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Background <p>Platinum resistance remains a major cause of treatment failure in ovarian cancer (OC). Cancer-associated fibroblasts (CAFs), key components of the tumor microenvironment, play critical roles in OC progression. Inhibin subunit beta A (INHBA) and its putative receptor endoglin (ENG) have been linked to OC chemoresistance, but their functional interaction in mediating cisplatin resistance remains unclear.</p> Methods <p>Single-cell RNA sequencing (scRNA-seq) was performed to characterize CAF subsets and assess INHBA and ENG expression in OC tissues. Immunohistochemistry (IHC) and immunofluorescence (IF) staining was conducted on tissue microarrays to evaluate protein expression and co-localization. Primary CAFs and normal fibroblasts (NFs) were isolated. INHBA was knocked out in CAFs via CRISPR/Cas9, and ENG was stably knocked down in cisplatin-resistant OC cells by lentiviral shRNA. The INHBA-ENG axis was investigated through in vitro assays, co-immunoprecipitation (Co-IP), molecular docking, and in vivo xenograft models.</p> Results <p>scRNA-seq resolved four CAF subsets, with myoCAF1 being dominant in platinum-resistant tumors. INHBA was specifically restricted to myoCAF1, while ENG was enriched in epithelial cells, and their mRNA levels showed a strong positive correlation. Consistently, IHC confirmed significant upregulation of INHBA/ENG in OC, especially in platinum-resistant cases. CAF-derived INHBA promoted OC cell proliferation, invasion, EMT, and cisplatin resistance. Molecular docking suggested a high-affinity INHBA-ENG interaction, which was confirmed by Co-IP in OC-CAF co-cultures. ENG knockdown reversed cisplatin resistance, an effect abrogated by recombinant INHBA. In vivo, CAF-derived INHBA promoted tumor growth and cisplatin resistance in an ENG-dependent manner.</p> Conclusions <p>MyoCAFs-derived INHBA binds to ENG on OC cells, inhibits apoptosis, induces EMT, and promotes cisplatin resistance. The INHBA–ENG axis represents a promising therapeutic target for overcoming platinum resistance in OC.</p>

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INHBA secreted by cancer-associated fibroblasts promotes cisplatin resistance and malignant progression of ovarian cancer via ENG-mediated suppression of apoptosis and induction of EMT

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Xinyue Liu,
  • Yan Han,
  • Zhichao Qin,
  • Xinghua Li,
  • Yuping Suo

摘要

Background

Platinum resistance remains a major cause of treatment failure in ovarian cancer (OC). Cancer-associated fibroblasts (CAFs), key components of the tumor microenvironment, play critical roles in OC progression. Inhibin subunit beta A (INHBA) and its putative receptor endoglin (ENG) have been linked to OC chemoresistance, but their functional interaction in mediating cisplatin resistance remains unclear.

Methods

Single-cell RNA sequencing (scRNA-seq) was performed to characterize CAF subsets and assess INHBA and ENG expression in OC tissues. Immunohistochemistry (IHC) and immunofluorescence (IF) staining was conducted on tissue microarrays to evaluate protein expression and co-localization. Primary CAFs and normal fibroblasts (NFs) were isolated. INHBA was knocked out in CAFs via CRISPR/Cas9, and ENG was stably knocked down in cisplatin-resistant OC cells by lentiviral shRNA. The INHBA-ENG axis was investigated through in vitro assays, co-immunoprecipitation (Co-IP), molecular docking, and in vivo xenograft models.

Results

scRNA-seq resolved four CAF subsets, with myoCAF1 being dominant in platinum-resistant tumors. INHBA was specifically restricted to myoCAF1, while ENG was enriched in epithelial cells, and their mRNA levels showed a strong positive correlation. Consistently, IHC confirmed significant upregulation of INHBA/ENG in OC, especially in platinum-resistant cases. CAF-derived INHBA promoted OC cell proliferation, invasion, EMT, and cisplatin resistance. Molecular docking suggested a high-affinity INHBA-ENG interaction, which was confirmed by Co-IP in OC-CAF co-cultures. ENG knockdown reversed cisplatin resistance, an effect abrogated by recombinant INHBA. In vivo, CAF-derived INHBA promoted tumor growth and cisplatin resistance in an ENG-dependent manner.

Conclusions

MyoCAFs-derived INHBA binds to ENG on OC cells, inhibits apoptosis, induces EMT, and promotes cisplatin resistance. The INHBA–ENG axis represents a promising therapeutic target for overcoming platinum resistance in OC.