Recent advances in the role of long non-coding RNAs in ovarian cancer chemoresistance

Abstract

Ovarian cancer (OC) remains a leading cause of cancer-related mortality among women, with a persistently low five-year survival rate. Currently, the primary treatment modalities for OC include surgery and systemic chemotherapy. However, despite initial therapeutic efficacy, the majority of patients eventually experience relapse and drug resistance, severely limiting clinical outcomes. Consequently, there is an urgent need to elucidate the molecular mechanisms underlying OC and develop innovative strategies to overcome chemoresistance. Long non-coding RNAs (lncRNAs), emerging as novel transcriptional regulators, exhibit aberrant expression and mutations closely associated with tumorigenesis, metastasis, and drug resistance. As promising biomarkers and therapeutic targets, lncRNAs hold significant potential for advancing cancer treatment. Growing evidence indicates that lncRNAs contribute to chemoresistance in OC through various mechanisms, including functioning as competing endogenous RNAs (ceRNAs) to sequester miRNAs, participating in epigenetic regulation, influencing metabolism, impairing DNA damage repair, and modulating key signaling pathways, thereby affecting the efficacy of cisplatin, carboplatin, and paclitaxel. This review summarizes the mechanistic roles and recent advances in lncRNA research related to OC chemoresistance, aiming to provide novel perspectives and pathways to address this clinical challenge.

Introduction

Ovarian cancer (OC), one of the most common malignancies of the female reproductive system, ranks third in incidence among gynecological cancers. Due to its asymptomatic early stages and limitations in diagnostic and therapeutic strategies, a significant number of OC patients are diagnosed at advanced stages, rendering OC the fifth leading cause of cancer-related mortality in women globally. The current standard treatment for OC involves cytoreductive surgery combined with platinum-based chemotherapy. Although most patients initially respond well to chemotherapy, achieving substantial survival benefits, approximately 70% of these individuals eventually experience relapse, with chemoresistance posing a major clinical obstacle to sustained therapeutic efficacy. Thus, unraveling the precise mechanisms of chemoresistance is critical for enhancing the effectiveness of OC treatment strategies [1, 2].

Long non-coding RNAs (lncRNAs) are a class of RNA molecules longer than 200 nucleotides that lack protein-coding potential [3]. Structurally, they are similar to mRNAs, which are transcribed by RNA polymerase II, processed with a 5’ cap and a polyadenylated 3’ tail, and their initial transcripts can be spliced. Despite this similarity, lncRNA genes differ fundamentally from protein-coding genes, as they contain far fewer exons (~ 2.8) and do not possess an open reading frame (ORF) [4, 5]. Recent studies have increasingly demonstrated that lncRNAs play pivotal roles in regulating gene expression at transcriptional, post-transcriptional, and translational levels [6]. Widespread dysregulation of lncRNAs has been observed across various cancer types, where they modulate tumor initiation, progression, and drug resistance through diverse molecular pathways. Consequently, lncRNAs hold promise as potential biomarkers for early cancer detection and novel therapeutic targets to overcome drug resistance [7, 8]. Specifically, in OC, chemoresistance involves intricate mechanisms, many of which are closely linked to lncRNA activity [9]. This review consolidates current insights into the mechanistic roles of lncRNAs in OC chemoresistance and highlights recent research advances, aiming to provide actionable references for future investigations in this field.

lncRNA overview and tumor drug resistance

Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins. Among these, lncRNAs exceed 200 nucleotides in length and exhibit both specificity and conservation throughout mammalian evolution. Initially dismissed as “transcriptional noise”, lncRNAs were largely overlooked in early research [10]. However, with advancements in technology, their critical roles in human biological processes have gradually been uncovered [11]. Functionally, lncRNAs regulate gene expression through multiple mechanisms (Fig. 1): Epigenetic regulation: Modulating DNA methylation, chromatin remodeling, and histone modifications. Transcriptional control: Regulating the transcription of neighboring genes and interacting with transcription factors. Post-transcriptional modulation: Splitting into non-coding fragments, enhancing mRNA stability, regulating alternative splicing, and competitively inhibiting miRNAs [8, 12, 13]. lncRNAs are classified based on their genomic location (e.g., intergenic, intronic, sense, or antisense lncRNAs, with antisense being the most common), their mode of action (cis-acting or trans-acting), and their functional roles (e.g., guides, decoys, scaffolds, or signaling molecules) [14–16].

Fig. 1.

Overview of lncRNA Mechanisms in Gene Regulation

Drug resistance is a multifactorial process involving reduced intracellular drug accumulation, enhanced drug efflux, activation of DNA repair systems, dysregulated cell proliferation, and apoptosis. Recent advances in high-throughput technologies and bioinformatics have expanded our understanding of non-coding genomic elements, revealing lncRNAs as key epigenetic regulators in tumor progression, invasion, and chemoresistance [17]. XIST is overexpressed in colorectal cancer, where it promotes invasion, migration, and epithelial-mesenchymal transition (EMT) via the XIST/miR-200b-3p/ZEB1 pathway [18]. In esophageal cancer, lncRNA VLDLDR and ABCG2 are upregulated during multidrug resistance development. VLDLDR carried in extracellular vesicles (EVs) from resistant cells modulates ABCG2 expression in recipient cells, driving chemoresistance [19]. These cases from different cancer types not only establish the central role of lncRNAs in regulating drug resistance but also provide a theoretical basis and research framework for systematically exploring the functional mechanisms of lncRNAs in OC.

Existing evidence demonstrates that lncRNAs extensively participate in the development of tumor drug resistance through diverse core molecular mechanisms. Their primary modes of action encompass: serving as molecular sponges for miRNAs, competitively binding to release miRNA-mediated repression of their target genes and thereby modulating the expression of resistance-associated genes; regulating key signaling pathways (such as PI3K/AKT, Wnt/β-catenin, etc.), interfering with the functionality of critical pathway components to promote tumor cell survival; directly influencing protein function, including altering the stability, activity, or localization of transcription factors, enzymes, and other proteins, consequently disrupting drug responses. Furthermore, lncRNAs enhance tumor self-renewal and chemoresistance by maintaining cancer stem cell properties; they shape cell fate decisions during drug treatment by regulating apoptosis and autophagy; and they programmatically control the transcriptional activity of resistance genes through epigenetic recruitment of modifying complexes, mediating histone modifications or DNA methylation. These interconnected mechanisms collectively constitute a complex regulatory network governing lncRNA influence on tumor drug resistance [20]. Zhu et al. demonstrated that LINC00942 promotes chemoresistance by stabilizing c-Myc mRNA through inhibition of MSI2 degradation [21]. Li et al. revealed that OTUD6B-AS1 downregulates miR-26a-5p and upregulates metadherin (MTDH). The OTUD6B-AS1/miR-26a-5p/MTDH axis drives paclitaxel resistance in triple-negative breast cancer (TNBC) by suppressing DNA repair and activating autophagy [22]. Given these insights, it is imperative to delineate the precise molecular mechanisms underlying lncRNA-mediated chemoresistance in malignancies. Such efforts may pave the way for novel therapeutic approaches to overcome drug resistance in chemotherapy.Based on this mechanistic framework and the lessons learned from these case studies, subsequent research should focus on elucidating the OC-specific lncRNA regulatory network, aiming to develop new strategies to reverse its chemoresistance.

