As of July 2023, the keyword search resulted in 295 publications from the PubMed repository. The two-step screening process resulted in 73 eligible publications for information extraction (Fig. 1). All eligible studies exclusively used tissue samples and/or cell lines. However, this outcome was not predetermined; namely, sample types were not specifically defined during the search process as one of selection criteria. Notably, there was a relatively low annual publication count on the topic of interest, in particular the association of miRNAs with ovarian cancer chemotherapy (Fig. S1), averaging only two publications per year. The countries of the first authors were also mostly centralized to China and the United States (Fig. S2). Furthermore, 36% of the eligible studies focused on cisplatin therapy (Fig. 2). Cisplatin is a potent chemotherapy drug used in the treatment of several cancers, including OC. It is part of a class of drugs known as platinum-containing compounds and it exerts its anticancer effects by binding to and damaging the DNA in cancer cells. This damage interferes with the ability of the cells to divide and grow, ultimately leading to cell death (16).

There was a notable proportion of studies amongst the eligible studies that focused on understanding the role of miRNAs in influencing treatment outcomes (79.45%; Fig. 3), indicating substantial unknown aspects regarding treatment outcomes in OC from the perspective of miRNAs. This hypothesis was strengthened by the wide variety of miRNAs studied in the eligible studies, in which there were cumulatively 66 miRNAs investigated. A total of nine of those miRNAs were identified by the Human Gene Database (17), which were associated with OC, although they were not specific to the disease. Moreover, four miRNAs were not reported to be associated with any diseases (Table SIII).

OC is known for its high mortality rate, often due to chemoresistance. This resistance significantly limits the effectiveness of treatment and often leads to the recurrence of the disease and poor patient outcomes (10,18). Table SIV presents the eligible studies that evaluated the association between miRNAs and therapy outcomes in OC, with a focus on studies that used miRNAs to assess why specific therapeutic interventions yielded suboptimal results.

miR-21 is a well-known miR that is associated with therapy resistance in OC. It is known as oncomiR in several other cancers, including cervical, colorectal and breast cancer (19). Abnormally highly expressed miR-21 may regulate drug resistance via augmented apoptotic pathways (20). As such, whether through natural compounds like icariin or by modulating c-MYB expression, targeting miR-21 may hold promise for enhancing the efficacy of therapies, particularly against drug resistance in OC. Icariin was assessed by Li et al (21) as a potential alternative therapy for OC. Icariin, the primary bioactive compound present in epimedium, a traditional Chinese medicinal herb, demonstrates diverse pharmacological properties including bolstered immune function, anticancer potential, cardiovascular enhancement and modulation of endocrine activity (21). Moreover, icariin has been reported to suppress miR-21 expression in OC cells, although the precise mechanisms underlying modulation of miR-21 expression by icariin remains unknown (21). Another study on cisplatin-resistant therapy indicated that miR-21 serves a crucial role in c-MYB-induced cisplatin resistance (22). c-MYB is a transcription factor protein encoded by the MYB gene and dysregulation of c-MYB has been implicated in several cancers, including OC, where it contributes to tumor progression and chemotherapy resistance (22). Silencing c-MYB has been reported to lead to reduced miR-21 levels, decreased epithelial-mesenchymal transmission (EMT), lowered cisplatin resistance and increased β-catenin phosphorylation (22).

