Paeonol protects against cisplatin-induced premature ovarian failure via anti-inflammatory and antioxidant activities: an integrated approach of network pharmacology, molecular dynamics simulation, and experimental validation

Cisplatin (CIS), a widely used platinum-based chemotherapeutic agent, often induces ovarian toxicity that severely threatens female reproductive health. Paeonol (PAE), a bioactive compound found in peony, exhibits multiple pharmacological activities. This study investigates the multitarget protective mechanisms of PAE against cisplatin-induced premature ovarian failure (POF) using network pharmacology, molecular docking, and molecular dynamics simulations. We identified 93 potential targets of PAE and discovered significant activation of inflammation-related pathways, particularly the IL-17 and TNF signaling pathways. Protein-protein interaction (PPI) network analysis pinpointed ten core hub genes, including NFKB1, TNF, and IL6. Molecular docking and dynamics simulations confirmed PAE's stable binding to key targets like IL-6 and TNFα. In vitro experiments demonstrated that PAE significantly reduced oxidative stress markers (ROS, MDA, and LDH) and restored SOD activity in cisplatin-damaged KGN cells, while downregulating pro-inflammatory factors (TNFα and IL-6). Mechanistic studies revealed that PAE protects ovaries by synergistically regulating the IL-17 signaling pathway to inhibit POF. This research elucidates PAE's ovarian protective mechanisms from a multi-omics perspective, offering new evidence for natural compound-based POF prevention and treatment strategies.

Cisplatin; Inflammation; Molecular docking; Molecular dynamics simulation; Network pharmacology; Oxidative stress; Paeonol; Premature ovarian failure.