lncRNAs and OC

The initiation and development of OC involve a complex, multi-step biological process characterized by fundamental alterations in cellular homeostasis. This process encompasses multiple key aspects including dysregulated cell proliferation, evasion of apoptosis, sustained angiogenesis, enhanced migratory capacity, tissue invasion, and eventual distant metastasis [23, 24]. These pathological transformations are driven by the accumulation of genetic and epigenetic alterations that progressively disrupt normal cellular regulatory networks. In recent years, long non-coding RNAs (lncRNAs) have been shown to play crucial roles as important regulatory molecules in the molecular network of OC, influencing various aspects of tumor biology through multiple mechanisms. Therefore, in-depth elucidation of the specific contributions of lncRNAs in OC pathogenesis is essential for developing novel diagnostic biomarkers, advancing targeted therapeutic strategies, and formulating effective preventive measures [25, 26].

The multifunctional nature of p53, with its prominent tumor suppressor activity, and the involvement of lncRNAs in this process have attracted widespread research interest. This has opened new avenues for exploring the vast and complex regulatory network of the p53 gene. Notably, the abundance and heterogeneity of lncRNAs, along with their diverse mechanisms of action, make them important mediators of p53. Recent research on the functional aspects of lncRNAs indicates that their dysregulated expression is associated with tumorigenesis in various cancer types. Several lncRNAs have been found to be coordinately regulated by the p53 transcription factor, while p53 also requires these lncRNAs to express its tumor suppressor activity. In OC, a limited number of p53-associated lncRNAs have been identified that regulate multiple regulatory circuits, including tumor initiation and progression, metastasis, apoptosis, and some are even known to participate in DNA damage response (DDR). Given the complexity of this network, lncRNAs can function both as oncogenes and tumor suppressors, and their connection with p53 as both effectors and regulators further expands the platform for identifying and characterizing more p53-related lncRNAs in OC [26].

Specific research cases are as follows: Jie Liu et al. found that lncRNA IL21-AS1 is upregulated in OC tissues, particularly in advanced-stage patients, and its expression level shows a significant positive correlation with clinical stage. Functional studies revealed that IL21-AS1 protects OC cells from macrophage-mediated phagocytosis and promotes tumorigenesis through the dual axes of IL21-AS1/HIF-1α/CD24 and IL21-AS1/miR-561-5p/CD24 [27]. These findings not only reveal a novel mechanism of immune escape in OC but also provide potential targets for future immunotherapy strategies.Beyond the immunomodulatory roles of IL21-AS1, other lncRNAs promote OC progression through different mechanisms. Si Li He et al. discovered that lncRNA KCNQ1OT1 expression is elevated in OC tissues and cells, showing a negative correlation with reduced EIF2B5 levels. Mechanistically, KCNQ1OT1 drives OC metastasis by recruiting DNA methyltransferases to the EIF2B5 promoter region, inducing its hypermethylation and silencing [28]. This finding highlights the important role of lncRNAs in regulating gene expression through epigenetic mechanisms in OC. The regulatory functions of lncRNAs also extend to the post-transcriptional level. In epithelial OC, lncRNA HOXD-AS1 acts as a competing endogenous RNA (ceRNA) by sponging miR-186-5p, leading to upregulation of PIK3R3. Further research confirmed that this regulatory axis not only affects tumor cell proliferation but also significantly enhances their invasive capacity. The HOXD-AS1/miR-186-5p/PIK3R3 axis promotes epithelial-mesenchymal transition (EMT), as evidenced by changes in characteristic marker expression. Clinically, the molecular signature of high HOXD-AS1 and PIK3R3 expression coupled with low miR-186-5p levels is strongly associated with poor prognosis in epithelial OC patients [29], indicating the potential value of this molecular marker in prognostic assessment.

In summary, the accumulating evidence collectively underscores the paramount importance of lncRNA research in OC. These multifaceted molecules participate in virtually all aspects of OC pathogenesis through diverse mechanisms including immune regulation, epigenetic modification, and post-transcriptional control. The continued investigation of lncRNAs not only deepens our fundamental understanding of ovarian carcinogenesis but also opens promising avenues for developing novel diagnostic biomarkers and targeted therapeutic strategies. As research progresses, lncRNAs are increasingly demonstrating their potential as crucial components in advancing both basic science and clinical applications for this devastating disease.

Mechanisms and research advances of lncRNAs in OC chemoresistance

Chemotherapy remains a cornerstone of OC treatment, with platinum-based agents (e.g., cisplatin, carboplatin) and taxanes (e.g., paclitaxel)., paclitaxel) serving as first-line therapeutic options. The standard regimen combines cytoreductive surgery with platinum-based chemotherapy. However, most advanced-stage patients develop recurrence and chemoresistance after initial treatment, often accompanied by cross-resistance to other chemotherapeutic drugs. High recurrence rates and chemoresistance are key contributors to the dismal prognosis of OC. Emerging evidence highlights the critical involvement of lncRNAs in mediating chemoresistance, offering novel insights into overcoming this clinical challenge.

Cisplatin

Cisplatin, also known as cis-diamminedichloroplatinum, is a platinum-containing anticancer drug. It primarily exerts its antitumor effects by disrupting DNA function and inhibiting the mitotic process, and it is one of the cornerstone chemotherapeutic agents for OC. In the context of cisplatin resistance in OC, numerous dysregulated lncRNAs have been identified. Their mechanisms are diverse and can be categorized into several key themes, with detailed information summarized in Table 1.

Table 1.

