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. 2025 Oct 5;19(1):e70034. doi: 10.1049/syb2.70034

Deciphering the Molecular Mechanisms of Polycystic Ovary Syndrome and Flaxseed Therapy Through Transcriptomics and Machine Learning

Siyu Tian 1, Qiang Tang 2, Shijie Liu 3, Yang Yu 4, Juanjuan Kang 5,✉, Min Shen 2,✉
PMCID: PMC12497539  PMID: 41047472

ABSTRACT

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder characterised by heterogeneous clinical and molecular phenotypes. Flaxseed, widely used in traditional Chinese medicine and as a nutritional supplement, has shown promising therapeutic potential for PCOS. In this study, we integrated transcriptomic data with machine learning‐based analytical approaches and network pharmacology to investigate the molecular mechanisms underlying PCOS and to identify the potential targets and pathways modulated by flaxseed. Differentially expressed genes (DEGs) and PCOS‐related targets were systematically identified from GEO, GeneCards and DisGeNet databases. Bioactive compounds in flaxseed were predicted using TCMSP, SwissTargetPrediction and INPUT2.0. Functional and pathway enrichment analyses were conducted to explore mechanistic insights. Core targets were prioritised using Centiscape network topology parameters and LASSO regression, followed by molecular docking validation using AutoDock. Our results revealed that flaxseed's therapeutic action may primarily involve modulation of immune regulation, insulin signalling, apoptosis and inflammation pathways. Key active compounds, notably β‐sitosterol and stigmasterol, exhibited strong binding affinities with critical targets, such as IL1B, GSK3B and HMGCR, suggesting potential anti‐inflammatory and antioxidant effects. The findings provide a theoretical foundation for future experimental studies and support the development of flaxseed‐based therapeutic strategies for PCOS through precision medicine frameworks.

Keywords: complex networks, data mining, learning (artificial intelligence)

This study integrates transcriptomic analysis, machine learning and network pharmacology to explore the molecular mechanisms of flaxseed in the treatment of polycystic ovary syndrome (PCOS). Core targets, including IL1B, GSK3B and HMGCR, were identified and validated through molecular docking and immune infiltration analysis. The findings highlight the therapeutic potential of flaxseed in modulating inflammation, insulin signalling and hormonal regulation in PCOS.

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1. Introduction

Polycystic ovary syndrome (PCOS) is a prevalent gynaecological endocrine disorder with an uncertain aetiology, affecting 5%–20% of reproductive‐aged women [1]. It is characterised by reproductive dysfunction, elevated androgen levels, polycystic ovarian morphology and metabolic disturbances, including insulin resistance and obesity. These factors increase the risk of chronic conditions, such as type 2 diabetes [2], hyperlipidaemia and hypertension [3], imposing significant health and psychological burdens for affected individuals.

Current drug therapies for PCOS are often ineffective. Oral contraceptives are commonly prescribed to regulate follicle‐stimulating hormone and luteinizing hormone levels in patients with menstrual cycle disorders, thus restoring the menstrual cycle. Although drug therapy can alleviate PCOS symptoms, these hormone modulators may negatively impact metabolic function and lipid metabolism [4]. Moreover, the recurrence rate is high after discontinuation of medication, leading to substantial economic burdens for both patients and society [5]. Furthermore, some patients respond poorly to ovulation induction therapy, while others remain unable to conceive despite treatment. These therapies may also increase the risks of multiple pregnancies and ovarian hyperstimulation syndrome [6]. Given the multifactorial nature of PCOS, a multidisciplinary treatment approach is essential. Lifestyle and dietary interventions are central to managing the condition, as they directly influence metabolic and endocrine pathways [7]. Additionally, herbal medicine has recently gained attention for its potential role in treating PCOS, particularly in improving metabolic parameters, insulin sensitivity and hormonal balance [8]. However, comprehensive research on the underlying mechanisms of these treatments remains limited.

