Shiyong Zhang

Targeting GPX4-Dependent Ferroptosis via a Dihydroartemisinin-Conjugated Cross-Linked Lipoic Acid Nanodrug for Endometrial Carcinoma Therapy

Endometrial cancer (EC) is a significant global cause of cancer-related mortality. Chemoresistance is a major challenge in treating advanced or recurrent EC, necessitating the search for new anti-EC drugs. Dihydroartemisinin (DHA)-induced ferroptosis shows promise as a therapy for EC, but its poor solubility and insufficient antitumor potency hinder its clinical use. A novel nanodrug delivery system, DHA@cLAVs, was developed using cross-linked lipoic acid to enhance DHA solubility and antitumor efficacy. Benefiting from the pro-oxidant effects of lipoic acid on tumor cells and its improved water solubility, DHA@cLAVs outperformed DHA alone, showing promising ferroptosis-based antitumor effects via the c-jun/c-fos-GPX4 pathway in both in vitro and in vivo experiments, offering promising prospects for endometrial carcinoma treatment.

Linoleic Acid–Glucosamine Hybrid for Endogenous Iron-Activated Ferroptosis Therapy in High-Grade Serous Ovarian Cancer

As the most common subtype in ovarian malignancies, high-grade serous ovarian cancer (HGSOC) made less therapeutic progress in past decades due to the lack of effective drug-able targets. Herein, an effective linoleic acid (LA) and glucosamine (GlcN) hybrid (LA-GlcN) was synthesized for the treatment of HGSOC. The GlcN was introduced to recognize the glucose transporter 1 (GLUT 1) overexpressed in tumor cells to enhance the uptake of LA-GlcN, and the unsaturated LA was employed to trigger ferroptosis by iron-dependent lipid peroxidation. Since the iron content of HGSOC was ∼5 and 2 times, respectively, higher than that of the normal ovarian cells and low-grade serous ovarian cancer cells, these excess irons make them a good target to enhance the ferroptosis of LA-GlcN. The in vitro study demonstrated that LA-GlcN could selectively kill HGSOC cells without affecting normal cells; the in vivo study revealed that LA-GlcN at the dose of 50 mg kg