Research Status of lncRNAs in Cisplatin Resistance in OC

No.	lncRNA	Expression Level	Drug	Molecular Mechanism	References
1	CTSLP8	high	cisplatin	CTSLP8/PKM2/c-Myc	[30]
2	ASB16-AS1	high	cisplatin	ASB16-AS1/miR−3918/GOLM1	[31]
3	TMEM147-AS1	high	cisplatin	AURKA/DDX5/TMEM147-AS1/let−7	[32]
4	WDFY3-AS2	high	cisplatin	WDFY3-AS2/hsa-miR−139−5p/SDC4	[33]
5	DANCR	high	cisplatin	HOXB2/DANCR/ERK or HOXB2/DANCR/ABCA1(ABCG1)	[34]
6	CHRF	high	cisplatin	CHRF/miR−10b	[35]
7	TUG1	high	cisplatin	TUG1/miR−4687−3p or miR−6088/DNA polymerase eta	[36]
8	LNC00115	high	cisplatin	LNC00115/miR−7/ERK	[37]
9	PART1	high	cisplatin	YY1/PART1/miR−512−3p/CHRAC1	[38]
10	MALAT1	high	cisplatin	MALAT1/e Notch1	[39]
11	MCF2L-AS1	high	cisplatin	SP1/MCF2L-AS1/IGF2BP1/IGF2/MEK/ERK	[40]
12	ACTA2-AS1	high	cisplatin	ACTA2-AS1/miR−378a−3p/Wnt5a	[41]
13	HOXA11-AS	high	cisplatin	P62, Beclin1, and LC3	[42]
14	UCA1	high	cisplatin	UCA1/miR−143/FOSL2	[43]
15	PANDAR	high	cisplatin	PANDAR–SFRS2–p53	[44]
16	HOTAIR	high	cisplatin	HOTAIR/HOXA7	[45]
17	CTD−2288O8.1	high	cisplatin	CTD−2288O8.1/EGFR/AKT	[17]
18	PHGDH	high	cisplatin	DDX3X/PHGDH	[1]
19	EBIC	high	cisplatin	EBIC/Wnt/β-catenin	[46]
20	NKILA	low	cisplatin	c-Myb-NKILA-LIN28A-let−7	[47]
21	NCALD	low	cisplatin	NCALD/CX3CL1	[48]
22	PLADE	low	cisplatin	PLADE/R-loop and DNA damage	[49]
23	LincRNA 00261	low	cisplatin	LincRNA 00261/miR−545−3p/MT1M	[50]
24	lncRNA CERNA1	low	cisplatin	CERNA1/BCL2L10/DNMT1	[51]
25	GAS5	low	cisplatin	GAS5/E2F4/PARP1/MAPK	[52]
26	LOC730101	low	cisplatin	LOC730101/BECN1 or LOC730101/p62/RNF168	[53]

ceRNA networks

Yang Fan et al. discovered that ASB16-AS1 is highly expressed in OC cells. Downregulating its expression inhibits OC cell proliferation, invasion, migration, and chemoresistance. miR-3918 is a binding target of ASB16-AS1, and suppressing miR-3918 expression reverses the changes in OC cell behavior caused by ASB16-AS1 downregulation. GOLM1, a downstream regulatory gene of miR-3918, is enhanced by ASB16-AS1, thereby promoting malignant biological behaviors in OC cells. In summary, ASB16-AS1 acts as a ceRNA to competitively bind miR-3918, upregulate GOLM1 expression, and drive OC progression and chemoresistance [31]. TMEM147-AS1 can adsorb let-7b/7c-5p, downstream targets of the AURKA/DDX5 complex, through a ceRNA mechanism, thereby upregulating AURKA expression and forming an AURKA/DDX5/TMEM147-AS1/let-7 feedback loop. This feedback loop activates the lipophagic pathway via sequential phosphorylation of GSK3β and nuclear entry of β-catenin, ultimately contributing to chemotherapy resistance in EOC [32].

Yue Wu et al. discovered that WDFY3-AS2 may contribute to cisplatin resistance in OC cells by modulating the miR-139-5p/SDC4 axis. Downregulating WDFY3-AS2 expression suppresses OC cell proliferation, migration, invasion, reduces stem cell generation, induces apoptosis, and thereby lowers the risk of cancer recurrence and metastasis [33]. Xinyan Jiang et al. found that LINC00115 is upregulated in OC tissues and cisplatin-resistant patient samples. It acts as an RNA sponge to regulate miR-7 expression, thereby upregulating the ERK gene and promoting platinum resistance, invasion, and migration in OC cells. As an oncogene, LINC00115 contributes to OC recurrence and metastasis [37]. Hongbo Yang et al. discovered that YY1 induces PART1 overexpression via the miR-512-3p/CHRAC1 axis, driving chemotherapy resistance in OC [38]. Lin Bai et al. demonstrated that downregulating MALAT1 expression in vitro and in vivo reduces chemoresistance in OC cells, increases apoptosis in resistant cells, and enhances chemosensitivity. This finding suggests a potential ceRNA mechanism for MALAT1, although the precise molecular targets (miRNAs and messenger RNAs) involved in this process remain to be fully elucidated [39]. ACTA2-AS1 was found to act as a sponge for miR-378a-3p, preventing its binding to Wnt5a and thereby enhancing cisplatin tolerance in OC cells [41]. Caihua Dong et al. reported that NCALD expression is reduced in OC tissues and correlates with shorter overall survival (OS), progression-free survival (PFS), and postoperative survival (PPS). Notably, NCALD transcript levels are significantly lower in drug-resistant OC cells. Further studies indicate that NCALD acts as a ceRNA to regulate CX3CL1 expression, influencing immune cell infiltration and chemoresistance [48].

Collectively, these studies underscore the ceRNA mechanism as a crucial paradigm wherein lncRNAs function as molecular sponges for miRNAs. By competitively binding miRNAs, lncRNAs derepress their downstream target genes, subsequently activating multiple pathways associated with pro-survival, invasion, and stemness, ultimately leading to chemoresistance. This network-based regulation highlights the functional versatility of lncRNAs. However, a significant challenge lies in the contextual specificity of these interactions, as the outcome is highly dependent on the relative expression levels of the lncRNA, miRNA, and target mRNA within the cellular milieu. Furthermore, the potential for one lncRNA to interact with multiple miRNAs adds a layer of complexity for therapeutic targeting. Beyond this indirect post-transcriptional regulation, lncRNAs can also influence gene expression through more direct mechanisms, such as epigenetic regulation.

