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. 2026 Jul 29;15(1):50. doi: 10.1038/s41389-026-00646-w

CYBRD1 is transcriptionally regulated by RUNX1 and mediates JAK2/STAT3 signaling activation during ovarian cancer progression

Yalong Deng 1,2,#, Qiyu Gan 2,#, Xia Huang 1, Liang Zhu 3, Lina Liu 2, Guozeng Wang 2, Linlin Chang 2, Rui Shi 2, Sufeng Qiang 2, Wenzhi Duan 2, Qin Liu 1, HuiMin Lei 3, Jingxin Cheng 1,2,✉
PMCID: PMC13645810  PMID: 42844251

Abstract

Metastasis and chemoresistance are the leading causes of death in high-grade serous ovarian carcinoma (HGSOC). Our previous studies revealed that the membrane protein cytochrome b reductase 1 (CYBRD1) is a critical prognostic marker for HGSOC, but its role in HGSOC progression and molecular mechanisms remain unclear. Here, we reveal that CYBRD1 is a druggable factor that drives chemoresistance and tumor progression in HGSOC. Importantly, compared with that in their cisplatin-sensitive counterparts, CYBRD1 expression is elevated in cisplatin-resistant cells. Through genetic manipulation, we showed that CYBRD1 inhibition effectively re‑sensitizes cells to cisplatin and suppresses proliferation, migration, and invasion. Targeted gene expression profiling indicated that CYBRD1 inhibition markedly attenuated JAK2/STAT3 signaling. Using point mutants, we confirmed that phosphorylation of CYBRD1 at Tyr252 is essential for the interaction with JAK2, subsequent activation of JAK2/STAT3 signaling and mediating HGSOC progression. CYBRD1 inhibition significantly restored cisplatin sensitivity and exerted a synergistic tumoricidal effect. In vivo, combined CYBRD1 inhibition and cisplatin markedly reduced tumor metastasis. Furthermore, we found that RUNX1 regulates CYBRD1 transcription. These findings highlight that the combination of CYBRD1 inhibitors and conventional chemotherapy is a promising therapeutic strategy for HGSOC, especially in chemoresistant patients.

Subject terms: Ovarian cancer, Cancer therapeutic resistance

Introduction

Ovarian cancer (OC) is the most fatal gynecological malignancy, with more than 300,000 new cases annually and 200,000 deaths [1, 2]. High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive histological subtype and is characterized by delayed detection [3]. Despite advances in treatment strategies and the advent of targeted therapies, the long-term survival rate for advanced HGSOC remains largely unchanged. Many issues, such as metastasis, recurrence, and chemotherapy resistance, remain unresolved. Identifying HGSOC-specific genes has become key to improving therapeutic outcomes.

Membrane proteins (MPs) are proteins attached to or integrated into the cell membrane or organelle membranes to regulate intercellular interactions [4]. MP dysregulation is associated with tumor initiation, progression, and metastasis [5, 6] and is emerging as an important therapeutic target for cancer [7]. Several studies have shown that cytochrome b reductase 1 (CYBRD1) is an important member of the cytochrome B561 family [8] and regulates cell adhesion and metastasis by modulating focal adhesion kinase phosphorylation in lung adenocarcinoma and colorectal cancer [9, 10]. In our previous research, CYBRD1 was identified as a prognostic biomarker in HGSOC [11]; however, its role in pathophysiology and chemotherapeutic response remains elusive.

In this study, we further examined the expression and biological functions of CYBRD1 in HGSOC. We found that elevated CYBRD1 expression in clinical HGSOC tissues is significantly associated with poor progression-free survival and overall survival, particularly in patients who received platinum-based chemotherapy. CYBRD1 promoted the malignant progression of HGSOC in vitro, mechanistically interacting with JAK2 via residues 248-263aa and Tyr252 to activate STAT3 signaling. Furthermore, our research revealed significantly elevated RUNX1 expression in HGSOC and confirmed that RUNX1 transcriptionally regulates CYBRD1 expression. The inhibition of CYBRD1 enhanced cisplatin sensitivity and exerted synergistic tumoricidal effects in vivo. Together, these findings suggest that CYBRD1 is a driver of HGSOC progression and chemoresistance, suggesting that it may serve as a potential therapeutic target.

Result

High CYBRD1 expression is associated with poor survival in platinum-treated HGSOC patients

To identify key MPs involved in HGSOC progression, we analyzed genes that were differentially expressed between advanced (stage III-IV) and early (stage I-II) HGSOC tissues from the TCGA-OV cohort, which was composed of 376 individuals ( | Log2FC | ≥1, q < 0.05), and 1665 upregulated genes were identified. In the GSE51373 dataset, which is composed of 16 platinum-resistant HGSOC cases and 16 platinum-sensitive HGSOC cases, 388 genes were significantly upregulated in platinum-resistant HGSOC. Overlapping these datasets, we identified 35 highly upregulated genes in advanced platinum-resistant HGSOC (Fig. 1A, B). TCGA-OV transcriptomic analysis revealed that CYBRD1 was a poor prognostic marker for PFS (HR = 1.54, P < 0.001) and OS (HR = 1.38, P = 0.0026) (Fig. 1C and D; Supplementary table 2 and 3) in patients with HGSOC, and TCGA datasets analysis showed that the other genes exhibit inferior prognostic value compared with CYBRD1 (Fig. S1). Immunohistochemistry (IHC) of clinical samples revealed predominant nuclear CYBRD1 expression in HSGOC tissues (median IHC score: 6.0) compared with normal ovarian epithelial samples (median IHC score: 3.0) (Fig. 1E, F). Additionally, high CYBRD1 expression was significantly correlated with ascites volume (GSE51831) (Fig. 1G). Platinum-resistant and platinum-sensitive HGSOC tissues were significantly different (P < 0.05), as shown in the representative IHC staining images in Fig. 1H, and high CYBRD1 expression levels were correlated with poor OS in patients with HGSOC (Fig. 1I). The clinical features of the patients are shown in Supplementary table 1. These results demonstrated the pathological and clinical pivotal role of CYBRD1 in progression and platinum resistance in patients with HGSOC.