Cisplatin stands as the prominent platinum-based therapy entwined with miR regulation, based on the results of the present systematic review, which revealed that 36% of the total eligible studies focused on cisplatin therapy. The emergence of cisplatin resistance poses a formidable challenge to effective treatment. The following miRNAs were mentioned due to their pivotal roles in orchestrating this resistance phenomenon: i) A high expression of miR-93 has been reported to be associated with cisplatin resistance and it can target genes that regulate apoptosis. L-tetrahydropalmatine (L-THP; an anticancer compound obtained mainly from genera Stephania and Corydalis) has been reported to suppress miR-93 expression whilst increasing PTEN levels, a pivotal tumor suppressor in OC (23). Furthermore, PTEN small interfering (si)RNA-treated cells increased survival, which was reversed by the AKT inhibitor Triciribine. L-THP enhanced OC cell sensitivity to cisplatin by modulating the miR-93/PTEN/AKT pathway (23); ii) in cisplatin-resistant OC cells, miR-1271 is often overexpressed. It can target tumor suppressors and cell cycle regulators like p53 and cyclin B1, promoting cell survival and reducing apoptosis. This, in turn, makes cancer cells more resistant to the cytotoxic effects of cisplatin (24); iii) miR-302 is known to influence cisplatin resistance through multiple mechanisms. It can affect drug transporters and drug-metabolizing enzymes. In certain cases, miR-302 can downregulate copper transporters such as solute carrier family 31 member 1, leading to decreased intracellular cisplatin accumulation. This limits the access of the drug to its target DNA (25); iv) miR-138-5p appears to influence cisplatin resistance through its ability to regulate cellular senescence and stemness. The miR was reported to be downregulated in cisplatin resistance cell-lines. Increasing miR-138-5p levels (either by inducing HOX transcript antisense RNA siRNA or by its mimics) improved chemosensitivity and reduced enhancer of zeste 2 polycomb repressive complex 2 subunit and sirtuin 1 expression, which are key players in cisplatin resistance (26); and v) high expression of miR-149-3p in OC tissues has been reported in cisplatin-resistant OC cells. Knockdown of miR-149-3p inhibited cisplatin resistance and malignant traits in OC cells. Mechanistically, miR-149-3p targeted cyclin dependent kinase inhibitor 1A and TIMP metallopeptidase inhibitor 2 to promote cisplatin resistance and EMT in OC (27). Fig. 4 summarizes key insights on cisplatin resistance from the eligible studies presented in this sub-section.

Notably, there appears to be potential associations between the aforementioned miRNAs, indicating overlapping molecular pathways or biological processes affected in OC. Table I provides a comparative analysis of the effectiveness of those miRNAs: miR-21 and miR-93 are associated with cisplatin resistance by regulating apoptosis pathways in several types of cancer; miR-1271 and miR-149-3p are also associated with cisplatin resistance in ovarian cancer cells by modulating multiple pathways involved; and miR-302 and miR-138-5p are associated with drug transport in cancer cells through the stem pathway and several other pathways. However, the aforementioned miRNAs require further experimental validation to ensure their significance and clinical implications, which further may offer promise for optimizing therapy outcomes in OC management.

The present review explored studies in which miRs were used to improve standard treatment outcomes via the transfection of anti-miRs or mimic-miRs. This pursuit aimed to both enhance treatment effectiveness and gain more insights into alternative instances where therapeutic interventions failed to achieve the intended outcomes, by either reinstating miR expression in tumor suppressor genes or by inhibiting the activity of oncogenic miRNAs, referred to as ‘mimic-miRs’ and ‘anti-miRs’, respectively. By assessing the scientific evidence, the present review aimed to present how miRNA-based interventions offer their potential for optimizing therapeutic strategies. The present review identified 10 studies that reported that mimic- and/or anti-miRs could help improve therapy outcomes, and cumulatively ten miRNAs of interest were discussed (Table II). Notably, none of the studies were registered in a clinical trials database. Moreover, cisplatin and paclitaxel were the most common type of therapies used in the experimental studies (Fig. 2).

