Integrative single-cell analysis reveals Bu-Shen-Huo-Xue Formula rescues iron-overloaded ovarian function via rewiring IFN-γ/JAK/STAT/CXCL10-driven immune-stromal interactions and BNIP3-mediated mitophagy in endometriosis

Zhexin Ni, Ni Z, Zhao Q, Qianqian Zhao, Yangshuo Li, Li Y, Shanshan Mei, Mei S, Yu J, Jin Yu, Ding J, Jie Ding, Xiaolan Liang, X Liang, Liang X, Shuai Sun, Sun S, Yuqing Wang, Wang Y, Wen Cheng, Cheng W, Zhou W, Wei Zhou, Yu C, Chaoqin Yu
Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026 · vol. 157 , pp. 158343 · doi:10.1016/j.phymed.2026.158343 · PMID:42208103 · W7162195101
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This study integrated single-cell data to show Bu-Shen-Huo-Xue Formula reverses iron overload in ovaries by altering immune-stromal crosstalk and promoting mitophagy, impacting endometriosis progression.

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Abstract

BACKGROUND: Ovarian endometriosis (OE) is a leading cause of female infertility. Our previous work identified iron overload-driven oxidative stress and mitochondrial dysfunction in granulosa cells as key pathogenic features, yet the mechanism of the clinically effective Bu-Shen-Huo-Xue Formula (BHF) remains unclear. PURPOSE: To determine how BHF mitigates OE-associated ovarian injury and infertility, and to identify key bioactive constituents and molecular targets. METHODS: An OE mouse model was treated with BHF to evaluate pelvic adhesions, lesion volume, fibrotic remodeling, and reproductive outcomes. Integrated single-cell RNA sequencing (scRNA-seq) and Stereo-seq were used to define iron overload-associated ovarian niches. Granulosa cell mitochondrial function, ROS, senescence, and BNIP3-PINK1/Parkin-dependent mitophagy were assessed. Serum pharmacochemistry was performed to identify BHF constituents and validate target engagement. RESULTS: BHF reduced pelvic adhesions, lesion volume, and fibrotic remodeling, and improved reproductive outcomes in OE mice. Iron overload established a corpus luteum-proximal immuno-fibrotic niche characterized by interferon programs and JAK-STAT activation; BHF attenuated this niche by suppressing CXCL10-mediated immune recruitment and fibroblast activation. At the follicular level, iron overload induced excessive BNIP3-PINK1/Parkin-dependent mitophagy, resulting in mitochondrial dysfunction, ROS accumulation, senescence, and stress-associated metabolic reprogramming; BHF restored mitochondrial homeostasis and alleviated these alterations. Ononin was identified as a major circulating constituent that directly binds BNIP3 and inhibits iron-induced mitophagy, preserving granulosa-cell function. CONCLUSION: BHF acts as a multi-target intervention that protects against OE-associated ovarian injury by dampening iron overload-linked immuno-fibrotic remodeling and restraining BNIP3-dependent mitophagy; ononin is a BNIP3-targeting bioactive component with therapeutic potential.

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Condition tags

endometriosis

MeSH descriptors

Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal Drugs, Chinese Herbal

Citation neighborhood (2-hop)

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. Outer rings show 2-hop neighbours — papers reached through the immediate citers/citees. [ collapse to 1-hop ]

References (64)

SciLite annotations

chemicals 9
iron iron iron iron iron ononin iron iron ononin
organisms 2
transgenic mice mus sp.

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