New Insights into Ferroptosis Initiating Therapies (FIT) by Targeting the Rewired Lipid Metabolism in Ovarian Cancer Peritoneal Metastases

Abstract

Ovarian cancer is one of the most lethal gynecological cancers worldwide. The poor prognosis of this malignancy is substantially attributed to the inadequate symptomatic biomarkers for early diagnosis and effective remedies to cure the disease against chemoresistance and metastasis. Ovarian cancer metastasis is often relatively passive, and the single clusters of ovarian cancer cells detached from the primary ovarian tumor are transcoelomic spread by the peritoneal fluid throughout the peritoneum cavity and omentum. Our earlier studies revealed that lipid-enriched ascitic/omental microenvironment enforced metastatic ovarian cancer cells to undertake metabolic reprogramming and utilize free fatty acids as the main energy source for tumor progression and aggression. Intriguingly, cell susceptibility to ferroptosis has been tightly correlated with the dysregulated fatty acid metabolism (FAM), and enhanced iron uptake as the prominent features of ferroptosis are attributed to the strengthened lipid peroxidation and aberrant iron accumulation, suggesting that ferroptosis induction is a targetable vulnerability to prevent cancer metastasis. Therefore, the standpoints about tackling altered FAM in combination with ferroptosis initiation as a dual-targeted therapy against advanced ovarian cancer were highlighted herein. Furthermore, a discussion on the prospect and challenge of inducing ferroptosis as an innovative therapeutic approach for reversing remedial resistance in cancer interventions was included. It is hoped this proof-of-concept review will indicate appropriate directions for speeding up the translational application of ferroptosis-inducing compounds (FINs) to improve the efficacy of ovarian cancer treatment.

Ferroptosis and the ubiquitin-proteasome system: exploring treatment targets in cancer

“…Therefore, protecting cells against elastin-induced ferroptosis can be achieved by silencing LOXs ( Lee et al, 2022 ). Multiple mechanisms exist by which lipid peroxides cause damage to cells, including the generation of ROS through the amplification of lipid peroxidation processes, alterations to the membrane’s physical structure, and lipid peroxidation byproducts ( Zhan et al, 2022 ).…”

Targeting Oncometabolites in Peritoneal Cancers: Preclinical Insights and Therapeutic Strategies

“…Several studies investigated the potential of oncometabolites as therapeutic targets in peritoneal cancers by focusing on the metabolic pathways altered in cancer cells [ 92 , 93 , 94 ]. The unique metabolic phenotype of peritoneal cancer cells also presents an opportunity for targeted therapies.…”

Dysregulation of Cholesterol Homeostasis in Ovarian Cancer

“…Various studies have suggested that aberrant lipid metabolism including cholesterol metabolism positively correlates with metastasis in OC [ 23 , 62 , 63 ]. Fluidity versus membrane rigidity in metastatic cancer cells is governed by the production of lipid rafts packed in the liquid phase order to facilitates a variety of cellular signaling pathways that are interconnected with cancer-related processes [ 53 , 64 ].…”