Discovery of ferroptosis-inducing R4VP compounds for targeting aggressive cancers

Sep 22, 2026

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Aggressive and therapy-resistant cancers undermine treatment and correlate with poor survival, making pathway- and compound-based intervention essential. RNF4, an E3 ubiquitin ligase, supports tumorigenesis by stabilizing oncoproteins and promoting DNA repair, contributing to worse outcomes in multiple carcinoma and melanoma contexts. The study designs R4VP dual degrader compounds linking VHL and RNF4, driving RNF4 loss and ferroptotic death via GPX4 targeting, preferentially in EGFR-pathway tumor-driving mutants. R4VPs kill RTKi-resistant melanoma and primary sarcoma cells while sparing non-tumorigenic cells.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

RNF4 in oncoprotein stabilization and cancer prognosis

Design of R4VP dual degrader compounds

Ferroptosis induction through GPX4 modification

Selectivity for EGFR-pathway tumor-driving mutations

Therapeutic implications for hard-to-treat cancers

Oncogene [www.nature.com/onc](www.nature.com/onc) ARTICLE OPEN Discovery of ferroptosis-inducing R4VP compounds for targeting aggressive cancers Avital Oknin-Vaisman 1,7, Deepanjan Panda2,7, Rostislav Novak1,3, Ghazal Kheshaiboun 1, Eliya Bitman-Lotan 1, Satish Gandhesiri2, Rubina Kazi4, Nikolett Pahor5, Viktoria von Heyl zu Herrnsheim 5, Yamen Abu Ahmad 1, Guy Kamnesky2, Thorsten Mosler4, Markus E. Diefenbacher 5,6, Ashraf Brik 2 ✉ and Amir Orian 1 ✉ © The Author(s) 2026 | | Aggressive and therapy-resistant cancers present a signiﬁcant challenge to treatment and are associated with poor patients’survival. Identifying molecular pathways and compounds that target these pathways is critical for improving patient outcomes. RNF4, an E3 Ubiquitin ligase, is pivotal for tumorigenesis in part by stabilizing oncoproteins and its role in DNA repair, thereby enhancing cancer cell survival and driving tumorigenesis. Elevated RNF4 levels are associated with poor prognosis in patients with carcinomas, melanoma, and sarcoma. Here, we describe the design and development of R4VPs, dual degrader compounds connecting two E3 ubiquitin ligases; Von Hippel-Lindau protein (VHL) with RNF4 . R4VPs promote RNF4 degradation and thereby reduce the levels of its stabilized phosphorylated oncoproteins, while concomitantly eliminating VHL. R4VPs selectively induce ferroptotic cell death in cancer cells, sparing non-tumorigenic and primary cells in part by binding and modifying the antiferroptotic selanoproteins GPX4 . R4VPs-induced ferroptosis preferentially targeting cells harboring tumor-driving mutations in the EGFR pathway, whereas it does not affect PI3K-transformed cells. As a consequence, R4VPs effectively induce cell death in Receptor Tyrosine Kinase inhibitor-resistant melanoma and primary patient sarcoma cells. Our ﬁndings highlight the potential of selective | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | ferroptosis inducers, such as R4VPs, as a therapeutic strategy for hard-to-treat cancers. | | | | | Oncogene (2026) 45:2727–2742; [https://doi.org/10.1038/s41388-026-03829-2](https://doi.org/10.1038/s41388-026-03829-2) | | | | | | INTRODUCTION Despite signiﬁcant advances in cancer therapies, the patient’s response to treatment for aggressive, advanced, and/or therapyresistant tumors remains a challenge. Cancer development and progression are intimately linked to increased oncoprotein stabilization. Moreover, the development of resistance to chemotherapy and molecular treatments such as receptor tyrosine kinase inhibitors (RTKi), and/or immune check-point inhibitors (ICI) in melanoma is associated with increased oncoprotein stabilization [1–8] . These hallmarks are observed in most patients; therefore, overcoming therapy resistance is an unmet clinical need. Thus, the development of tailored precision therapeutics targeting aggressive and therapy-resistant tumors is required for improving patient outcomes. We recently discovered a novel ubiquitin-dependent pathway that stabilizes and potentiates oncoprotein activity, promoting tumorigenesis. In this pathway, oncoprotein stabilization requires their phosphorylation by mitogenic kinases regardless of the ubiquitin machinery or the degrons that mediate the degradation of these otherwise short-lived oncoproteins [7, 9–11] . The central enzyme in this pathway is the ubiquitin ligase RNF4, which ubiquitinates these oncoproteins, catalyzing the generation of heterotypic K11-and K33-linked polyubiquitin chains. This atypical ubiquitination results in the stabilization and enhancement of the transcriptional activity of multiple oncogenic transcription factors, such as phosphorylated c-Myc, β-catenin c-Jun, among others [9] . In addition to protein stabilization, RNF4 plays various roles in cancer development. Among these functions are DNA damage repair, nuclear protein control, e

FAQs

What problem does the study address in cancer treatment?

Aggressive, advanced, and therapy-resistant tumors show limited response to current treatments, and therapy resistance remains a major unmet clinical need.

How do R4VP compounds affect RNF4 and VHL?

R4VPs are dual degrader compounds that promote RNF4 degradation while concomitantly eliminating VHL, reducing stabilized phosphorylated oncoproteins.

Why are R4VPs described as inducing ferroptosis selectively?

R4VPs selectively induce ferroptotic cell death in cancer cells by binding and modifying antiferroptotic proteins, including GPX4, and preferentially target cells with EGFR-pathway tumor-driving mutations.

Sep 22, 2026

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