Epigenetic regulation

Studies have revealed that CTSLP8 can directly bind to PKM2, and the CTSLP8/PKM2 complex interacts with promoter regions to upregulate c-Myc expression. This process enhances OC cell proliferation and glycolysis, leading to cisplatin resistance. However, the precise molecular details and regulatory dynamics of this pathway remain incompletely elucidated and warrant further investigation [30]. Mei-Ling Tian et al. investigated LINC00261 in platinum-resistant EOC. They observed hypermethylation of the LINC00261 promoter and significant downregulation in EOC tissues. LINC00261 methylation levels inversely correlated with its RNA expression, and its hypermethylation/low expression was associated with shorter PFS and OS in EOC patients. Mechanistically, LINC00261 suppresses cisplatin resistance, proliferation, migration, and invasion in SKOV3 cells by regulating MT1M via miR-545-3p [50]. Another study revealed that CERNA1, predominantly localized in the nucleus of OC cells, is downregulated in OC tissues and cells. Nuclear CERNA1 enhances BCL2L10 (a tumor suppressor) expression by luring DNMT1 away from the BCL2L10 promoter region, thereby promoting cisplatin-induced apoptosis and reducing chemoresistance [51]. Epigenetic regulation, particularly DNA methylation, plays a key role in lncRNA-associated cisplatin resistance. LncRNAs are both subjects and regulators of epigenetic modifications. Promoter hypermethylation leading to lncRNA silencing, or lncRNAs recruiting epigenetic modifiers like DNMTs to alter the chromatin state of target genes, provides a stable and heritable mechanism for modulating apoptosis and drug response. The reversibility of epigenetic marks offers therapeutic opportunities, but a major bottleneck is achieving targeted manipulation of specific epigenetic events in cancer cells without causing global epigenetic disturbances. It is important to note that the regulatory influence of lncRNAs extends beyond the genome to the functional state of the cell, including its metabolic profile.

Metabolic reprogramming

Downregulation of HOXA11-AS increases autophagy-related protein expression, alters platinum sensitivity, reduces OC cell proliferation, and promotes apoptosis [42]. Additionally, lncRNA LOC730101 contributes to chemoresistance mechanisms by binding BECN1 to inhibit its phosphorylation, thereby blocking BECN1-VPS34 autophagosome formation and reducing autophagy. This enhances OC cell sensitivity to cisplatin and PARP inhibitors. LOC730101 also suppresses RNF168 expression and activity via p62, impairing H2A ubiquitination-mediated DNA damage repair and further promoting drug sensitivity [53]. lncRNAs influence cisplatin resistance by reprogramming cellular metabolism (e.g., enhancing glycolysis) and regulating autophagy processes. This interplay underscores how cancer cells adapt their energy homeostasis and stress responses to survive chemotherapy. Targeting lncRNAs involved in metabolic reprogramming or autophagy holds promise for altering the fundamental fitness of resistant cells. However, a critical challenge is the dual and often context-dependent role of autophagy (being either pro-survival or pro-death) and the metabolic plasticity of cancer cells, which can lead to compensatory mechanisms. To survive, cells must also effectively manage the primary damage inflicted by cisplatin, which is DNA damage.

DNA damage response

HOXB2 is highly expressed in OC cells and is associated with poor prognosis and cisplatin resistance in patients. Experimental studies demonstrated that inhibiting HOXB2 both in vitro and in vivo impairs OC cell growth and cisplatin resistance. RNA-Seq-based analyses revealed that HOXB2 regulates ATP-binding cassette transporter members and the ERK signaling pathway. Further experiments confirmed that HOXB2 enhances chemoresistance and cancer proliferation by modulating the expression of the lncRNA DANCR, which influences its downstream effectors ABCA1, ABCG1, and ERK signaling. These findings validate that high HOXB2 expression correlates with platinum resistance and poor prognosis in OC [34]. Ryosuke Sonobe et al. found that the TUG1 gene is significantly upregulated in platinum-resistant OC patient samples. Depleting TUG1 increased cisplatin sensitivity in OC cell lines SKOV3 and KURAMOCHI. Combination therapy using cisplatin and TUG1-targeting antisense oligonucleotides delivered via a drug delivery system effectively reduced tumor burden in xenograft mouse models. Mechanistically, TUG1 acts as a ceRNA to downregulate miR-4687-3p and miR-6088, both of which target DNA polymerase eta (POLH). Overexpression of POLH reversed the effects of TUG1 depletion on cisplatin-induced cytotoxicity. This study demonstrates that TUG1 upregulation enables OC to tolerate DNA damage through POLH elevation [36]. Hanyuan Liu et al. uncovered the unique role of lncRNA PLADE in OC. PLADE enhances cisplatin sensitivity by disrupting HNRNPD to induce R-loop accumulation and DNA damage, offering new insights into overcoming chemoresistance [49].

lncRNAs play a dual role in cisplatin resistance by influencing DNA damage repair capacity. This highlights the functional dichotomy: some lncRNAs promote resistance by enhancing the expression of DNA repair proteins like POLH, allowing cells to tolerate cisplatin-induced DNA damage, while others, like PLADE, can sensitize cells by exacerbating DNA damage. The net effect on chemosensitivity depends on the balance between these opposing forces. A major challenge is harnessing this knowledge therapeutically, as promoting DNA damage risks genomic instability, while inhibiting repair-promoting lncRNAs must be carefully balanced to avoid harming normal cells. Ultimately, the signals from these diverse mechanisms are integrated and executed through core cellular signaling pathways.

Signaling pathway modulation

CHRF is highly expressed in platinum-resistant OC cells and linked to chemoresistance. Wen Xi Tan et al. identified through online databases and experimental validation that miR-10b plays a pivotal role in CHRF-mediated cisplatin resistance. It induces resistance in ES2 cells, OVCAR cells, and SKOV3-OC cells. Mechanistic studies revealed that activation of the EMT and STAT3 signaling pathways underlies CHRF-miR-10b axis-driven cisplatin resistance. Downregulating CHRF reversed EMT, STAT3 activation, and cisplatin resistance, while altering miR-10b expression also affected platinum-resistant cell behavior. These results confirm the CHRF-miR-10b axis as a potential therapeutic target for sensitizing resistant OC cells [35]. Xue Yan Zhang et al. found that the proto-oncogene c-Myb is highly expressed in platinum-resistant OC cells, while lncRNA NKILAexpression is reduced. NKILA promotes invasion and stemness in resistant cells but does not affect proliferation or cell cycle. This suggests a potential interaction between c-Myb and NKILA, mediated by the stemness-related factor LIN28A, which inhibits let-7 expression. Thus, the c-Myb-NKILA-LIN28A-let-7 axis may represent a novel therapeutic target pathway in OC [47]. Research also indicates that lncRNA GAS5 is significantly downregulated in OC and correlates with poor prognosis. GAS5 inhibits cisplatin resistance and tumor progression by suppressing the E2F4-PARP1-MAPK axis, highlighting its potential as a therapeutic target to enhance chemosensitivity [52]. MCF2L-AS1, induced by SP1, interacts with IGF2BP1 to promote platinum resistance in OC through the IGF2/MEK/ERK pathway [40].

