Multi-level evidence reveals PANK2 as a potential target of PFOA/PFOS-induced bone metabolism disruption: From network toxicology to in vitro validation

Yiming Shao; Wenhao Fan

doi:10.1016/j.ecoenv.2025.118593

Multi-level evidence reveals PANK2 as a potential target of PFOA/PFOS-induced bone metabolism disruption: From network toxicology to in vitro validation

Ecotoxicol Environ Saf. 2025 Jun 27:302:118593. doi: 10.1016/j.ecoenv.2025.118593. Online ahead of print.

Authors

Yiming Shao¹, Wenhao Fan²

Affiliations

¹ Department of Laboratory Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China; Center of Stem Cell and Regenerative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China. Electronic address: yiming9710@163.com.
² Department of Foot and Ankle Surgery, Zhengzhou Orthopedic Hospital Affiliated to Henan University, Zhengzhou, China.

PMID: 40580631
DOI: 10.1016/j.ecoenv.2025.118593

Abstract

Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) are two representative per- and polyfluoroalkyl substances (PFAS) that have attracted increasing attention due to their environmental persistence and potential health risks, while their bone toxicity remains unclear. In this study, we systematically investigated the toxicological mechanisms of PFOA and PFOS on bone metabolism by integrating network toxicology, molecular docking and molecular dynamics simulations, and in vitro cellular experiments. Pantothenate kinase 2 (PANK2) was identified as a key target through the intersection of multiple databases and cross-validation using three machine learning algorithms. Molecular docking and dynamics simulations demonstrated that PFOA and PFOS can stably bind to PANK2 protein. In vitro experiments further confirmed that both PFOA and PFOS significantly suppressed PANK2 expression in bone marrow mesenchymal stem cells (BMSCs), leading to a disruption in the balance between osteogenic and adipogenic differentiation. Additionally, gene set enrichment analysis (GSEA) suggested that PANK2 may participate in bone metabolic regulation via chemokine signaling pathway and the neuro-osteogenic axis. This study highlights for the first time the critical role of PANK2 in PFAS-induced osteoporosis and provides novel mechanistic insights and potential therapeutic targets for the prevention and treatment of environmentally induced bone metabolic disorders.

Keywords: Molecular docking; Molecular dynamics simulations; Network toxicology; Osteoporosis; PANK2; PFOA; PFOS.