RECQL4 as a novel drug target against ovarian cancer

Ovarian cancer is characterized by poor specificity and unfavorable prognosis. Therefore, exploring new mechanisms of ovarian cancer development, identifying specific new targets, and developing effective therapeutic drugs based on these new targets have become the focus of current research. This study collected clinical case tissues from high-grade serous ovarian cancer (HGSC) patients and found that the expression of RecQ-like helicase 4 (RECQL4) was positively correlated with the malignancy of ovarian cancer but negatively correlated with its prognosis. From the chemical library of traditional Chinese medicine and ethnic medicines established by our research group in Guizhou, we screened out an effective target, a fluorinated tanshinone analogue (TC12-1), which can effectively inhibit and bind to RECQL4. In vitro experiments showed that TC12-1 induced apoptosis and inhibited cancer cell invasion and metastasis. Additionally, TC12-1 can induce DNA damage, enhancing replication fork stress and blocking the cell cycle at the S phase in cancer cells. The compound effectively inhibited tumor growth and metastasis in subcutaneous tumor models and in orthotopic ovarian cancer mouse models, showing no significant toxicity to vital organs in tumor animal models. The molecular mechanism of TC12-1 targeting RECQL4 in anti-ovarian epithelial cell carcinoma involves the regulation of key genes such as γ-H2AX, PRPA32, ATM, RAD50, CHK2, P53, P21, Bax, Cyclin E, and CDC2, thereby affecting the cell cycle and DNA replication signaling pathways. The results provide theoretical support for developing specific ovarian cancer therapeutic drugs using RECQL4 as a new target.