Fig. 1. CYBRD1 expression is upregulated in HGSOC and is associated with poor prognosis.

Fig. 1

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A Venn diagram of upregulated differential genes in platinum-resistant advanced serous ovarian cancer (HGSOC) from the TCGA database and GEO database (GSE51373). Differentially expressed genes were defined as those whose |log2FC | > 1 and adjusted p value < 0.05. B Volcano plot of the genes whose transcription differed between platinum-resistant HGSOC tissue and platinum-sensitive HGSOC tissue. Genes whose log2FC > 1 and adjusted p value < 0.05 are marked in red. Genes whose log2FC < -1 and adjusted p value < 0.05 are marked in blue. C Influence of CYBRD1 expression levels on progression-free survival and (D) overall survival in patients with HGSOC in the TCGA database. E Expression of CYBRD1 in normal tissue and HGSOC tissue. F Comparison of CYBRD1 expression levels between normal tissue and tumor tissue (HGSOC). G Expression levels of CYBRD1 in HGSOC patients grouped by low-volume ascites ( ≤ 200 mL) and high-volume ascites ( ≥ 1000 mL) in the GEO database (GSE51831). H Comparison of CYBRD1 expression levels in platinum-sensitive and platinum-refractory HGSOC tissue. I Overall survival of patients with low CYBRD1 expression and high CYBRD1 expression in the Shanghai East Hospital HGSOC cohort composed of 114 individuals. E, G, I The results are shown as the means ± SEMs. **p < 0.01. n = 3 per group.

CYBRD1 enhances HGSOC malignancy by activating JAK2-STAT3 signaling

We further investigated CYBRD1 expression levels in seven ovarian cancer cell lines, A2780, SKOV3, HEYA8, OVCAR3, OVCAR5, OVCAR8, and COV362, and RT‒PCR and western blotting revealed heterogeneous CYBRD1 expression (Fig. 2A, B). OVCAR3 cells expressed high levels of CYBRD1, whereas OVCAR5 cells expressed low levels, and these two cell lines were selected for subsequent experiments. Furthermore, we investigated the role of CYBRD1 in malignant behaviors, and the results showed that overexpression of CYBRD1 increased the migration, invasion, and proliferation of OVCAR5 cells, whereas CYBRD1 knockdown suppressed these malignant behaviors in OVCAR3 cells (Fig. 2C–H). These findings highlight CYBRD1 as a promising therapeutic target for HGSOC. To investigate CYBRD1 downstream signaling in HGSOC, RNA sequencing and gene set enrichment analysis (GSEA) were performed on siCYBRD1-OVCAR3 cells, and the results confirmed that the JAK–STAT pathway is downstream of CYBRD1 (Fig. 2I). Further analysis of JAK1, JAK2, and STAT3 expression in HGSOC cell lines by western blot revealed that modulation of CYBRD1 altered the levels of phosphorylated JAK2 (pJAK2) and phosphorylated STAT3 (pSTAT3) but not phosphorylated JAK1 (Fig. 2J). pSTAT3, the active form of STAT3, is translocated to the nucleus and regulates target gene expression. To further validate the regulatory relationship between CYBRD1 and the JAK2/STAT3 pathway, we performed rescue experiments using small-molecule JAK2/STAT3 activators (Colivelin and CoumermycinA1) and inhibitors (AZD1480, Stattic, and ruxolitinib). Our results demonstrated that the activators can rescue the inhibitory effects of CYBRD1 knockdown on proliferation (Fig. 2K), colony formation, migration, and invasion in OVCAR3 cells (Fig. S2A–C), whereas the inhibitors restored the malignancy-promoting effect of CYBRD1 overexpression in OVCAR5 cells (Fig. S2D–I). These results revealed that the JAK2/STAT3 pathway is downstream of CYBRD1 in HGSOC.

Fig. 2. CYBRD1 enhances OC malignancy by activating JAK2-STAT3 signaling.

Fig. 2

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A The mRNA and (B) protein expression levels of CYBRD1 in seven ovarian cancer cell lines (A2780, SKOV3, OVCAR5, OVCAR8, COV362, HEYA8, OVCAR3) were detected by qPCR and western blotting. C mRNA and (D) protein expression of CYBRD1 in OVCAR5 (left) and OVCAR3 (right) after treatment with empty plasmid, CYBRD1 overexpression (OE) plasmid (500 ng), or CYBRD1 siRNAs (20 nM) or mock control for 72 h, as detected by qPCR and western blotting. E Transwell assays and (F) wound healing assays of OVCAR5 and OVCAR3 cells treated with the CYBRD1 overexpression plasmid (500 ng), empty plasmid, CYBRD1 siRNAs (20 nM) or mock control for 48 h. G Viability assays of OVCAR5 and OVCAR3 cells treated with the CYBRD1 overexpression plasmid, empty plasmid, CYBRD1 siRNA (20 nM), or mock control for 72 h. H Colony formation assays of OVCAR5 and OVCAR3 cells treated with the CYBRD1 overexpression plasmid, empty plasmid, CYBRD1 siRNAs (20 nM) or mock control for 10 days. I GSEA of RNA-seq datasets revealed a JAK/STAT signaling pathway in OVCAR3 cells transfected with CYBRD1 siRNAs for 36 h compared with that in the mock control. J The expression of phospho-JAK1 (pJAK1), pJAK2, and pSTAT3 in OVCAR3 and OVCAR5 cells transfected with CYBRD1 siRNAs (20 nM), mock control, or CYBRD1-overexpressing (OE) plasmids (500 ng) or empty plasmids for 36 h was detected by western blotting. K Viability assays of mock control OVCAR3 cells and shCYBRD1-OVCAR3 cells alone or in combination with Colivelin (1 μM) or CoumermycinA1 (0.1 μM) for 72 h, as determined by a CCK-8 assay. G, H, K Data are shown as the means ± SEMs (n = 3 replicates). *p < 0.05; **p < 0.01; ***p < 0.001. Co Colivelin (1 μM), Cou CoumermycinA1 (0.1 μM).