Numerous studies suggest that flaxseed, a traditional Chinese medicine and nutritional supplement, may offer therapeutic benefits for PCOS. Its safety is well‐established due to its status as a food source. Flaxseed is rich in fats, proteins, dietary fibre, minerals, α‐linolenic acid, lignans, mucilage, and various vitamins. These components exhibit significant antioxidant properties and demonstrate potential health benefits, particularly in lipid‐lowering and blood pressure reduction [9]. Additionally, flaxseed has been shown to effectively lower androgen levels in the adjunctive treatment of prostate cancer, a condition closely linked to elevated androgen levels [10]. Animal studies have further confirmed that flaxseed can significantly reduce testosterone levels in a rat model of PCOS [11]. A randomized, double‐blind, placebo‐controlled trial conducted by Golara Mirmasoumi et al. confirmed the positive role of ω‐3 fatty acids from flaxseed oil in the treatment of PCOS [12]. Moreover, a clinical retrospective study, through a comprehensive analysis of nine relevant publications, suggested that flaxseed has beneficial effects in regulating lipid metabolism, reducing oxidative stress, improving insulin resistance, and modulating menstrual cycles [13].

Despite these promising findings, the lack of a systematic explanation for flaxseed's mechanisms remains a gap in the literature. Therefore, our study utilises transcriptomic data to explore the pathophysiological mechanisms of PCOS, employing machine learning [14, 15, 16, 17, 18] and network pharmacology to predict potential targets and pathways for flaxseed treatment. This research study aims to lay the foundation for future investigations.

2. Materials and Methods

2.1. Identification of Differentially Expressed Genes and Disease Targets for PCOS

We queried the GEO database using the keyword ‘polycystic ovarian syndrome’, filtering for data from ‘Homo sapiens’ and ‘Expression profiling by array’. After excluding unrelated studies from the screening results, we selected the GSE54248 dataset, which includes the healthy and PCOS peripheral blood mRNA expression profiles. Differentially expressed genes (DEGs) were identified and screened using the ‘limma’ R language with the criteria of ‘AdjPvalue ≤ 0.05’ and ‘|logFC| > 0.684’ (average (|logFC|) + 2std(|logFC|)) for further investigation of the pathological mechanisms. In this process, we further employed quantile normalisation to improve the reproducibility of our analysis.

To identify PCOS disease targets, we searched the GeneCards [19] and DisGeNet [20] databases with the keyword ‘polycystic ovarian syndrome’. Targets were filtered by selecting those with a relevance score at least twice the median to ensure an appropriate quantity, and then they were deduplicated and merged with DEGs to identify potential therapeutic targets for PCOS, which were used to explore the mechanism of flaxseed treatment.

2.2. Identification and Target Prediction of Flaxseed Active Ingredients

Active ingredients of flaxseed were identified by screening the TCMSP database [21] with criteria of oral bioavailability (OB) ≥ 30% and drug‐likeness (DL) ≥ 0.18. SMILES representations of these ingredients were obtained from the PubChem database [22] for target prediction. If relevant information could not be retrieved from PubChem, the NovoPro online tool was employed to convert 3D molecular structures to SMILES representations [23].

Targets of Flaxseed ingredients were obtained from TCMSP and INPUT2.0 databases [24]. Additionally, The SwissTargetPrediction [25] tool was utilized to predict ingredient targets with a probability greater than 0.5. The targets of flaxseed ingredients were integrated and de‐duplicated.

2.3. Network Analysis and Key Target Identification for Flaxseed in PCOS Treatment

The potential targets for flaxseed in treating PCOS were identified using Venny 2.1.0. A comprehensive network integrating Traditional Chinese Medicine, ingredients, diseases, and targets was constructed with Cytoscape 3.9.1 [26, 27]. PPI network among these targets were obtained from the STRING database. Key genes were selected using the Centiscape 2.2.0 plugin, based on node closeness, betweenness and degree values. Subsequently, the LASSO algorithm, implemented using the ‘glmnet’ package in R with ten‐fold cross‐validation, was applied to determine the optimal lambda value. This lambda value was then used to construct the model and further identify core genes.

2.4. Bioinformatics Analysis of DEGs and Potential Targets of Flaxseed

DEGs were analysed using Gene Set Enrichment Analysis (GSEA) with the ‘clusterProfiler’ package in R. GSEA was performed using 1000 permutations with the ‘phenotype’ labelling mode [28]. Immune cell infiltration abundance in samples was calculated using the ‘Cibersort’ package. Rank‐sum tests were employed to compare the levels of 22 immune cells between the PCOS and healthy groups, identifying the immune cells with significant differences in infiltration. Spearman correlation analysis was conducted to assess the relationship between key gene expression and the infiltration of differential immune cells. GO and KEGG pathway enrichment analyses for DEGs and targets were carried out using the Metascape [29], with thresholds set at the min overlap of 3, the p value of 0.01, and min enrichment of 1.5 [30].