lncRNAs modulate cisplatin resistance by regulating key signaling pathways such as EMT, STAT3, and MAPK/ERK. These lncRNAs often act as crucial upstream integrators, weaving together inputs from ceRNA networks, epigenetic changes, and metabolic shifts to coordinately regulate cell survival, invasion, and stemness maintenance. The convergence of various lncRNAs on established oncogenic pathways like MAPK/ERK suggests their roles as key nodal points. However, the high degree of crosstalk and redundancy within these signaling networks presents a challenge, as inhibiting a single lncRNA might be insufficient to abrogate pathway activity completely.

Carboplatin

Carboplatin, a second-generation platinum-based antitumor drug, holds a pivotal and irreplaceable position in the treatment of OC due to its significant therapeutic efficacy.

ceRNA

By deeply analyzing TCGA (The Cancer Genome Atlas) data from patients with varying chemotherapy responses, Anqi Wu et al. identified resistance-associated differentially expressed genes (DEGs) and further narrowed down PFI (progression-free interval)-linked DEGs. Comprehensive GO and pathway enrichment analyses, protein-protein interaction (PPI) studies, transcription factor regulation exploration, and ceRNA-mediated lncRNA regulatory network analysis revealed both overlaps and distinctions between the two DEG sets. Ultimately, the authors validated the MNX1-AS1/hsa-miR-4697-3p/HOXB13 axis as a decisive regulator of carboplatin sensitivity in OC cell lines within the complex DEG-ceRNA network [54]. Additional studies indicate that lncRNA-H19 and STAT3 expression are significantly elevated in carboplatin-resistant OC cells, while miR-29b-3p is downregulated. Silencing lncRNA-H19 enhances carboplatin efficacy. Mechanistically, lncRNA-H19 acts as a ceRNA for miR-29b-3p, regulating its downstream target STAT3. Abnormal STAT3 activation ultimately drives carboplatin resistance in EOC cells [55]. The ceRNA mechanism remains a fundamental model for lncRNA-mediated carboplatin resistance.

Epigenetic regulation

Qin Xu et al. utilized bioinformatics analysis to uncover the role of TLR8-AS1as a lncRNA regulating cancer-associated fibroblasts in OC. In vitro and in vivo experiments further demonstrated that TLR8-AS1 promotes OC cell metastasis and chemoresistance by stabilizing TLR8 mRNA to upregulate TLR8 expression, thereby activating the NF-κB signaling pathway. Analysis of TCGA data revealed that TLR8-AS1 is significantly upregulated in OC tissues compared to adjacent normal tissues, and its high expression correlates with metastasis, recurrence, and poor prognosis in patients, providing critical insights for treatment and prognostic evaluation [56]. Cecilie Abildgaard et al. elucidated the core role of lncRNA SNHG12 in epigenetic regulation through extensive database mining and rigorous experimental validation, identifying it as a key mediator of carboplatin resistance in OC. This discovery opens new avenues for understanding chemoresistance mechanisms [57]. Epigenetic regulation via lncRNAs contributes significantly to carboplatin resistance. These findings reinforce that lncRNAs can exert influence through mRNA stability and pathway activation, extending beyond classic ceRNA roles. The clinical correlation of TLR8-AS1 underscores its potential translational relevance.

Metabolic reprogramming

lncRNA XIST promotes carboplatin resistance by activating autophagy via the miR-506-3p/FOXP1 axis [58]. lncRNAs influence chemoresistance by modulating autophagic flux, a key metabolic stress response.

DNA damage response

The DNA damage-induced lncRNA CTBP1-DT encodes the DDUP protein, which contributes to carboplatin resistance [59]. lncRNAs can impact drug response through encoding functional micropeptides involved in damage management.

Signaling pathway modulation

lncRNA BC200 expression is markedly reduced in OC tissues compared to normal tissues. Inhibiting BC200 enhances OCr cell proliferation, while carboplatin induces BC200 expression, and elevated BC200 levels increase carboplatin sensitivity in these cells [60]. lncRNAs are integral components of signaling networks that determine cellular sensitivity to carboplatin.

In summary, aberrant lncRNA expression plays a central role in carboplatin resistance in OC through diverse mechanisms. These findings offer novel insights and potential targets for overcoming chemoresistance. All the above information is summarized in Table 2.

Table 2.

Research Progress on lncRNAs in Carboplatin Resistance in OC

No.	LncRNA	Expression Level	Drug	Molecular Mechanism	References
1	TLR8-AS1	high	carboplatin	TLR8-AS1/TLR8/NF-kB	[56]
2	SNHG12	high	carboplatin	SNHG12/miRNA−129/SOX4	[57]
3	MNX1-AS1	high	carboplatin	MNX1-AS1/hsa-miR−4697−3p/HOXB13	[54]
4	LncRNA H19	high	carboplatin	LncRNA H19/microRNA−29b−3p/STAT3	[55]
5	CTBP1-DT	high	carboplatin	CTBP1-DT/DDUP	[59]
6	LncRNA XIST	high	carboplatin	LncRNA XIST/miR−506−3p/FOXP1	[58]
7	BC200	low	carboplatin	---	[60]

Paclitaxel

Paclitaxel, a natural-derived anticancer agent, is a cornerstone of first-line chemotherapy regimens for all subtypes of OC, particularly when combined with platinum-based drugs. However, paclitaxel resistance remains a major challenge in clinical management. In recent years, the role of lncRNAs in regulating paclitaxel resistance in OC has garnered increasing attention as a novel research focus.