CYBRD1 interacts with JAK2 via the Tyr252 site

To investigate the mechanism through which CYBRD1 regulates the JAK2/STAT3 pathway, we conducted coimmunoprecipitation (co-IP) experiments using antibodies against JAK2 and STAT3. The results revealed that CYBRD1 interacts with JAK2 and STAT3, including their active forms (pJAK2 and pSTAT3), in OVCAR3 cells (Fig. 3A). Knockdown of CYBRD1 reduced the binding of CYBRD1 to JAK2 and STAT3 and decreased the levels of pJAK2 and pSTAT3 (Fig. 3B). PhosphoSitePlus identifies phosphorylation sites of CYBRD1 (Fig. 3C). AlphaFold Server predictions indicate that CYBRD1 interacts with JAK2 at residue Tyr252 (Fig. 3D). To validate this binding mode, FLAG‑tagged CYBRD1 wild‑type (WT) and two mutants (Del 248-263aa and Y 252 A) were expressed in OVCAR5 cells, and co‑IP (Fig. 3E) revealed that FLAG‑CYBRD1 WT associated with endogenous JAK2 and STAT3, while both mutants exhibited reduced binding, indicating that the intracellular domain (248–263 aa) and Tyr252 are critical for the interaction of CYBRD1 with JAK2. Our findings demonstrate that CYBRD1 interacts with JAK2 and STAT3 via its intracellular domain (248–263aa) and Tyr252 site, thereby activating STAT3 signaling in HGSOC cells.

Fig. 3. CYBRD1 interacts with JAK2 and STAT3 via the Tyr252 site.

Fig. 3

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A The interaction of JAK2, STAT3 and CYBRD1 was analyzed by endogenous co-IP assays with anti-JAK2 and anti-STAT3 antibodies in OVCAR3 cells. IgG was used as a negative control. B Endogenous Co-IP assays were performed using anti-JAK2 and anti-STAT3 antibodies in OVCAR3 cells transfected with Mock control or CYBRD1 siRNAs (20 nM) for 36 h; IgG was used as a negative control. C AlphaFold3 was used to predict the spatial conformation of the interaction between CYBRD1 and JAK2. D The phosphorylation sites of CYBRD1 were analyzed using a protein phosphorylation website. E Anti-Flag Co-IP assays of the CYBRD1-JAK2 interaction in OVCAR5 cells transfected with empty plasmid, pcDNA3.1(-) flag-tagged CYBRD1 WT plasmid (500 ng), deletions (500 ng) or mutant (500 ng) for 36 h. EV was used as a negative control. EV, empty plasmid. WT, CYBRD1 wild-type plasmid. Del(248-263aa), CYBRD1 deletions. Mut (Y252A), CYBRD1 mutant. Each experiment was repeated three times.

CYBRD1 knockdown causes tumor suppression and enhances the tumoricidal effect of cisplatin in vivo

Previous studies, public databases, and clinical samples via IHC have suggested a correlation between CYBRD1 expression and sensitivity to platinum chemotherapy. To further validate these observations in OC cell lines, we measured the IC50 values of cisplatin in OVCAR3, COV362, and OVCAR5 cells, which exhibit varying levels of CYBRD1 expression (Fig. 4A). Correlation analysis revealed that higher CYBRD1 expression correlated with increased cisplatin IC50 values across these cell lines (Fig. 4B). CYBRD1 knockdown significantly reduced the IC50 value of cisplatin in OVCAR3 cells, whereas CYBRD1 overexpression markedly increased the IC50 value of cisplatin in OVCAR5 cells (Fig. 4C, Fig. S3). To evaluate whether CYBRD1 knockdown enhances the tumoricidal effect of cisplatin in vivo, we performed combination treatment studies with shCYBRD1 and cisplatin in HGSOC cell-derived xenograft (CDX) models (Fig. 4D and E; Fig. S4). As illustrated in Fig. 4F-H, the tumor sizes and weights of the combined-treated mice were notably lower than those of the shCYBRD1- or cisplatin-treated mice. Hematoxylin and eosin (H&E) and Ki-67 immunostaining further revealed that shCYBRD1 increased cisplatin-induced tumor necrosis and reduced tumor proliferation (Fig. 4I). Additionally, shCYBRD1 treatment was associated with reduced pSTAT3 levels in the OVCAR3 xenografts (Fig. 4I). We then evaluated the effect of shCYBRD1 on tumor metastasis using luciferase-labeled OVCAR3 (OVCAR3-luc) cells inoculated via intraperitoneal injection to develop abdominal OC xenografts (Fig. 4J). Mice were randomized into control, cisplatin (2 mg/kg body weight, biw), shCYBRD1, and Combo (shCYBRD1 plus cisplatin) groups, and tumor metastases were tracked using luciferin-based bioluminescence imaging. Importantly, compared with the shCYBRD1 group, the control group of OVCAR3-luc xenografts exhibited more intense and diffuse bioluminescence signals at the endpoint (Day 42) (Fig. 4K). Moreover, compared with the control treatment, the Combo treatment significantly suppressed tumor metastatic foci and even improved the survival of mice (Fig. 4L and M). Multiple organs (heart, liver, intestine, lung, pancreas, and kidney) were harvested from the sacrificed mice for bioluminescence assays. Similarly, the organ signals of the control group were stronger than those of the shCYBRD1 group (Fig. 4N). As shown in Fig. 4N, compared with the shCYBRD1 group, the control group of OVCAR3-luc xenografts exhibited higher bioluminescence intensity, indicating that shCYBRD1 suppressed tumor metastasis in mice harboring OVCAR3-luc xenografts. Overall, our findings indicate that shCYBRD1 enhances the antitumor efficacy of cisplatin and reduces resistance to this agent both in vitro and in vivo, highlighting CYBRD1 as a potential therapeutic target for overcoming cisplatin resistance.