2.5. Molecular Docking

The mol2 format files for major ingredients were downloaded from the TCMSP database, and protein structure files were retrieved from the PDB database. AutoDockTools 1.5.6 was used to remove water molecules and add hydrogen atoms, and saved the files in pdbqt format. The target protein acted as the receptor, whereas the processed ingredients served as small‐molecule ligands. The size of grid box was defined, and molecular docking was performed using AutoDock Vina scripts. The docking results were visualised using PyMOL.

3. Results and Discussion

3.1. DEGs Analysis of PCOS

Transcriptomics analysis identified 190 DEGs, with 107 upregulated and 83 downregulated (Figure 1A). GO and KEGG enrichment analyses were performed based on these DEGs (Figure 1B). In biological processes (BP), these DEGs were predominantly involved in immune response, apoptosis, inflammation and cell differentiation. In cellular components (CC), they were linked to ficolin‐1‐rich granules, receptor complexes, biological membranes and cellular folds. Molecular functions (MF) highlighted their association with NAD + nucleotide enzyme activity, protein kinase regulation and p53 binding. The enriched KEGG pathways included tuberculosis, Th17 differentiation, JAK‐STAT signalling, carbon metabolism, cytokine–receptor interactions, measles, prostate cancer, PI3K‐Akt signalling pathway, amoebiasis and MAPK signalling pathway. GSEA analysis indicated that upregulated pathways were associated with toll‐like receptor (TLR) signalling, lipid metabolism, and atherosclerosis, whereas downregulated pathways were related to ribosomes, DNA replication and primary immunodeficiency (Figure 1C,D). It is noteworthy that TLR signalling pathway upregulated according to GSEA is closely associated with inflammatory response in immune cells. The inflammatory response is primarily mediated by immune cells, such as macrophages and dendritic cells. TLRs, which are crucial components of pathogen recognition receptors, are expressed on the surface of immune cells. Upon recognising pathogen‐associated molecules, TLRs initiate an immune response, including inflammation [31, 32]. Activation of pattern recognition receptors (PRRs) stimulates transcription factors, such as nuclear factor‐κB (NF‐κB), activating protein‐1 (AP‐1), and interferon regulatory factor 3 (IRF3), leading to the expression of inflammatory mediators [33]. Although inflammation is typically a protective response of the immune system to external stimuli, excessive and chronic inflammation contributes to inflammatory diseases, which is one of the hallmark features of PCOS. Furthermore, numerous studies suggest that TLRs play a critical role in the development of PCOS, influencing androgen metabolism, insulin resistance, and embryo quality, among other factors [34, 35].

FIGURE 1.

FIGURE 1

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DEGs analysis of PCOS. (A) Volcano map of DEGs. (B) GO and KEGG combination bubble diagram. (C) Upregulation pathway of GSEA. (D) Downregulation pathway of GSEA.

The enrichment pathways of DEGs mostly focus on immune signalling, cells and their differentiation (more in immune cells). These findings highlight the autoimmune characteristics of PCOS and suggest that future treatment strategies for PCOS could consider immune regulation as a therapeutic aspect. Additionally, pathways related to insulin signalling, inflammation, cell structure development, differentiation, apoptosis and lipid metabolism were also identified. Pervious research studies indicate that PCOS, characterised by hyperandrogenism, insulin resistance, and chronic low‐grade inflammation, often begins with hyperandrogenism due to ovarian dysfunction, leading to metabolic and hormonal changes [3]. On the other hand, hyperinsulinemia can cause insulin resistance, and insulin resistance also can exacerbate hyperandrogenism [36, 37]. This interaction is mutually reinforcing and contribute to clinical manifestations, such as hirsutism, acne, alopecia, follicular development and ovulation disorders. Additionally, low‐grade inflammation can impair insulin efficacy, further worsening insulin resistance [38], which may indirectly worsen hyperandrogenism. Elevated androgen levels can also trigger inflammatory factors secretion, intensifying chronic inflammation [39].

