# LncPEDS1-AS promotes UTUC resistance to lipid peroxidation by regulating PEDS1 expression via DDX23

## TL;DR

This study identifies a long non-coding RNA, LncPEDS1-AS, that helps UTUC resist lipid peroxidation by regulating PEDS1 through DDX23, offering a new therapeutic target.

## Contribution

The study reveals a novel regulatory axis involving LncPEDS1-AS, DDX23, and PEDS1 in UTUC resistance to lipid peroxidation.

## Key findings

- LncPEDS1-AS interacts with DDX23 to regulate PEDS1 splicing and maturation.
- Targeting LncPEDS1-AS with ASO therapy reduces tumor growth and increases ROS sensitivity in UTUC.
- Ultra-long antisense lncRNAs like LncPEDS1-AS have significant regulatory roles in cancer biology.

## Abstract

Upper tract urothelial carcinoma (UTUC) is a rare malignancy with a significantly poorer prognosis than bladder cancer (BC). One distinguishing feature of UTUC is its enhanced resistance to reactive oxygen species (ROS)-induced lipid peroxidation, a phenomenon closely associated with adverse clinical outcomes. However, the molecular mechanisms underlying this resistance remain largely unexplored. In this study, we identify LncPEDS1-AS, an ultra-long (>6900 nt) antisense lncRNA, as a key regulator of ROS resistance in UTUC. Mechanistically, LncPEDS1-AS interacts with the splicing factor DDX23, forming a nuclear RNA-protein complex that facilitates the splicing and maturation of PEDS1 pre-mRNA. PEDS1 encodes plasmanylethanolamine desaturase, which plays a protective role against lipid peroxidation. Based on these findings, we developed an antisense oligonucleotide (ASO) therapy strategy targeting LncPEDS1-AS, which effectively suppressed tumour growth and enhanced tumour cells’ ROS sensitivity both in vitro and in vivo. Moreover, our findings also highlight the distinctive molecular features and regulatory capacity of ultra-long antisense lncRNAs such as LncPEDS1-AS, which merit further comprehensive exploration in cancer biology.

The LncPEDS1-AS-DDX23-PEDS1 axis is involved in resistance to lipid peroxidation and plays a critical role in the prognosis of UTUC (Created with BioRender.com).

The LncPEDS1-AS-DDX23-PEDS1 axis is involved in resistance to lipid peroxidation and plays a critical role in the prognosis of UTUC (Created with BioRender.com).