Fig. 4. CYBRD1 knockdown causes tumor suppression and enhances the tumoricidal effect of cisplatin in vivo.

Fig. 4

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A Cisplatin IC50 (μM) of OVCAR3, COV362, and OVCAR5 cells detected by CCK-8. B Heatmap of CYBRD1 levels and the IC50 values of cisplatin for OVCAR3, COV362, and OVCAR5 cells. C Cisplatin IC50 values of OVCAR3 and OVCAR5 cells treated with Mock control, CYBRD1 siRNAs (20 nM), or an empty plasmid or a CYBRD1 overexpression plasmid (500 ng) plus various concentrations of cisplatin for 72 h, as determined by a CCK-8 assay. D Schematic illustration of the experimental design of the OVCAR3-CDX. E The knockdown efficacy of DOX-inducible OVCAR3 treated with DOX (0.8 μg/mL) for 72 h was detected by western blotting. DOX, doxycycline. F Tumor growth curves, G tumor volumes and H tumor weights of OVCAR3 shCYBRD1-CDX tumors. Water containing 1 mg/mL DOX (in 25 mg/mL sucrose) or the vehicle control (25 mg/mL sucrose) was administered to each group (n = 8). Cisplatin (intraperitoneally injected, 2 mg/kg body weight, twice a week) and Combo (DOX plus cisplatin) were used. I H&E staining, Ki67, CYBRD1 and p-STAT3 staining, and comparisons of these indicated molecules in resected OVCAR3-CDX tumors. J Schematic illustration of the OVCAR3-luc experimental design. Doxycycline-tet-on-shCYBRD1-expressing OVCAR3-luc cells were intraperitoneally injected into BALB/c nude mice. The mice were treated as described above (n = 5). Bioluminescent signals (BLI) were measured via an IVIS imaging system twice a week. K The bioluminescence signals of the indicated groups on Day 7 and Day 42 were quantified by BLI. L Survival curves of OVCAR3-bearing mice in different groups. M Effect of combined treatment with shCYBRD1 and cisplatin on OVCAR3 tumor growth. Weekly average photonic flux. N BLI of multiple organs on Day 56. A, B, F, H–I, K, L The data are shown as the means ± SEMs. (n = 3 replicates). ns, not statistically significant. *p < 0.05; **p < 0.01; ***p < 0.001. C the t-tests was performed.

RUNX1 transcriptionally regulates CYBRD1 expression in HGSOC

To elucidate the regulatory mechanism of CYBRD1, we first identified 20 highly correlated transcriptional regulators (score ≥ 6.0) that were upstream of CYBRD1 through ChIP-seq data in the Cistrome Data Browser Toolkit (http://dbtoolkit.cistrome.org/) (Fig. 5A). Analysis of the TCGA-OV data confirmed that RUNX1 expression correlated significantly with OS (P < 0.001) and disease-specific survival (DFS) (P = 0.001) in OC patients (Fig. 5B). Moreover, a positive correlation was observed between RUNX1 and CYBRD1 expression (Fig. 5C). Analysis of TCGA data (n = 427) revealed that RUNX1 expression was significantly higher in OC tissues than in normal ovarian epithelial tissues (Fig. 5D). The UCSC Genome Browser (https://genome.ucsc.edu/) revealed evidence of RUNX1 binding to the CYBRD1 promoter region (Fig. 5E). Subsequent double luciferase reporter gene assays confirmed that RUNX1 overexpression increased the enrichment of the CYBRD1 promoter region (Fig. 5F–G). In addition, nuclear localization assays verified the presence of RUNX1 in the nucleus (Fig. 5H), and DNA pull-down assays revealed a physical interaction between RUNX1 and the CYBRD1 promoter (Fig. 5I). These findings collectively demonstrate that RUNX1 directly binds to the CYBRD1 promoter and transcriptionally regulates CYBRD1 expression, indicating that RUNX1 is involved in the aggressiveness and prognosis of OC.

Fig. 5. RUNX1 transcriptionally regulates CYBRD1 expression in ovarian cancer.