Thus, the mechanism underlying this process likely involves the combined influence of environmental and genetic factors, with hyperandrogenism potentially preceding and triggering systemic chronic low‐grade inflammation. This inflammation, in turn, mediates the development of insulin resistance, which further exacerbates the hyperandrogenism. Regardless of which factor appears first, the relationship among hyperandrogenism, inflammation, and insulin resistance is causal, mutually influential, and cyclically self‐reinforcing, collectively contributing to reproductive dysfunction and metabolic disorders in PCOS. Overall, insulin resistance, hyperandrogenism and inflammation are not only the major pathological factors of PCOS but also the key targets for its treatment.

3.2. The Potential Mechanisms of Flaxseed in the Treatment of PCOS

Seven flaxseed ingredients were identified (Supporting Information S1: Table S1), corresponding to 278 targets. Besides, 2054 potential therapeutic targets for PCOS were identified from the combination of DEGs, GeneCards and DisGeNet. The overlap between these potential therapeutic targets and the flaxseed ingredients targets resulted in 115 potential therapeutic targets (Figure 2A). A comprehensive network of ingredients, disease and targets was constructed (Figure 2B).

FIGURE 2.

FIGURE 2

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Potential mechanistic analysis of flaxseed in the treatment of PCOS. (A) Identification of potential targets for flaxseed in the treatment of PCOS. (B) TCM‐ingredients‐disease‐targets network. Green nodes represent active ingredients and orange nodes represent potential therapeutic targets. (C) GO enrichment result of potential targets for flaxseed in the treatment of PCOS. (D) KEGG enrichment result of potential targets for flaxseed in the treatment of PCOS.

GO and KEGG enrichment analyses of the 115 targets were performed using Metascape. The BP results indicate that flaxseed is related to cellular responses to hormones, growth factors and lipopolysaccharides, as well as steroid metabolism, blood circulation, MAPK cascade reactions, and the development of female reproductive organs (Figure 2C). In terms of CC, flaxseed is associated with membrane stability, membrane proteins, cell structures and signalling. MF analysis revealed associations with steroid binding, protein kinase activity, phosphorylation pathways and various receptors, including G protein‐coupled receptors and vitamin D receptors. Notably, literature indicates that vitamin D may aid in treating PCOS [40]. KEGG analysis identifies core signalling pathways involved in flaxseed treatment of PCOS, including cancer‐related pathways, lipid metabolism and atherosclerosis, serotonin synapses, progesterone‐mediated oocyte maturation, p53 signalling pathway, ovarian steroidogenesis, MAPK signalling pathway, TNF signalling pathway, and PI3K‐Akt signalling pathway (Figure 2D).

Both GO and KEGG analyses suggest that the therapeutic targets of flaxseed for PCOS are primarily focused on pathways related to sex hormone production and response, cell differentiation and development, lipid metabolism and inflammatory signalling. These pathways align with the three key pathological mechanisms of PCOS outlined earlier. They are crucial for insulin signalling and closely associated with the development of insulin resistance. Tumour necrosis factor‐alpha (TNF‐α) can mediate the formation of insulin resistance through various ways, such as affecting glucose transporter type 4 (GLUT4) and insulin receptor substrate 1(IRS‐1), playing an important role in type 2 diabetes [41]. The PI3K‐Akt pathway induces insulin resistance by decreasing IRS‐1 related factors activity [42], whereas overexpression of the ERK pathway, part of the MAPK signalling, disrupts insulin signalling, leading to insulin resistance [43]. KEGG also identifies a cancer‐related pathway that warrants attention, with the bladder cancer results suggesting a potential co‐disease and co‐treatment mechanism between the two, offering a promising avenue for future research. Additionally, KEGG analysis indicates that flaxseed may exert a therapeutic effect by regulating the cell cycle. For example, the tumour suppressor protein p53, plays a crucial role by upregulating Bax (promoting apoptosis) and downregulating Bcl‐2 (inhibiting apoptosis), which increases granulosa cell death [44]. Follicular dysplasia is a prominent characteristic of PCOS, linked to granulosa cell apoptosis [45]. This apoptosis may contribute to infertility and recurrent miscarriage in PCOS patients.

