Jun Li

Targeting PRDX6-dependent localization and function of GPX4 enhances ferroptosis-mediated tumor suppression

Inducing lipid peroxidation-dependent ferroptosis is a promising anticancer strategy; however, the development of resistance poses a considerable challenge. This study identifies peroxiredoxin 6 (PRDX6) as a crucial modulator of glutathione peroxidase 4 (GPX4), affecting its localization and functional roles, thus contributing to ferroptosis resistance. PRDX6, endowed with phospholipase A2 activity, catalyzes the conversion of peroxy-phospholipids to lysophospholipids and oxidized fatty acids. Through targeted structural mutations and biochemical analyses, we demonstrate that PRDX6 binds to GPX4 via a C47 disulfide bond, facilitating GPX4's membrane translocation and enhanced production of hydroxy fatty acids. Combining the inhibition of PRDX6 with ferroptosis inducers increases lipid peroxidation, effectively suppressing tumor growth in liver and ovarian cancer mouse models, including patient-derived models. Furthermore, high PRDX6 expression correlates with shorter progression-free survival across multiple human cancer types. Collectively, our findings delineate a PRDX6-dependent mechanism in ferroptosis defense, offering new perspectives for targeted cancer therapy.

Oxycodone vs the Combination of Fentanyl and Remifentanil for General Anesthesia in Laparoscopic Uterine Myomas Surgery: A Prospective, Randomized, Controlled Study

This study evaluated whether oxycodone alone could substitute for fentanyl combined with remifentanil for general anesthesia in laparoscopic uterine myoma surgery. 90 adult female patients were randomized into three groups: oxycodone 0.35 mg/kg (Group A), oxycodone 0.30 mg/kg (Group B), or fentanyl 5 μg/kg (Group C) for induction. Anesthesia was maintained with propofol plus saline (Groups A/B) or remifentanil (Group C). Primary outcomes included Numerical Rating Scale (NRS) pain scores in the Post-Anesthesia Care Unit (PACU). Secondary outcomes were intubation reaction, vital signs, extubation/PACU times, Ramsey Sedation Scores (RSS) in PACU, NRS pain scores and adverse events within 48 hours postoperatively. Intubation reactions were rare (one case each in Groups B/C, none in Group A). Group B had significantly lower PACU NRS scores than Group C (0.6 ± 0.7 vs 1.3 ± 1.4, P = 0.011), while Group A showed a nonsignificant trend (0.8 ± 0.9 vs 1.3 ± 1.4, P = 0.051). RSS scores, extubation/PACU times, and 48-hour NRS scores were comparable. However, oxycodone groups had longer postoperative evacuation times than fentanyl group (Group A vs Group C: 20.0 ± 7.3 hours vs 16.5 ± 5.1 hours, P=0.038; Group B vs Group C: 20.3 ± 8.2 hours vs 16.5 ± 5.1 hours, P=0.034). Oxycodone alone provides superior early postoperative analgesia compared to fentanyl-remifentanil in laparoscopic myoma surgery but may delay bowel recovery.

The DDUP protein encoded by the DNA damage-induced CTBP1-DT lncRNA confers cisplatin resistance in ovarian cancer

Abstract Sustained activation of DNA damage response (DDR) signaling has been demonstrated to play vital role in chemotherapy failure in cancer. However, the mechanism underlying DDR sustaining in cancer cells remains unclear. In the current study, we found that the expression of the DDUP microprotein, encoded by the CTBP1-DT lncRNA, drastically increased in cisplatin-resistant ovarian cancer cells and was inversely correlated to cisplatin-based therapy response. Using a patient-derived human cancer cell model, we observed that DNA damage-induced DDUP foci sustained the RAD18/RAD51C and RAD18/PCNA complexes at the sites of DNA damage, consequently resulting in cisplatin resistance through dual RAD51C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms. Notably, treatment with an ATR inhibitor disrupted the DDUP/RAD18 interaction and abolished the effect of DDUP on prolonged DNA damage signaling, which resulted in the hypersensitivity of ovarian cancer cells to cisplatin-based therapy in vivo. Altogether, our study provides insights into DDUP-mediated aberrant DDR signaling in cisplatin resistance and describes a potential novel therapeutic approach for the management of platinum-resistant ovarian cancer.

SLC27A4-mediated selective uptake of mono-unsaturated fatty acids promotes ferroptosis defense in hepatocellular carcinoma

Aberrant lipid metabolism mediated by the selective transport of fatty acids plays vital roles in cancer initiation, progression, and therapeutic failure. However, the biological function and clinical significance of abnormal fatty acid transporters in human cancer remain unclear. In the present study, we reported that solute carrier family 27 member 4 (SLC27A4) is significantly overexpressed in 21 types of human cancer, especially in the fatty acids-enriched microenvironment surrounding hepatocellular carcinoma (HCC), breast cancer, and ovarian cancer. Upregulated SLC27A4 expression correlated with shorter overall and relapse-free survival of patients with HCC, breast cancer, or ovarian cancer. Lipidomic analysis revealed that overexpression of SLC27A4 significantly promoted the selective uptake of mono-unsaturated fatty acids (MUFAs), which induced a high level of MUFA-containing phosphatidylcholine and phosphatidylethanolamine in HCC cells, consequently resulting in resistance to lipid peroxidation and ferroptosis. Importantly, silencing SLC27A4 significantly promoted the sensitivity of HCC to sorafenib treatment, both in vitro and in vivo. Our findings revealed a plausible role for SLC27A4 in ferroptosis defense via lipid remodeling, which might represent an attractive therapeutic target to increase the effectiveness of sorafenib treatment in HCC.

Clinicopathological Characteristics and Prognosis of 91 Patients with Seromucinous and Mucinous Borderline Ovarian Tumors: a Comparative Study

To explore the differences in clinicopathological characteristics and prognosis between seromucinous borderline ovarian tumors (SMBOTs) and mucinous borderline ovarian tumors (MBOTs). Ninety-one patients with SMBOTs and MBOTs who underwent surgery at the Obstetrics and Gynecology Hospital of Fudan University from July 2006 to January 2015 were included. The median onset age of patients with SMBOTs (29 years, 20-77) was younger than that of patients with MBOTs (37 years, 16-71). SMBOTs were more likely to be exogenous and show bilateral ovarian involvement and had a smaller average tumor size of 10.63 cm, while MBOTs were more prone to endogenous growth and show unilateral involvement and had a larger average tumor size of 18.55 cm (p < 0.05). Compared with MBOTs, SMBOTs were characterized by the expression of Mullerian differentiation markers (p < 0.05). Recurrence occurred in 15.8% patients with SMBOT and 9.1% patients with MBOT. One case of SMBOT (2.6%) and one case of MBOT (2.3%) progressed to malignancy during follow-up, but no disease-related death was observed. Age less than 40 years was a risk factor for recurrence, while the effect of fertility-sparing surgery (FSS) on recurrence requires a larger sample size to be validated. The clinical characteristics of SMBOTs and MBOTs are similar but also quite different. High expression of Mullerian differentiation markers in SMBOT may indicate a better response to hormone therapy. Repeated FSS should be performed with caution and fully informed because of the risk of recurrence and progression to malignancy.

Ongoing genome doubling shapes evolvability and immunity in ovarian cancer

Single-cell whole-genome sequencing of 30,260 tumour genomes from 70 samples across 41 patients in the SPECTRUM cohort reveals that ongoing whole-genome doubling drives tumour evolvability and immune evasion in high-grade serous ovarian cancer.