Fig. 5

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A The top 20 potential transcriptional regulators of CYBRD1 in the Cistrome Data Browser database. B Comparison of RUNX1 expression between serous ovarian cancer and normal ovarian tissue. C Influence of RUNX1 expression levels on the overall survival and disease-specific survival of patients in the TCGA-OC database. D Correlations of RUNX1 and CYBRD1 expression in the TCGA and Genotype-Tissue Expression (GTEx) databases. E Potential binding sites of CYBRD1 on the RUNX1 promoter predicted by the UCSC database. F Structure of the constructs used in the luciferase reporter gene tests and (G) the fold change in CYBRD1 promoter activity in 293 T cells with RUNX1 overexpression compared with that in the control group. H RUNX1 was stained with FITC-conjugated phalloidin after OVCAR5 cells were treated with 500 ng of the RUNX1 overexpression (OE) plasmid for 48 h. Representative images were captured by laser scanning confocal microscopy (scale bar: 50 mm). I DNA pull-down assay showing the binding of RUNX1 to the CYBRD1 promoter region. Biotin-labeled CYBRD1 DNA probes were incubated with nuclear extracts from OVCAR3 cells. Bound proteins were detected by western blotting. Input and negative control samples are included. D, G Data are shown as the means ± SEMs. (n = 3 replicates). **p < 0.01; ***p < 0.001.

RUNX1 promotes HGSOC progression via CYBRD1-mediated JAK2/STAT3 signaling activation

To investigate the functional implications of CYBRD1 in OC mediated by RUNX1, we conducted knockdown and overexpression experiments in OVCAR3 and OVCAR5 cells, respectively. Knockdown of RUNX1 in OVCAR3 cells significantly reduced the protein levels of CYBRD1 and downstream pSTAT3, mirroring the findings in clinical tissue samples (Fig. 6A). Conversely, overexpression of RUNX1 in OVCAR5 cells increased CYBRD1 and pSTAT3 levels (Fig. 6A). Additionally, overexpression of RUNX1 significantly promoted OVCAR5 cell proliferation, colony formation, invasion and migration and was partially attenuated by knockdown of CYBRD1 (Fig. 6B–E). Moreover, knockdown of RUNX1 expression significantly reduced OVCAR3 cell proliferation, colony formation, invasion, and migration, but these effects were partially reversed by the overexpression of CYBRD1 (Fig. 6F-I). In addition, RUNX1 overexpression promoted OVCAR5 cell migration, which was markedly attenuated by CYBRD1 knockdown but rescued upon cotreatment with the STAT3 activator Colivelin (Fig. 6J), and western blotting further verified this finding (Fig. S5). IHC revealed positive co-expression correlations of RUNX1, CYBRD1, and pSTAT3 in human HGSOC specimens (Fig. 6K). Collectively, these findings demonstrated that RUNX1 mediates the activation of STAT3 and promotes HGSOC progression.

Fig. 6. RUNX1 promotes OC progression via CYBRD1-mediated JAK2/STAT3 signaling pathway activation.

Fig. 6

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A The expression of CYBRD1 and downstream molecules in OVCAR3 (left) and OVCAR5 (right) cells transfected with RUNX1 siRNAs (20 nM), mock control, or RUNX1 overexpression (OE) plasmids (500 ng) or empty plasmids for 36 h was detected by western blotting. B Viability assays of OVCAR5 cells incubated with empty plasmid or RUNX1 overexpression plasmid (500 ng) alone or in combination with the shCYBRD1 plasmid for 72 h. C Colony formation assays of OVCAR5 cells treated with empty plasmid or RUNX1 overexpression plasmid (500 ng) alone or in combination with the shCYBRD1 plasmid for 10 days. D Transwell assays of OVCAR5 cells treated with empty plasmid or RUNX1 overexpression plasmid (500 ng) alone or in combination with shCYBRD1 for 48 h. E Wound healing assays of OVCAR5 cells treated with empty plasmid or RUNX1 overexpression plasmid (500 ng) alone or in combination with the shCYBRD1 plasmid for 48 h. F Viability assays of OVCAR3 cells treated with mock control, RUNX1 siRNAs (20 nM) alone or in combination with the CYBRD1 overexpression (OE) plasmid (500 ng) for 72 h. G Colony formation assays of OVCAR3 cells incubated with mock control, RUNX1 siRNAs (20 nM) alone or in combination with the CYBRD1 overexpression plasmid (500 ng) for 10 days. H Transwell and (I) wound healing assays of OVCAR3 cells incubated with mock control or RUNX1 siRNAs (20 nM) alone or in combination with the CYBRD1 overexpression plasmid (500 ng) for 48 h. J Rescue effect of CYBRD1 knockdown on cell migration ability in RUNX1-overexpressing OVCAR5 cells and the abrogation effect of the STAT3 activator Colivelin. Wound healing assays of OVCAR5 cells treated with empty plasmid or RUNX1 overexpression plasmid (500 ng) alone or in combination with shCYBRD1 plasmid and Colivelin (1 μM) for 48 h. Scale bar: 100 µm. K IHC staining of RUNX1, CYBRD1, and p-STAT3 and comparisons of these indicated molecules in high-grade serous ovarian carcinoma tissues. (Scale bar: 100 µm). B–J Data are shown as the means ± SEMs. (n = 3 replicates). *p < 0.05; **p < 0.01; ***p < 0.001; and ****p < 0.0001.

Discussion

Cisplatin remains the first-line treatment for HGSOC. However, effective strategies are urgently needed to overcome inherent disease progression and cisplatin resistance [12]. CYBRD1, a member of the cytochrome B561 family, has attracted increased attention in the context of the malignant progression of multiple tumors [8]. Our previous study revealed that CYBRD1 expression was upregulated in OC tissues compared with normal tissues and was significantly correlated with lymph node metastasis, advanced stage, high pathological grade, and poor prognosis in a TCGA database screening combined with validation in the GEO database and East Hospital cohort [11]. In this study, we revealed that CYBRD1 is a druggable transmembrane protein in HGSOC whose RUNX1-driven, Tyr252-dependent activation of JAK2/STAT3 promotes tumor progression and cisplatin resistance (Fig. 7). CYBRD1 inhibition restored cisplatin sensitivity, suppressed metastatic phenotypes, and synergized with cisplatin in vivo, supporting the combination of a CYBRD1 inhibitor and chemotherapy as a potential strategy for treating platinum-resistant HGSOC.