3.3. Identification of Core Therapeutic Targets in PCOS

The Centiscape algorithm identified 24 key genes based on PPI network (Figure 3A,B), and LASSO analysis ultimately selected three core genes: IL1B, GSK3B and HMGCR (Figure 3C), which may serve as potential therapeutic targets.

FIGURE 3.

FIGURE 3

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Core target screening. (A) PPI network of the potential targets. (B) Core targets filtered by Centiscape algorithm. (C) Core targets filtered by LASSO.

IL1B (Interleukin 1β) is an inflammatory factor produced by immune cells, critical for follicle development, ovulation and fertilization [46]. Donesky et al. found that IL1B promotes progesterone degradation and inhibits oestrogen formation, and both hormones have anxiolytic effects [47]. Thus, IL1B may influence PCOS symptoms, menstrual cycles, and follicle development. GSK‐3β (Glycogen Synthase Kinase 3β) is a conserved serine/threonine kinase involved in various signalling proteins and transcription factors. It is associated with insulin signalling pathways and hepatic glycogen metabolism, regulating cell differentiation, proliferation, survival and apoptosis and potentially addressing the abnormal apoptosis of granulosa cells in PCOS ovaries. Studies suggest that PCOS patients face a higher risk of dyslipidemia and cardiovascular diseases compared to age‐matched women [48]. HMGCR (3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase), a key enzyme in the mevalonate pathway of cholesterol biosynthesis. It may be an important target for flaxseed in managing PCOS‐related obesity and preventing long‐term cardiovascular diseases.

3.4. Immune Cell Infiltration Patterns in PCOS and Their Association With Key Targets

Immune Infiltration analysis (Figure 4A) reveals significant differences between CD8+ T cells and neutrophil subpopulations (p < 0.05). The PCOS group have lower levels of CD8+ T cells and higher levels of neutrophils compared to the healthy group. Single‐gene analysis indicates that GSK3B has the strongest positive correlation with neutrophils (Spearman's r = 0.95), whereas HMGCR is most negatively correlated with CD8+ T cells (Spearman's r = −0.79) (Figure 4B).

FIGURE 4.

FIGURE 4

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Immune infiltration analysis. (A) Difference analysis of 22 immune cells between healthy and PCOS groups. * represents the p value of 0.01–0.05, ns represents no significance. (B) Spearman correlation between core targets and immune cells.

Clinical studies have identified characteristic changes in peripheral blood T cell subpopulations in PCOS patients, including increased CD4+ T cells, decreased CD8+ T cells and a higher CD4+/CD8+ ratio, which are associated with infertility and recurrent miscarriage [49]. Elevated neutrophil counts, indicative of chronic inflammation, may serve as potential biomarkers for PCOS [50]. Additionally, GSK‐3β has been shown to reduce inflammation and neutrophil levels, thereby mitigating tissue damage [51]. As one of the targets of flaxseed, this suggests that flaxseed may play an anti‐inflammatory role by affecting the proliferation and differentiation of T cells and neutrophils through GSK‐3β. However, the specific mechanism needs further study. A large number of literature have shown that intake of flaxseed has health effects such as lowering serum lipid levels and reducing body weight, but whether it is related to HMGCR remains to be explored. A study on anti‐HMGCR‐related myopathy also found CD4+ and CD8+ T cells in muscle biopsy samples [52]. These findings may provide insight into the relationship between core genes and immune cell subpopulations. Furthermore, immune infiltration analysis reveals that T cells and neutrophils are associated with HMGCR, with neutrophils showing a positive correlation and T cells a negative correlation. We hypothesise that these associations may be mediated by indirect factors, such as obesity, which is closely linked to inflammation, rather than direct mechanisms, because immune cells are directly related to inflammation, whereas HMGCR, as a key enzyme in cholesterol metabolism, is directly involved in obesity. Regarding the observed differences in correlations, we suggest that the relationship between the core target and immune cells may be influenced by immunological markers of PCOS, resulting in changes that align with these markers. However, further research is required to confirm this hypothesis. A retrospective study [33] has shown that certain components of flaxseed exert immunosuppressive activity on T cells, thereby promoting immunomodulatory and anti‐inflammatory effects. The mechanisms underlying these effects involve several molecular pathways, such as toll‐like receptors and TNF‐α. Notably, the NF‐κB pathway plays a crucial role in this process. Whether considering the key genes and immune cells mentioned above, or flaxseed and immune cells, these findings further underscore the importance of flaxseed in immune regulation in PCOS.

