Qingxin Jianpi Decoction Alleviates Cyclophosphamide‐Induced Diminished Ovarian Reserve Via Activation of the PI3K/AKT/Nrf2 Axis and Suppression of Ferroptosis

Abstract Diminished ovarian reserve (DOR), marked by reduced oocyte quantity and quality, remains therapeutically challenging. This study evaluates the protective effects of Qingxin Jianpi Decoction (QXJP) against cyclophosphamide (CTX)‐induced DOR via integrated network pharmacology and experimental validation. Bioactive compounds in QXJP are screened (TCMSP: OB ≥30%, DL ≥0.18) and targets predicted (SwissTargetPrediction). Functional enrichment analysis is performed using DAVID. CTX‐induced DOR rats receive QXJP (low/medium/high doses) or resveratrol. Ovarian histology, hormone levels (FSH, LH, E2, and AMH), apoptosis (Bax/Bcl‐2, cleaved Caspase‐3), ferroptosis markers (SLC7A11, ACSL4, MDA, and 4‐HNE), and PI3K/AKT/Nrf2 pathway activity are quantified by Western blot or ELISA. Network pharmacology identifies 176 bioactive compounds targeting 297 DOR‐associated genes, highlighting the PI3K‐AKT pathway. QXJP restores estrous cyclicity, increases follicle counts, reduces fibrosis, and rebalances FSH, LH, E2, and AMH levels (all p < 0.01). It suppresses granulosa cell apoptosis (decreased Bax/Cleaved Caspase‐3, increased Bcl‐2), attenuated ferroptosis‐related alterations (upregulated SLC7A11, downregulated MDA, 4‐HNE, and ACSL4), and activates PI3K/AKT/Nrf2 signaling (increased p‐PI3K/PI3K, p‐AKT/AKT ratios; upregulates Nrf2, HO‐1, and GPX4, p < 0.05). QXJP ameliorates CTX‐induced DOR by attenuating ovarian apoptosis and ferroptosis via the PI3K/AKT/Nrf2 pathway. This multi‐target mechanism underscores its potential as a herbal therapy for DOR.