Fig. 7. Working model illustrating the findings of the current study.

Fig. 7

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CYBRD1 upregulation promotes ovarian cancer progression and cisplatin resistance, and a mechanistic study revealed that CYBRD1 activates JAK2/STAT3 signaling and is regulated by RUNX1.

Previous studies have revealed that CYBRD1, a transmembrane protein, promotes tumor activity through abnormal iron accumulation and modulation of focal adhesion kinase phosphorylation [9, 13]. These actions contribute to the alteration of multiple signaling pathways, including the activation of the JNK/c-Jun pathway and the suppression of the AKT and ERK pathways, observed across various malignancies. We found that CYBRD1 mediates cisplatin resistance in HGSOC mainly through activation of the JAK2/STAT3 pathway. Bioinformatics analysis revealed that CYBRD1 interacts with JAK2 via its intracellular domain, especially at Tyr252, influencing both its catalytic activity and its interaction with STAT3. Mutational analysis using flag-tagged CYBRD1 mutants (Del 248-263aa and Y252A) further confirmed that these mutations attenuate the association of CYBRD1 with STAT3, reinforcing the importance of the intracellular domain of CYBRD1 in binding to STAT3.

The JAK2/STAT3 pathway, a pivotal hub for multiple oncogenic signaling pathways, has been extensively studied in cancer biology [14, 15]. STAT3 is an established oncogene, with pSTAT3 playing a key role in the development, metastasis, and chemotherapy resistance of OC through the transcriptional regulation of key genes and signaling networks, including EMT, the cell cycle, E2F signaling, and stem cell property maintenance [16–18]. Activation of the JAK-STAT3 pathway has been associated with platinum resistance in HGSOC cell lines such as A2780, with preclinical models demonstrating the potential of targeting STAT3 to reverse platinum resistance [19]. Since activation of the JAK2/STAT3 pathway markedly influences the survival of OC cells, inhibition of this pathway represents a promising therapeutic approach, particularly for chemotherapy-resistant patients. In our study, suppression of STAT3 activation using the direct inhibitor Stattic and the JAK1/2 inhibitors AZD1480 and ruxolitinib significantly inhibited the proliferation, colony formation, migration, and invasion of OVCAR3 ovarian cancer cell lines with high CYBRD1 expression. Notably, phase 1/2 clinical trials have demonstrated that ruxolitinib phosphate exerts cytotoxic effects on OC and synergistically enhances the antitumor efficacy of paclitaxel, cisplatin, and carboplatin, with no significant adverse effects, thereby successfully prolonging PFS in patients [20]. These findings suggest that elevated CYBRD1 expression may serve as a molecular biomarker for selecting patients who would benefit from treatment with JAK2 inhibitors such as ruxolitinib. Given the inherent druggable potential of CYBRD1, further investigations into small molecules targeting CYBRD1 will be the focus of our future research endeavors.

To further investigate the upstream regulatory molecules of CYBRD1, we identified Runt-related transcription factor 1 (RUNX1) as a potential transcriptional regulator of CYBRD1 from the Cistrome Data Browser database. RUNX1 resides on chromosome 21q22 and plays an important role in cancer by regulating the expression of tumor-related genes [21, 22]. RUNX1 is highly expressed in solid tumors such as skin cancer, head and neck squamous cell carcinoma, breast cancer, lung cancer, pancreatic cancer, cervical cancer, and endometrial cancer [23–26] and is considered a biomarker of poor prognosis [27–29]. Reports have demonstrated that the RUNX1-STAT3 pathway plays a key role in the occurrence of epithelial tissue-derived tumors [30] and that RUNX1 activates the JAK/STAT signaling pathway, thereby promoting the proliferation and metastasis of glioma cells [31]. Notably, our study reveals, for the first time, that the expression of RUNX1 in ovarian tissue is positively correlated with that of CYBRD1. Additionally, cell function experiments confirmed that RUNX1 activates CYBRD1-mediated JAK2/STAT3 signaling, thereby promoting the proliferation, colony formation, migration, and invasion of HGSOC cells. Further double luciferase reporter gene assays and DNA pull-down experiments indicated that RUNX1 directly occupies the CYBRD1 promoter and transcriptionally upregulates CYBRD1 expression. This study has several limitations. The nontranscriptional regulatory mechanism of CYBRD1 remains unexplored. In addition, the precise transcriptional binding sites between CYBRD1 and RUNX1 were not mapped. Given the pathological heterogeneity of OC, this study focused specifically on the mechanism of CYBRD1 in HGSOC. Clinical translation potential is limited by the absence of CYBRD1-targeted small-molecule inhibitors. These unresolved questions warrant further investigation in subsequent studies.

Materials and methods

Data collection and bioinformatics analysis

RNA-seq data and corresponding clinical data for 376 ovarian cancer patients were retrieved from the TCGA. Two additional transcriptome sequencing datasets from GEO (GSE51831 and GSE51373) were included to supplement the analysis of CYBRD1 expression and clinicopathological features in HGSOC. The KM plotter web tool (http://kmplot.com/analysis/) was used to evaluate the association between CYBRD1 expression and prognosis in HGSOC. Analysis of the correlation of CYBRD1 expression with clinicopathological variables was performed on patients with HGSOC from Shanghai East Hospital between 2010 and 2021, and the basic character of patients is showed in Supplementary table 1. This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Affiliated Shanghai East Hospital of Tongji University School of Medicine (Approval number: 2022-204). The requirement for informed consent was obtained from all participants.