3.5. Molecular Docking Validation of Key Bioactive Compounds and Their Potential Targets

Our analysis identified sitosterol and β‐sitosterol as the active ingredients with the highest number of targets, totaling 95 in the TCM‐ingredients‐disease‐targets network. Given their structural and chemical similarities, along with identical targets, we focused on β‐sitosterol and stigmasterol (which has 44 targets) to minimise redundancy. Although β‐sitosterol and stigmasterol do not exhibit the highest OB and DL values, they still show significant therapeutic potential.

To further investigate this hypothesis, we conducted a literature review. Previous research studies have demonstrated that β‐sitosterol offers many beneficial effects, including reducing blood cholesterol levels, preventing inflammation, modulating immune responses and combating oxidative stress [9, 53]. Stigmasterol can reduce plasma cholesterol, having antioxidant and anti‐inflammatory properties, and lowers liver glucose‐6‐phosphatase activity, enhancing insulin levels and exerting hypoglycemic effects plasma cholesterol levels. Although flaxseed contains other beneficial components, such as α‐linolenic acid and lignans, which offer therapeutic benefits for various chronic metabolic diseases, including PCOS, this study focuses specifically on the primary therapeutic compounds in flaxseed—β‐sitosterol and stigmasterol—based on previously discussed content and literature review. Accordingly, molecular docking studies were conducted to examine the interaction of these two active compounds with three key targets: IL1B, GSK3B and HMGCR.

Molecular docking studies indicated strong binding affinities between these ingredients and the core targets (energies below −5 kJ/mol‐1, Supporting Information S1: Table S2, Figure 5A–F), with β‐sitosterol showing the highest affinity for IL1B (−8.94 kJ/mol, one hydrogen bond) (Figure 5A).

FIGURE 5.

FIGURE 5

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Schematic diagram of molecular docking. (A) IL1B and β‐sitosterol. (B) HMGCR and β‐sitosterol. (C) GSK3B and β‐sitosterol. (D) IL1B and stigmasterol. (E) HMGCR and stigmasterol. (F) GSK3B and stigmasterol.

4. Conclusions

Flaxseed (the dried and mature seed of the flax family plant Linum usitatisimum L), known in Chinese medicine as Yamazi, is recognized for its ‘sweet taste, mild warmth, and nontoxic nature’. It is used to treat conditions such as ‘rubella and eczema’, ‘pulmonary tuberculosis’, and ‘intestinal heat and erysipelas’ according to traditional Chinese medicine theory [54]. Differential gene analysis suggests that PCOS shares mechanisms with these traditionally treated conditions. The sweet and mildly warm characteristics of flaxseed may be associated with its anti‐inflammatory properties and effects on circulation and metabolism. Functional analysis of potential PCOS targets reveals that flaxseed may benefit hormone imbalances, chronic inflammation and cellular oxidative stress in PCOS. KEGG pathway enrichment highlights insulin resistance pathways in PCOS, suggesting flaxseed's role in alleviating this condition.

Unlike traditional Chinese medicine therapies that tonify the liver and kidneys to support fertility, flaxseed primarily influences the Yangming meridian and the Foot Jueyin liver meridian [55]. It works by enhancing the body's Zhengqi (righteous qi) and expelling Xieqi (pathogenic qi), thus regulating blood and qi. In contrast to the term ‘tonic’, the concept of ‘adjustment’ more accurately reflects its effects. In other words, flaxseed might have advantages over its hormone‐like effects (similar to tonifying liver and kidney) in regulating overall circulation, metabolism, and inflammation (associated with the Yangming meridian and Foot Jueyin liver meridian). Its main active components, β‐sitosterol and stigmasterol, exhibit similar effects (Figure 6).

FIGURE 6.

FIGURE 6

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PCOS mechanism and treatment mechanism of flaxseed.