Jin and Wei (28) indicated that when miR-23a inhibition was coupled with cisplatin treatment in OC cells, there was a significant increase in the effectiveness of cisplatin in limiting cell proliferation. miR-23a had been previously reported to be upregulated in a chemotherapy-resistant OC cell and this led to a marked increase in the rate of apoptosis in cancer cells. However, this effect was not observed when cells were treated with cisplatin alone, emphasizing the role of miR-23a in suppressing cell death and promoting drug resistance (29). Another study reported how the downregulated miR let-7d-3p could improve therapy outcomes (30). let-7d-3p is a miR associated with tumor progression and chemotherapy resistance in OC, where it is reported to be upregulated. let-7d-3p is the passenger strand and used to be considered ‘non-functional’ (30). Moreover, it is part of the let-7 family, which is comprised of 13 members that are highly conserved across species. let-7 is a key regulator of differentiation, pluripotency and apoptosis in eukaryotic cells, and has a role in cell cycle deregulation, cell division, proliferation, angiogenesis and apoptosis (31). Thus, let-7 can be used as a molecular tool and marker in cancer therapy (31–34). Previous studies have reported that miR-let-7d-3p can be used as a diagnostic biomarker for non-invasive screening of ovarian cancer and its precursors (31–34). To observe the potential of the miR to enhance treatment outcomes, García-Vázquez et al (30) used a two-fold strategy: i) let-7d-3p was inhibited using an antagomiR, an antagonist designed to suppress the activity of miRNAs. This inhibition led to a marked decrease in cell proliferation and the activation of apoptosis. These outcomes suggest that inhibiting let-7d-3p with the antagomiR sensitizes OC cells to therapy and increases their susceptibility to cell death; and ii) carboplatin was introduced. let-7d-3p affects the Ras pathway, which is associated with therapy resistance; therefore, targeting let-7d-3p with an antagomiR may modulate key cellular processes and signaling pathways, including ErbB and hypoxia-inducible factor-1, which are implicated in tumor progression and drug resistance (30). As such, the antagomiR for let-7d-3p inhibited the activity of carboplatin, leading to reduced cell proliferation and increased apoptosis. Suppressing let-7d-3p using an antagomiR sensitized the OC cells to carboplatin and enhanced the effectiveness of the treatment by promoting apoptosis. This two-pronged approach, using an antagomiR and chemotherapy, offers a promising strategy to improve therapy outcomes and combat the challenges of drug resistance in OC (30–34).

The present review also investigated studies that focused on reinstating the expression of miRNAs which are associated as tumor suppressor genes, indicating that the injection of mimic-miR to OC cells (possibly in combination with another treatment) may yield an improved therapy outcome (35). miR-873 mimics were introduced into OC cells and the results revealed that the overexpression of miR-873 led to a marked increase in the sensitivity of the cells to cisplatin and paclitaxel. In another study, researchers aimed to enhance therapy outcomes for OC by using miR-424-3p mimics. This miR-based approach targeted the expression of galectin-3, an anti-apoptotic protein that is often overexpressed in OC and associated with resistance to chemotherapy, especially cisplatin (28). miR-424-3p mimics were transfected into OC cells to assess its impact on the expression of galectin-3. The results demonstrated that miR-424-3p mimics notably suppressed the expression of galectin-3 at the protein level. This downregulation of galectin-3 is critical as this protein is associated with inhibiting apoptosis, a process that serves a central role in the response of the cell to chemotherapy. Following that, the cell viability and proliferation rates decreased, indicating a reduced capacity for the cells to grow and divide. Moreover, apoptosis was enhanced, with the cells treated with miR-424-3p mimics and cisplatin demonstrating a marked increase in apoptosis compared with the control group. Another similar study that assessed the enhancement of platinum-based-therapy through mimic-miRs, reported similar results, although they used miR-186 as their main object of observation (33).

Finally, the present study investigated adjunctive substances that have the potential to enhance therapy outcomes in OC, with a focus on their interactions with anti- and mimic miRs. The aim was to provide insights into emerging strategies that leverage miRNAs in conjunction with other compounds to optimize the effectiveness of OC treatments. For example, nanoparticles have been used for targeted miR therapy as drug delivery systems for miRNA-based cancer therapy (36–38) (Table III). These nanoparticles were engineered to efficiently deliver anti-miR or miR-mimics payloads to OC cells, specifically either targeting overexpressed oncogenic miRNAs or reinstating miR expression in tumor suppressor genes. The five studies presented in Table III demonstrated innovative approaches to OC therapy by emphasizing the use of nanotechnology and miRNA-based strategies to target oncogenic miRNAs, sensitize drug-resistant cells, and enhance the precision and effectiveness of treatment.

