang Chi1ORCID,Lin Zonghan1ORCID,Liang Zhou2ORCID,Cui Yinhang1ORCID,Shang Zhihao3ORCID,Wei Yuanxun1ORCID,Chen Feng1ORCID

Affiliation:

1. Ruikang Hospital Affiliated with Guangxi University of Chinese Medicine, Nanning, Guangxi, China

2. Yulin Orthopedic Hospital of Integrated Traditional Chinese and Western Medicine, Yulin, Guangxi, China

3. Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China

Abstract

Background: Osteoporosis (OP) is an age-related skeletal disease. Kaempferol can regulate bone mesenchymal stem cells (BMSCs) osteogenesis to improve OP, but its mechanism related to disulfidptosis, a newly discovered cell death mechanism, remains unclear. Objective: The study aimed to investigate the biological function and immune mechanism of disulfidptosis- related ribophorin I (RPN1) in OP and to experimentally confirm that RPN1 is the target for the treatment of OP with kaempferol. Methods: Differential expression analysis was conducted on disulfide-related genes extracted from the GSE56815 and GSE7158 datasets. Four machine learning algorithms identified disease signature genes, with RPN1 identified as a significant risk factor for OP through the nomogram. Validation of RPN1 differential expression in OP patients was performed using the GSE56116 dataset. The impact of RPN1 on immune alterations and biological processes was explored. Predictive ceRNA regulatory networks associated with RPN1 were generated via miRanda, miRDB, and TargetScan databases. Molecular docking estimated the binding model between kaempferol and RPN1. The targeting mechanism of kaempferol on RPN1 was confirmed through pathological HE staining and immunohistochemistry in ovariectomized (OVX) rats. Results: RPN1 was abnormally overexpressed in the OP cohort, associated with TNF signaling, hematopoietic cell lineage, and NF-kappa B pathway. Immune infiltration analysis showed a positive correlation between RPN1 expression and CD8+ T cells and resting NK cells, while a negative correlation with CD4+ naive T cells, macrophage M1, T cell gamma delta, T cell follicular helper cells, activated mast cells, NK cells, and dendritic cells, was found. Four miRNAs and 17 lncRNAs associated with RPN1 were identified. Kaempferol exhibited high binding affinity (-7.2 kcal/mol) and good stability towards the RPN1. The experimental results verified that kaempferol could improve bone microstructure destruction and reverse the abnormally high expression of RPN1 in the femur of ovariectomized rats. Conclusion: RPN1 may be a new diagnostic biomarker in patients with OP, and may serve as a new target for kaempferol to improve OP.

Funder

Guangxi Chinese Medicine Multidisciplinary Interdisciplinary Innovation Team Project

Guangxi Natural Science Foundation

Scientific Research Project of Guangxi Zhuang Autonomous Region Administration of Traditional Chinese Medicine

Innovation Project of Guangxi Graduate Education

Publisher

Bentham Science Publishers Ltd.

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