Our study utilised transcriptomics, machine learning and network pharmacology to systematically investigate the pathological mechanisms of PCOS and the pharmacological roles of flaxseed in its treatment. The results suggest that flaxseed may target lipid metabolism, inflammation and cell cycle‐related pathways to exert therapeutic effects, which align with the core pathological mechanisms of PCOS, including insulin resistance, hyperandrogenism and chronic inflammation. These findings offer valuable insights into future treatment strategies. Network pharmacology revealed flaxseed influences multiple signalling pathways associated with PCOS, including TNF, PI3K‐Akt, MAPK and p53, interacting with key targets IL1B, GSK3B, and HMGCR, which affect hormone imbalance, abnormal cell apoptosis, and dysregulation of glucose/lipid metabolism [56]. For example, IL1B influences follicular development, ovulation and fertilization processes through signalling pathways such as NF‐κB and TNF. GSK‐3β inhibits its activity by phosphorylating glucose, thus reducing hepatic glycogen synthesis and increasing blood glucose levels, a process regulated by the insulin signalling pathway. Additionally, GSK‐3β can modulate the Bax/HKII ratio by affecting blood glucose concentration, which subsequently influences mitochondrial permeability and the release of cytochrome C, playing a role in the regulation of apoptosis. In PCOS, abnormalities in lipid metabolism are closely associated with the development of insulin resistance. However, further research is needed to investigate these mechanisms. Nevertheless, network pharmacology has provided insights into some of the underlying mechanisms, revealing that flaxseed plays a beneficial, significant, and multi‐targeted role in the progression of the core pathological mechanisms of PCOS. Immune analysis identified CD8+ T cells and neutrophils as the primary dysregulated immune cells in PCOS, closely linked to core targets. The key ingredients, β‐sitosterol and stigmasterol, showed high affinity for core targets [57].

This study through co‐analysis of PCOS pathological mechanism and flaxseed therapeutic mechanism, elucidates the potential flaxseed's mechanisms in treating PCOS and identifies key targets for clinical applications. We have demonstrated its potential as both a nutritional and pharmacological intervention for managing PCOS. We further explored the strong association between flaxseed and the three core pathological mechanisms of PCOS, confirming its significant value in treating this condition and providing new avenues for future research into PCOS treatment and flaxseed's therapeutic mechanisms. Notably, a preliminary clinical trial in PCOS patients [58] has reported that flaxseed supplementation improves insulin sensitivity, lipid metabolism and inflammatory state, which aligns with the bioinformatics predictions of this study. However, bioinformatics methods have inherent limitations, including the lack of experimental validation and robust clinical controls [59, 60, 61]. Future research efforts are encouraged to address these gaps by supplementing relevant vitro studies and enhancing clinical trials to evaluate the efficacy of flaxseed supplements.

Author Contributions

S.T. and Q.T. conceived and designed the work. S.T. performed the data collection and analysis. Q.T., S.L., and Y.Y. visualized the results. S.T. wrote the manuscript. J.K. and M.S. reviewed and edited the manuscript.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Supporting information

Supporting Information S1

SYB2-19-e70034-s001.docx (18KB, docx)

Tian, Siyu , Tang Qiang, Liu Shijie, Yu Yang, Kang Juanjuan, and Shen Min. 2025. “Deciphering the Molecular Mechanisms of Polycystic Ovary Syndrome and Flaxseed Therapy Through Transcriptomics and Machine Learning.” IET Systems Biology: e70034. 10.1049/syb2.70034.

Funding: This work was supported by National Natural Science Foundation of China (No. 62302066), Natural Science Foundation of Sichuan Province (No. 2024NSFSC1295), and Research Fund of Chengdu Medical College (No. CYZYB24‐09).

Handling Editor: Hao Lin

Siyu Tian and Qiang Tang contributed to the work equally and should be regarded as co‐first authors.

Contributor Information

Juanjuan Kang, Email: kangjuanjuan@cdutcm.edu.cn.

Min Shen, Email: Shenmin@cmc.edu.cn.

Data Availability Statement

The data that support the findings of this study are openly available in GEO at https://www.ncbi.nlm.nih.gov/geo/, reference number GSE54248.

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Associated Data

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

Supplementary Materials

Supporting Information S1

SYB2-19-e70034-s001.docx (18KB, docx)

Data Availability Statement

The data that support the findings of this study are openly available in GEO at https://www.ncbi.nlm.nih.gov/geo/, reference number GSE54248.

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