Reagents and cell culture

The human ovarian cell lines COV362, OVCAR3, HEYA8, A2780, SKOV3, OVCAR8, and OVCAR5 were obtained from the Institute of Cell Research, Chinese Academy of Sciences (Shanghai, China), and maintained at 37 °C with 5% CO2 in RPMI (OVCAR3, A2780, and SKOV3) or MEM (COV362, HEYA8, OVCAR8, and OVCAR5) supplemented with 10% fetal bovine serum and penicillin–streptomycin. The culture reagents were supplied by Gibco (USA). Cell lines were confirmed by short tandem repeat profiling, and mycoplasma testing was performed every six months.

Cell transfection

Cells were seeded to reach 30–60% confluence and transfected with siRNAs (and a negative control, siNC) from GenePharma (Shanghai, China) using Lipofectamine 3000 (Invitrogen) according to the manufacturer’s protocol. To overexpress CYBRD1 in OVCAR5, the CYBRD1 coding sequence was cloned and inserted into pcDNA3.1 to generate a CYBRD1 expression vector (oeCYBRD1), with empty pcDNA3.1 as the vector control, and expression changes were validated by qRT‑PCR and western blotting. For in vivo experiments, pTRIPZ-inducible lentiviral CYBRD1 shRNA from Dharmacon Reagents (Texas, USA) was generated by cotransfecting the pTRIPZ lentiviral vector and packaging plasmids into HEK293T packaging cells. After 48 h, the viral supernatant was filtered and used to infect OVCAR3 cells and to prepare cells for tumor formation assays in nude mice.

RNA-Seq analysis

Total RNA was extracted using a TaKaRa RNA extraction kit. RNA sequencing was performed on the BGISEQ‑500 platform (Beijing Genomics Institute, China). After quality filtering, the clean reads were quantified as fragments per kilobase of transcript per million mapped reads (FPKM) with RSEM. Differentially expressed genes between groups were identified using NOISeq (thresholds: fold change ≥ 2 and divergence probability ≥ 0.8). Pathway enrichment analysis was performed with GSEA v4.1.0, employing the Hallmark (H) and Gene Ontology (C5) collections from MSigDB v7.4.

RT‒qPCR

Total RNA was isolated using a TaKaRa kit according to the manufacturer’s protocol, and concentrations were quantified with a NanoDrop spectrophotometer (Thermo Fisher Scientific). RT‑qPCR was carried out on a LightCycler 480 II system (Roche). Gene expression was calculated using the 2 − ΔΔCt method with β‑actin as the internal reference.

Cell viability and cell growth assay

Cell proliferation was evaluated every 24 h using a Cell Counting Kit‑8 (Yeasen, Shanghai, China). Cells (3 × 104/well) were plated in 96‑well plates and cultured at 37 °C in 5% CO2. CCK‑8 reagent was added at 24-h intervals, the absorbance at 450 nm was measured on a Thermo Scientific microplate reader to generate a proliferation curve, and cell confluence was tracked with an IncuCyte ZOOM live‑cell analysis system (Essen BioScience).

Wound-healing assay

Cells were plated in 6-well plates and grown to 90% confluence. A wound was made with a pipette tip, detached cells were removed, and fresh medium supplemented with the specified compounds was added. Images were captured every 12 h with an inverted microscope, and wound closure was quantified using ImageJ.

Transwell assay

Cells were resuspended in serum-free medium and seeded into Corning upper chambers that were either coated with Matrigel or left uncoated. The lower chamber was filled with medium supplemented with 10% FBS. After 16–24 h of incubation, the cells that had passed through the membrane were fixed in 50% methanol and stained with 0.5% crystal violet for 30 min at room temperature. Invaded and migrated cells were quantified by counting cells in three randomly selected fields per membrane using microscopy (Olympus Corporation).

Colony formation assay

Cells (1000 cells/well) were plated in duplicate in 6-well plates and incubated in medium containing the required drugs. When the number of control clones reached 50 cells per clone (approximately 10 days), the colonies were fixed with 1.5 mL of 6.0% glutaraldehyde, stained with 0.5% crystal violet, and counted using ImageJ.

Western blot analysis

Total proteins were isolated from cells using RIPA buffer supplemented with protease and phosphatase inhibitors, and 30–50-μg samples were separated by 10% SDS‒PAGE, transferred to PVDF membranes, blocked for 2 h with nonfat milk, and incubated overnight at 4 °C with primary antibodies against the following proteins: CYBRD1 (Abcam, #ab66048), JAK2 (CST, #D2E12), p-JAK2 (CST, #Tyr1007), STAT3 (CST, #D3Z2G), p-STAT3 (CST, #Tyr705), RUNX1 (SAB, #32574), and β-actin (null, #2D4H5). The anti-flag antibody was obtained from Cell Signaling Technology. The following day, the membranes were incubated with HRP‑conjugated secondary antibodies for 1 h at room temperature, developed with ECL reagents, and imaged on an Odyssey Fc system (LI‑COR Biosciences).

Coimmunoprecipitation (co-IP)

Cells were disrupted in cold NP-40 lysis buffer containing protease and phosphatase inhibitors (Beyotime). The protein concentration was quantified with a BCA protein assay kit (Thermo Fisher Scientific), and 1–1.5 mg of total protein per sample was used for immunoprecipitation. For IP of endogenous protein, the lysates were rotated overnight at 4 °C with anti‑STAT3 or anti‑JAK2 antibodies and then incubated for 3 h with Protein A/G PLUS‑Agarose beads (Santa Cruz) to capture the immunocomplexes. For the Flag‑CYBRD1 pulldowns, the lysates were incubated overnight at 4 °C with anti‑Flag M2 magnetic beads (Sigma‑Aldrich). Bead pellets were washed three times with cold PBS, resuspended in 2× SDS loading buffer, and boiled for 5 min. Co-IP proteins were subsequently analyzed by western blotting.