ceRNA

Hui Zhao et al. discovered that lncRNA SDHAP1 promotes paclitaxel resistance in OC cells by competitively binding miR-4465 to regulate EIF4G2 expression. This finding highlights the mechanistic role of SDHAP1 in paclitaxel resistance [61]. Yuzi Zhao et al. investigated the PRLB gene in paclitaxel-resistant OC cells. They observed significant upregulation of PRLB in resistant cells, and its downregulation markedly reduced the IC50 values of CAOV3/Tax and SKOV3/Tax cells, increased apoptosis, and elevated expression of its directly bound miR-150-5p. Luciferase reporter assays confirmed that miR-150-5p overexpression reduced PRLB and RSF1 activity, which was abolished upon mutation of binding sites. Furthermore, RSF1 overexpression reversed the effects of PRLB knockdown, restoring IC50 values, reducing apoptosis, and rescuing RSF1 and p-p65 expression. These results demonstrate that lncRNA-PRLB promotes paclitaxel resistance by sponging miR-150-5p to activate the RSF1/NF-κB signaling pathway [62]. Other studies revealed additional mechanisms: lnc-SNHG1 induces paclitaxel resistance in A2780/Taxol cells via the miR-216b-5p/PAK2 axis [63]. HULC enhances paclitaxel resistance by adsorbing miR-137 to regulate ITGB8 expression [64]. Huilong Lin et al. identified a negative correlation between SNHG5 and miR-23a in OC tissues. Silencing miR-23a overcame paclitaxel resistance in SKOV3 and HeyA-8 cells, while miR-23a overexpression reversed SNHG5-mediated sensitization to paclitaxel. This suggests that SNHG5 enhances paclitaxel sensitivity by sponging miR-23a, offering a novel strategy to combat resistance [65]. Jihong An et al. reported that NEAT1 is upregulated in paclitaxel-resistant OC tissues and cells. Mechanistically, NEAT1 acts as a ceRNA for miR-194 to elevate ZEB1 expression, driving paclitaxel resistance [66]. Mi Zhang et al. identified KB-1471A8.2 as a nuclear-localized lncRNA downregulated in OC tissues and resistant cell lines. Its overexpression inhibited proliferation, invasion, migration, and paclitaxel resistance while increasing apoptosis. Mechanistically, KB-1471A8.2 acts by modulating CDK4, a key cell cycle regulator, providing new insights into therapeutic strategies [67]. The ceRNA mechanism is a predominant mode through which lncRNAs influence paclitaxel sensitivity, with most acting as oncogenic sponges, though some can function as sensitivity enhancers.

Epigenetic regulation

The study by the team led by Siyu Liu revealed the critical role of RFPL1S-202 in EOC. They found that RFPL1S-202 is significantly downregulated in EOC tissues and cell lines. Through gain- and loss-of-function studies, researchers demonstrated that RFPL1S-202 enhances the cytotoxicity of cisplatin or paclitaxel, suppresses OC cell proliferation, invasion, and migration in vitro, and inhibits liver metastasis in vivo. Mechanistically, RFPL1S-202 interacts with the DDX3X protein and reduces the expression of p-STAT1 and interferon (IFN)-induced genes by increasing m6A modification of IFNB1. This indicates that the lncRNA RFPL1S-202 acts as a tumor suppressor in OC chemoresistance and progression by downregulating the IFN-β-STAT1 signaling pathway through its interaction with DDX3X [68]. Yulian Xie et al. focused on LINC02489 in OC. They observed that LINC02489 expression is markedly reduced in metastatic and chemoresistant OC tissues. Overexpression of LINC02489 in chemoresistant SKOV3 cells significantly increased PKNOX2 expression while decreasing PTEN and mTOR levels, thereby inhibiting SKOV3 cell proliferation and invasion. This suggests that LINC02489 enhances paclitaxel sensitivity by upregulating PKNOX2 via m6A modification and modulating the PTEN/mTOR signaling pathway to suppress OC invasiveness [69]. These studies highlight an emerging layer of regulation where lncRNAs interface with RNA-binding proteins and epitranscriptomic mechanisms to fine-tune chemosensitivity, offering novel angles for therapeutic intervention.

Metabolic reprogramming

Xin Wu and their research team discovered that KHDRBS3 is highly expressed in tumor tissues, particularly in paclitaxel-resistant EOC cells. Experimental results demonstrated that downregulating KHDRBS3 expression significantly reduced glucose consumption and lactate production in SKOV3 and A2780 cell lines, whereas overexpression of KHDRBS3 markedly increased these metabolic indicators. Concurrently, the expression of glycolysis-related genes was elevated in KHDRBS3-overexpressing EOC cells. Through catRAPID analysis, RIP assays, and RNA-pulldown experiments, researchers identified an interaction between KHDRBS3 and MIR17HG. MIR17HG was found to ovarian canceinhibit KHDRBS3 activity, thereby reducing glycolysis, cell proliferation, and drug resistance. Further studies revealed that KHDRBS3 promotes glycolysis via CLDN6, and the effects of KHDRBS3 overexpression on paclitaxel resistance and glycolysis could be reversed by MIR17HG. In summary, the long non-coding RNA MIR17HG is downregulated under KHDRBS3 regulation, leading to upregulated CLDN6 expression, ultimately decreasing epithelial r sensitivity to paclitaxel and enhancing glycolytic processes [70].

lncRNAs can modulate paclitaxel resistance by reprogramming cellular glucose metabolism, linking energy homeostasis to drug response.

Signaling pathway modulation

Ke Huang et al. identified the unique role of the lncRNA SLC25A21-AS1 in OC. They confirmed that SLC25A21-AS1 inhibits OC cell proliferation, migration, and invasion by blocking EZH2-mediated silencing of KCNK4, while also enhancing chemosensitivity in OC cells and tissues [71]. Furthermore, the long and short isoforms of SNHG16 (SNHG16-L/S) exert opposite effects on paclitaxel resistance. SNHG16-L inhibits GATA3 transcription by binding CEBPB. Alternative splicing induced by PRPF6 shifts the balance towards the short form, relieving GATA3 suppression and promoting metastasis and resistance [72].

In summary, lncRNAs exhibit complex and multifaceted roles in paclitaxel resistance in OC. Notably, they can act as both drivers and suppressors of resistance. The functional antagonism between isoforms of the same lncRNA, as seen with SNHG16-L/S, adds another layer of regulatory complexity. Deepening our understanding of these mechanisms and their interactions will provide a crucial theoretical foundation for developing lncRNA-targeted strategies to overcome chemoresistance. All the above information is summarized in Table 3.

Table 3.