miR-21 serves a role in therapy resistance in OCs, indicating its potential to regulate drug resistance via apoptosis. Furthermore, it serves an important role in the oncogenic process as indicated by its association with the high proliferation, low apoptosis, high invasion and metastatic potential of cancer cells. Whilst evaluating the potential of anti-miR-21 as a therapeutic strategy for countering the oncogenic effects of miR-21 in OC, studies have concurrently explored the enhancement of treatment outcomes through the efficient nanoparticle-based delivery of anti-miR-21 to cancer cells whilst minimizing off-target effects. Biodegradable porous silicon nanoparticles were engineered to encapsulate an anti-miR-21 locked nucleic acid payload (38). Additionally, these nanoparticles displayed a tumor-homing peptide that enabled targeted distribution. This targeting peptide, CGKRK, ensured that the nanoparticles accumulated primarily in the tumor environment. CGKRK is a tumor-tracking peptide discovered by phage display techniques and it shows high selective binding affinity to neovascular endothelial cells and tumor tissue, but not to non-tumorigenic cells (39). Another nanoparticle, redox-sensitive, Polyethylene (PEG)-shielded carboxymethyl polyethylenimine (PEI) nanogels were used as a delivery system for anti-miR-21 (39). These nanogels were designed to efficiently deliver the anti-miR-21 to the OC cells by modifying branched PEI, which involved PEGylation (PEG2k-PEI) for steric shielding, redox-sensitive crosslinking for nanogel synthesis (PEG2k-PEI-ss nanogels) and carboxymethylation (PEG2k-CMPEI-ss) to modulate the properties of the polymer. Another study aimed to develop a novel polymeric drug delivery system (DDS) using star-shaped glucose-core polycaprolactone-polyethylene glycol (Glu-PCL-PEG) block copolymer nanoparticles. This system was used to deliver cisplatin and locked nucleic acid anti-miR-214 to OC cells. The study confirmed that nucleolin-mediated endocytosis of the targeted polymeric DDS containing both cisplatin and anti-miR-214 A2780 R cells led to enhanced apoptosis (40).

Other studies with a specific focus on addressing relapse and multidrug resistance issues have assessed let-7b (41) and miR-484 (42). Both studies recognized tumor suppressors with the capacity to target a range of oncogenes and chemoresistance-related genes. let-7b has an important role in growth and proliferation and induces apoptosis of cancer cells by inhibiting cell cycle progression through pathways such as CYP2J2 regulation and Wnt/B-catenin pathway. Downregulation of let-7b levels in clinical OC has been linked to chemotherapy resistance, heightened proliferation, invasion and relapse in EOCs. The restoration of let-7b expression was pivotal as it can significantly heighten sensitivity to chemotherapy whilst inhibiting oncogenic pathways and thwarting chemoresistance mechanisms (41). To ensure effective delivery of let-7b to tumor cells, innovative nanoparticle systems (namely, hyaluronic acid-based nanoparticles and Glu-PCL-PEG nanoparticles) were used to act as versatile delivery vehicles adept at transporting nucleic acids like miRNA. The delivery of let-7b to tumor cells involved using HA-PEI as a delivery vehicle, which is a versatile system known for efficient nucleic acid delivery, including miR (41). The strategic combination of let-7b with these nanoparticles represents a multifaceted approach aimed at reprogramming the miR profile within tumor cells.

Another study that also assessed a tumor suppressor miRNA, provided mechanistic insights into how the delivery of miR-484 via exosomes impacted the tumor vasculature and chemotherapy sensitization (42). It revealed that miR-484 may serve a role in vessel normalization, which enhances the response of cancer cells to chemotherapy-induced apoptosis. Mechanistically, miR-484 may achieve this effect by simultaneously inhibiting the expression of VEGF-A in cancer cells and its corresponding receptors in endothelial cells. The research demonstrates how miR-484 and exosomal delivery contributed to vascular normalization and chemotherapy sensitization in OC.

Despite the comprehensive nature of this systematic review, several limitations may affect the generalizability and applicability of the findings. First, this study was limited to the PubMed database, potentially excluding relevant studies indexed in other databases, such as Scopus, Web of Science or Embase. Second, the included studies varied widely in their methodologies, miRNAs investigated and therapeutic interventions used. This heterogeneity makes it challenging to draw definitive conclusions and compare results across studies. Finally, while the review highlighted associations between miRNAs and treatment outcomes, detailed mechanistic insights were often lacking. Understanding the precise molecular mechanisms is crucial for the development of effective therapeutic strategies.