Ovarian cancer, despite being less common than breast or lung cancer, is the deadliest gynecological malignancy. The majority of patients present with advanced-stage disease, and while initial responses to platinum-based chemotherapy are often favorable, most patients eventually develop platinum resistance, leading to treatment failure and poor outcomes. Understanding and overcoming platinum resistance represents one of the most pressing challenges in ovarian cancer research.

Circular RNAs, a class of non-coding RNAs characterized by their covalently closed loop structure, have emerged as important regulators of gene expression and cellular function. Unlike linear RNAs, circRNAs are resistant to exonuclease degradation, conferring greater stability. CircRNAs can function as microRNA sponges, protein decoys, and even templates for translation. Aberrant circRNA expression has been documented in multiple cancer types, where they contribute to tumor progression and therapeutic resistance.

This study identified circSFPQ_008, a circular RNA derived from the SFPQ gene, as a critical mediator of platinum resistance in ovarian cancer. The research team first compared circRNA expression profiles between platinum-sensitive and platinum-resistant ovarian cancer specimens, identifying circSFPQ_008 as significantly upregulated in resistant tumors. This finding was validated in independent patient cohorts and ovarian cancer cell lines.

Functional studies revealed that circSFPQ_008 overexpression conferred platinum resistance to sensitive ovarian cancer cells, while circSFPQ_008 knockdown sensitized resistant cells to platinum treatment. These effects were observed both in vitro and in vivo, demonstrating the physiological relevance of circSFPQ_008 in platinum resistance.

Mechanistically, the study uncovered a novel regulatory axis involving circSFPQ_008, the SFPQ protein, and BRCA1. circSFPQ_008 was found to interact with SFPQ, a DNA/RNA binding protein involved in multiple aspects of RNA metabolism. This interaction enhanced SFPQ stability and promoted its nuclear localization. SFPQ, in turn, directly regulated BRCA1 expression through transcriptional mechanisms.

The connection to BRCA1 is particularly significant given the established role of BRCA1 in platinum sensitivity. BRCA1 is a key component of the homologous recombination DNA repair pathway, and BRCA1-deficient tumors are characteristically sensitive to platinum agents and PARP inhibitors. By upregulating BRCA1 through the circSFPQ_008/SFPQ axis, ovarian cancer cells enhance their DNA repair capacity and resist platinum-induced DNA damage.

Therapeutic targeting of this axis was explored using antisense oligonucleotides against circSFPQ_008. Treatment with these agents effectively reduced circSFPQ_008 levels, downregulated BRCA1 expression, and sensitized resistant ovarian cancer cells to platinum chemotherapy. This proof-of-concept demonstration suggests that circSFPQ_008 could represent a viable therapeutic target.

The clinical implications of these findings are substantial. First, circSFPQ_008 expression could serve as a biomarker to predict platinum response, enabling personalized treatment selection. Second, therapeutic targeting of circSFPQ_008 could restore platinum sensitivity in resistant tumors. Third, the circSFPQ_008/SFPQ/BRCA1 axis represents a novel mechanism of platinum resistance distinct from classical BRCA1 mutations.

Future research directions include validation of these findings in larger clinical cohorts, development of clinically applicable circSFPQ_008 detection methods, and exploration of combination strategies pairing circSFPQ_008 targeting with platinum chemotherapy or other therapeutic agents.
DOI
10.1007/s11684-026-1201-7