Research Progress on lncRNAs in Paclitaxel and Other Chemotherapy Drug Resistance in OC

No.	lncRNA	Expression Level	Drug	Molecular Mechanism	References
1	SDHAP1	high	paclitaxel	SDHAP1/miR-4465/EIF4G2(ceRNA)	[61]
2	PRLB	high	paclitaxel	PRLB/miR-150-5p/RSF1/NF-jB(ceRNA)	[62]
3	SNHG1	high	paclitaxel	lnc-SNHG1/miR- 216b-5p/PAK2(ceRNA)	[63]
4	HULC	high	paclitaxel	HULC/miR-137/ITGB8	[64]
5	NEAT1	high	paclitaxel	NEAT1/miR-194/ZEB1	[66]
6	SNHG5	low	paclitaxel	SNHG5/miR-23a	[65]
7	MIR17HG	low	paclitaxel	KHDRBS3/MIR17HG/CLDN6	[70]
8	lncRNA KB−1471A8.2	low	paclitaxel	lncRNA KB-1471A8.2/CDK4	[67]
9	RFPL1S−202	low	paclitaxel	RFPL1S-202/DDX3X/IFN-β/STAT1	[68]
10	LINC02489	low	paclitaxel	LINC02489/PKNOX2/PTEN/mTOR	[69]
11	SLC25A21-AS1	low	paclitaxel	SLC25A21-AS1/EZH2/KCNK4	[71]
12	PVT1	high	doxorubicin	PVT1/YAP1	[73]
13	Linc00707	high	doxorubicin、methotrexate、paclitaxel、cisplatin	Linc00707/miR-382-5p/LRRK2(ceRNA)	[74]

Other chemotherapy drugs

OC develops resistance not only to platinum-based agents and taxanes but also to other chemotherapeutic drugs such as doxorubicin. Multidrug resistance (MDR) mediated by lncRNAs represents one of the core mechanisms underlying this phenomenon. Kevin Tabury et al. demonstrated that diminished PVT1 expression induces extensive transcriptomic reprogramming, driving alterations in cellular stress responses and metabolic pathways—particularly those mediating doxorubicin metabolism—thereby compromising chemosensitivity [73]. Notably, Min-Wen Zhao et al. identified LINC00707 as a critical mediator of MDR in OC. Their mechanistic investigation revealed that LINC00707 overexpression exacerbates chemoresistance through competitive binding to miR-382-5p, which subsequently activates the LRRK2 signaling axis, ultimately fostering an MDR phenotype in OC cells [74]. Together, these findings highlight the pivotal role of lncRNAs in mediating resistance to non-platinum-based chemotherapeutics. Targeting specific lncRNAs, such as PVT1 and LINC00707, may thus offer novel therapeutic avenues for overcoming multidrug resistance in OC.

Studies on lncRNAs in OC chemoresistance have revealed their functional diversity and complexity. They can either promote or suppress drug resistance through various mechanisms, including ceRNA networks, epigenetic modulation, metabolic reprogramming, DNA damage response, and pathway regulation (Fig. 2). A common theme is that lncRNAs act as versatile regulators interfacing with multiple cellular processes. To overcome tumor drug resistance, lncRNA-targeted therapeutic strategies have developed multi-layered and multi-mechanistic intervention approaches [75–81]. The most fundamental strategy involves using CRISPR-Cas9 technology to permanently delete the coding genes of oncogenic lncRNAs at the genomic level, achieving complete eradication. At the post-transcriptional level, techniques such as antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs/shRNAs) can be employed to specifically degrade already transcribed lncRNAs. A more refined approach is functional inhibition, which uses small molecule inhibitors or competitive nucleic acids (e.g., PNA) to block the interaction of lncRNAs with their binding proteins or DNA, rendering them “dysfunctional” without destroying the molecules themselves. Additionally, by targeting naturally occurring antisense transcripts (NATs), the suppression of tumor suppressor genes can be indirectly lifted, thereby restoring drug sensitivity in tumor cells. Meanwhile, innovative technology platforms like SINEUP aim to enhance the translation of specific tumor suppressor gene mRNAs, directly reinforcing their anti-cancer functions. These strategies collectively form a comprehensive toolkit ranging from gene deletion and transcript degradation to functional blockade and functional reactivation, offering strong potential for reversing drug resistance (Figure 3).

Fig. 2.

ommon Mechanisms of lncRNA-Mediated OC Chemoresistance

Fig. 3.

LncRNA-Targeted Therapeutic Strategies for OC Chemoresistance

The current bottleneck lies in translating these mechanistic insights and therapeutic strategies into clinical applications, which faces four major challenges [75]: first, the need to develop specific and efficient in vivo delivery systems for targeting agents (e.g., ASOs, siRNAs, CRISPR components); second, understanding the potential functional redundancy among lncRNAs; third, defining the precise context in which a specific lncRNA mechanism operates within the heterogeneous tumor microenvironment; and fourth, addressing the issue of lncRNA-mediated multidrug resistance, where a single lncRNA may contribute to adaptive responses to multiple chemotherapeutic agents. These findings collectively underscore the intricate regulatory networks of lncRNAs in cisplatin resistance and highlight both the substantial therapeutic potential and the significant challenges of targeting lncRNAs in OC treatment.

Clinical translational potential of lncRNAs as diagnostic, prognostic, and predictive biomarkers in OC (Fig. 4)

Fig. 4.

Value of lncRNAs as OC Risk Genes, Diagnostic Markers, Prognostic Markers and Therapeutic Targets

LncRNAs not only function as key molecules in multiple signaling pathways involved in chemotherapy resistance in OC but also demonstrate significant potential as clinical biomarkers. In terms of diagnosis, non-invasive or minimally invasive detection is an urgent clinical need. Beyond tumor tissue, researchers are actively exploring the possibility of detecting lncRNAs in blood (plasma/serum), exosomes, and ascites. For example, the exosome-derived lncRNA CATED can be secreted from high-grade serous ovarian carcinoma (HGSOC) cells via small extracellular vesicles (sEVs) and promotes platinum resistance by regulating the DHX36/RAP1A/MAPK pathway. This suggests that detecting exosomal CATED in blood or ascites could enable non-invasive diagnosis of resistance. Furthermore, antisense oligonucleotide (ASO) drugs targeting CATED have shown potential to reverse resistance in experimental models, offering new therapeutic avenues [76]. Utilizing circulating lncRNAs as biomarkers offers several advantages: they exhibit higher specificity and sensitivity compared to traditional protein biomarkers; they allow for dynamic monitoring of disease status, predicting survival time and recurrence risk; as a non-invasive method, they are more acceptable in clinical practice and offer good reproducibility; they can serve either as independent biomarkers or as effective complements to existing markers.

