What does this research mean for the field?

The circular RNA circSOD2 encodes a novel 149-amino acid peptide (SOD2-149aa) that promotes cisplatin resistance in bladder cancer by interacting with TRIM26 to stabilize GPX4, thereby inhibiting ferroptosis. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to explore how circSOD2 affects ferroptosis and chemoresistance in bladder cancer cells.

April 5, 2026

Abstract 7050: A novel 149-amino acid protein encoded by circSOD2 inhibits ferroptosis and promotes cisplatin resistance in bladder cancer.

Key Points

This research aims to explore how circSOD2 affects ferroptosis and chemoresistance in bladder cancer cells.
RNA sequencing to identify circSOD2 expression in cell lines and specimens
In vitro functional assays (CCK-8, colony formation) to assess cell proliferation and cisplatin resistance
In vivo studies using xenograft mouse models
Co-immunoprecipitation and GST pull-down assays to study protein interactions
Ribosome profiling and Western blot analyses to confirm protein-coding potential
circSOD2 is significantly upregulated in cisplatin-resistant bladder cancer cells
Overexpression of circSOD2 enhances proliferation and resistance to cisplatin
SOD2-149aa peptide interacts with TRIM26, leading to increased GPX4 stability
TRIM26-mediated K63-linked polyubiquitination protects GPX4 from degradation
Knockout of SOD2-149aa restores sensitivity to cisplatin in bladder cancer cells

Abstract

Abstract Circular RNAs (circRNAs) play pivotal roles in bladder cancer (BCa) tumorigenesis, metastasis, and chemoresistance, but their functional involvement in cisplatin-induced ferroptosis remains poorly defined. Herein, we identified circSOD2 as a significantly upregulated circRNA in cisplatin-resistant BCa cell lines and clinical specimens via RNA sequencing. Functional assays demonstrated that circSOD2 overexpression enhanced BCa cell proliferation and cisplatin resistance in vitro (CCK-8, colony formation, and ferroptosis detection assays) and in vivo (xenograft mouse models). Mechanistically, ribosome profiling and Western blot analyses confirmed the protein-coding potential of circSOD2, which translates into a novel 149-amino acid peptide (SOD2-149aa). Co-immunoprecipitation (Co-IP) and glutathione S-transferase (GST) pull-down assays verified that SOD2-149aa directly binds to the RING domain of tripartite motif 26 (TRIM26), a ubiquitin E3 ligase. This interaction activates TRIM26-mediated K63-linked polyubiquitination of glutathione peroxidase 4 (GPX4) — a key anti-ferroptotic enzyme — at lysine residue 148, thereby preventing GPX4 proteasomal degradation and enhancing its protein stability. Stabilized GPX4 efficiently scavenges lipid reactive oxygen species (ROS) and reduces iron-dependent lipid peroxidation, ultimately mitigating cisplatin-induced ferroptosis and conferring cisplatin resistance in BCa. Conversely, circSOD2 silencing or SOD2-149aa knockout abrogated TRIM26-GPX4 interaction, diminished GPX4 stability, and restored BCa cell sensitivity to cisplatin. Collectively, our findings uncover a novel circRNA-encoded peptide that regulates ferroptosis and chemoresistance via the TRIM26-GPX4 axis, highlighting circSOD2/SOD2-149aa as a promising prognostic biomarker and therapeutic target for overcoming cisplatin resistance in BCa. Citation Format: Shanqi Guo, Zhihong Lv, Nan Wang, Xingkang Jiang. A novel 149-amino acid protein encoded by circSOD2 inhibits ferroptosis and promotes cisplatin resistance in bladder cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7050.

Bookmark

Cite This Study

Guo et al. (Fri,) studied this question.

synapsesocial.com/papers/69d1fcfda79560c99a0a2b6e https://doi.org/https://doi.org/10.1158/1538-7445.am2026-7050

Bookmark