Luciferase reporter gene test

The CYBRD1 promoter segment encompassing the RUNX1 binding site was inserted into a pGL3 vector to drive firefly luciferase expression. Promoter activity was evaluated in three models: wild-type 293 T cells, control cells, and CYBRD1-overexpressing cells. Each was cotransfected with the promoter-driven firefly construct and a promoterless Renilla plasmid using Lipofectamine 3000 (Invitrogen) following the manufacturer’s protocol. Twenty-four hours after transfection, the cell lysates were analyzed with the Dual-Luciferase Reporter Assay System (E1910; Promega, USA), and luminescence was measured using an EnVision Nexus Multimode Microplate Reader (PerkinElmer).

Immunofluorescence

Immunofluorescence staining was performed on OVCAR5 cells after transfection with oeRUNX1 for 48 h. Coverslips were fixed in paraformaldehyde, permeabilized with Triton X-100, blocked in 1% BSA, incubated with an anti-RUNX1 antibody (SAB, #32574) followed by an anti-rabbit IgG (H + L, Alexa Fluor® 555 Conjugate) antibody (Beyotime, China, #A0453), and examined by fluorescence microscopy.

DNA pulldown assay

A total of 500 μg of nuclear protein extract combined with 5 μg of a biotin-labeled promoter double-stranded oligonucleotide probe and 100 μL of streptavidin magnetic beads (MCE, China, #HY-K028) were incubated overnight at 4 °C. Following centrifugation at 5000 × g for 5 min in a precooled fixed‑angle rotor, the protein–DNA–probe pellet was resuspended in 30 μL loading buffer. After being boiled for 10 min, the complexes were analyzed by immunoblotting.

Mouse tumor xenograft model

Female BALB/c nude mice (6–8 weeks old, 15 ± 1.7 g; Shanghai Promedican Pharmaceutical Technology Co., Ltd.) received subcutaneous injections of approximately 2 × 106 doxycycline‑tet‑on‑shCYBRD1 OVCAR3 cells into the right flank. Drinking water containing 1 mg/mL doxycycline in 25 mg/mL sucrose or the control (25 mg/mL sucrose) was provided one day before tumor inoculation. The mice were subsequently assigned to one of four groups: control (sucrose water), cisplatin (intraperitoneal cisplatin 2 mg/kg twice weekly), shCYBRD1 (doxycycline water), or Combo (doxycycline water plus cisplatin). The tumor volume was measured every 3 days with calipers and calculated as length × width2 × 0.5. The animals were sacrificed 42 days after implantation, and the tumors were collected for weighing and subsequent in vitro assays. In a parallel intraperitoneal model, 2 × 106 luciferase‑labeled doxycycline‑tet‑on‑shCYBRD1 cells were injected into the left lower quadrant (5 mice per group), and weekly body weight monitoring and bioluminescence imaging (BLI) were performed using an IVIS Spectrum system (PerkinElmer). Prior to imaging, the mice were given 150 mg/kg D-luciferin in sterile DPBS by intraperitoneal injection and anesthetized with isoflurane, after which images were acquired and analyzed using Live Imaging software. The animal studies were approved by the Animal Care and Use Committee of Tongji University.

Immunohistochemistry (IHC)

IHC was conducted using specific antibodies following previously established protocols [32].

Statistical analysis

Experiments were performed in triplicate or more. Data were processed using GraphPad Prism v8.0 (GraphPad Software, La Jolla, CA, USA) and SPSS v25 (IBM Corp., Armonk, NY, USA), and the results are reported as the means ± standard deviations. Continuous variables were compared by Student’s t‑test or one‑way ANOVA. The IC50 determination was performed using GraphPad Prism software with nonlinear regression analysis. Dose–response curves were generated by plotting cell viability against the logarithm of drug concentration, and IC50 values were calculated by fitting the data to a Log (drug concentration) model. The P < 0.05 was considered to indicate statistical significance (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001); ns, not significant.

Supplementary information

Supplementary Tables (22.6KB, docx)
41389_2026_646_MOESM2_ESM.pdf (6.1MB, pdf)

supplementary figures and figure legends

Author contributions

Yalong Deng and Qiyu Gan conceived and designed the experiments, authored, approved the final manuscript. Xia Huang, Lina Liu, Sufeng Qiang, and Wenzhi Duan analyzed the data and prepared figures. Guozeng Wang, Linlin Chang, Qin Liu and Rui Shi provided suggestions on the study design and analyzed the data. Liang Zhu and Huimin Lei reviewed the manuscript, Jingxin Cheng and Liang Zhu designed and supervised the research, Jingxin Cheng obtained funding. Liang Zhu and Huimin Lei gave intelligent support. All authors read and approved the final manuscript.

Funding

This work was funded by the National Natural Science Foundation of China (grant number 82260587), and the Fundamental Research Funds for the Central Universities (grant number 22120240343).

Data availability

Data available on request from the corresponding author.

Competing interests

The authors declare no competing interests.

Ethics approval

The study was approved by the Ethical Committee of Shanghai East Hospital (NO: 2022-204).

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Yalong Deng, Qiyu Gan.

Supplementary information

The online version contains supplementary material available at https://doi.org/10.1038/s41389-026-00646-w.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Tables (22.6KB, docx)
41389_2026_646_MOESM2_ESM.pdf (6.1MB, pdf)

supplementary figures and figure legends

Data Availability Statement

Data available on request from the corresponding author.

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