While most studies assessing the ability of lncRNAs to predict disease progression and clinical outcomes have been performed on cancer tissue samples, a limited number of analyses based on blood samples indicate that circulating lncRNAs can also reflect cancer prognosis. Regarding prognosis, multiple studies have confirmed that the expression levels of specific lncRNAs are significantly correlated with patients’ OS and PFS. For instance, high expression of LINC02776 and LINC00886 is an independent risk factor for poor prognosis. A 6-lncRNA risk model based on neutrophil extracellular traps (NETs) can effectively stratify patient prognosis risk [77, 78]. Additionally, lncRNAs such as WDFY3-AS2, GAS5, TLR8-AS1, MNX1-AS1, and RFPL1S-202 have also been reported to be associated with OC prognosis.

In the realm of predictive biomarkers, lncRNAs show prominent potential for determining patient sensitivity to specific chemotherapeutic agents like platinum-based drugs or paclitaxel. For example, CATED and LINC02776 have been confirmed to directly mediate platinum resistance; inhibiting LINC02776 can enhance cellular sensitivity to platinum drugs and PARP inhibitors. LOC730101 influences drug sensitivity by regulating autophagy and serves as a potential marker for predicting response to platinum and PARP inhibitors [79]. These findings provide a basis for identifying potentially resistant patients before treatment and implementing personalized interventions.

Beyond therapeutic targeting, the clinical translation of lncRNAs as diagnostic or prognostic biomarkers also faces significant hurdles. These include the standardization of detection methods (from sample collection to RNA extraction and quantification), the lack of large-scale, multi-center prospective cohort validation, and the impact of high tumor heterogeneity on the consistency of lncRNA-based biomarkers. Future research should focus on optimizing predictive models through multi-omics integration and artificial intelligence algorithms, as well as conducting well-designed clinical trials to advance the translation of lncRNAs from mechanistic insights to practical clinical applications [76, 80].

Challenges and future directions in lncRNA research

The field of lncRNA research is at a critical juncture, transitioning from foundational knowledge to clinical application—a process fraught with challenges yet brimming with immense opportunities. The core challenges stem from the inherent properties of lncRNAs themselves: their high structural flexibility and heterogeneity make them resistant to traditional structural biology methods, while their cell-type-specific and spatiotemporally dynamic expression necessitate precise characterization within complex contexts such as normal development and disease states. These characteristics complicate target identification and functional validation, exacerbated by the fact that most lncRNAs remain functionally uncharacterized and exhibit low sequence conservation across species, limiting the availability of reliable animal models. Fortunately, a new generation of technological tools is enabling breakthroughs. The integration of third-generation long-read sequencing, super-resolution imaging, CRISPR-based functional screening tools, chemical probing, and computational modeling allows us to map the dynamic interactome of lncRNAs with unprecedented resolution at the single-molecule level, holding promise for resolving the spatial architecture of key complexes and laying the groundwork for intervention. As we advance toward therapeutic applications, major bottlenecks in clinical translation include drug delivery, tissue specificity, and safety. Oligonucleotide therapeutics (e.g.ASOs, siRNAs) face issues such as low in vivo delivery efficiency, rapid degradation, off-target accumulation in liver and kidneys, and poor penetration into solid tumors. Counterstrategies focus on developing intelligent delivery systems (e.g., targeted nanoparticles, local administration routes) and employing unique chemical modifications to enhance stability and prolong duration of action. Concurrently, safety concerns—including off-target effects, immunogenicity, and potential hepatotoxicity—must be systematically addressed through multi-sequence validation, optimized chemical modifications (e.g., 2’-MOE), and the use of more predictive models like organoids. Looking ahead, the field aims to leverage these technological advances to overcome fundamental mechanistic barriers while tackling delivery and safety challenges, ultimately fostering a paradigm shift from “undruggable” perceptions toward personalized medicine (tailoring therapies based on patient-specific lncRNA profiles) and combination strategies (synergizing with existing treatments), thereby realizing the vast clinical potential of precisely targeting lncRNAs to overcome chemotherapy resistance in OC [75, 81].

Summary and perspectives

In the realm of women’s health, OC remains a stealthy and lethal adversary. Although its incidence ranks third after cervical and endometrial cancers, OC consistently claims the highest mortality rate [82–84], underscoring its grave threat. The mechanisms underlying chemoresistance in OC are multifaceted and interconnected, and this review has only partially elucidated these complexities. Recent studies highlight the immense potential of lncRNAs in addressing chemoresistance, positioning them as critical therapeutic targets. Importantly, these molecular pathways are not isolated; they interact through known and yet-to-be-discovered connections. Thus, constructing a comprehensive and precise network of chemoresistance mechanisms, identifying key regulatory nodes, and developing targeted strategies to dismantle resistance are pivotal. Moving forward, dedicated efforts—including time, resources, and expertise—are essential to unravel this life-threatening challenge. Future priorities include validating potential therapeutic targets and optimizing chemotherapy regimens tailored to molecular profiles, which hold immense promise for improving treatment outcomes and reducing mortality in OC.

Abbreviations

OC

Ovarian cancer

lncRNAs

Long non-coding RNAs

ORF

Open reading frame

ncRNAs

Non-coding RNAs

EMT

Epithelial-mesenchymal transition

EVs

Extracellular vesicles

miRNA

microRNA

MTDH

Metadherin

TNBC

Triple-negative breast cancer

EOC

Epithelial ovarian cancer

ceRNA

Competing endogenous RNA

POLH

Polymerase eta

OS

Overall survival

PFS

Progression-free survival

PPS

Postoperative survival

TCGA

The Cancer Genome Atlas

DEGs

Differentially expressed genes

PFI

Progression-free interval

PPI

Protein-protein interaction

IFN

Interferon

MDR

Multidrug resistance

HGSOC

High-grade serous ovarian carcinoma

sEVs

Small extracellular vesicles

ASO

Antisense oligonucleotide

NATs

Natural antisense transcripts

NETs

Neutrophil extracellular traps

Authors’ contributions

SSD, QG, wrote the paper; HTF compiled the tables. The author(s) read and approved the final manuscript.

Funding

This study was supported by the Natural Science Foundation of Hunan Province (2024JJ8209); Health Research Project of Hunan Provincial Health Commission (W20243082).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

N/A.

Consent for publication

The corresponding author has received consent for publication.

Competing interests

The authors declare no competing interests.