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REVIEW article

Front. Oncol.
Sec. Cancer Molecular Targets and Therapeutics
Volume 14 - 2024 | doi: 10.3389/fonc.2024.1484515

Targeting the SMURF2-HIF1α Axis: A New Frontier in Cancer Therapy

Provisionally accepted
Emile Youssef Emile Youssef 1*Shuai Zhao Shuai Zhao 2Connor Purcell Connor Purcell 2Gary L Olson Gary L Olson 3Wafik El-Deiry Wafik El-Deiry 4*
  • 1 Smurf-Therapeutics, Providence, United States
  • 2 Brown University, Providence, Rhode Island, United States
  • 3 Provid Pharmaceuticals, Inc.,, Monmouth Junction, United States
  • 4 Warren Alpert Medical School, Brown University, Providence, Rhode Island, United States

The final, formatted version of the article will be published soon.

    The SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) has emerged as a critical regulator in cancer biology, modulating the stability of Hypoxia-Inducible Factor 1-alpha (HIF1α) and influencing a network of hypoxia-driven pathways within the tumor microenvironment (TME). SMURF2 targets HIF1α for ubiquitination and subsequent proteasomal degradation, disrupting hypoxic responses that promote cancer cell survival, metabolic reprogramming, angiogenesis, and resistance to therapy. Beyond its role in HIF1α regulation, SMURF2 exerts extensive control over cellular processes central to tumor progression, including chromatin remodeling, DNA damage repair, ferroptosis, and cellular stress responses. Notably, SMURF2's ability to promote ferroptotic cell death through GSTP1 degradation offers an alternative pathway to overcome apoptosis resistance, expanding therapeutic options for refractory cancers.This review delves into the multifaceted interactions between SMURF2 and HIF1α, emphasizing how their interplay impacts metabolic adaptations like the Warburg effect, immune evasion, and therapeutic resistance. We discuss SMURF2's dual functionality as both a tumor suppressor and, in certain contexts, an oncogenic factor, underscoring its potential as a highly versatile therapeutic target. Furthermore, modulating the SMURF2-HIF1α axis presents an innovative approach to destabilize hypoxia-dependent pathways, sensitizing tumors to chemotherapy, radiotherapy, and immune-based treatments. However, the complexity of SMURF2's interactions necessitate a thorough assessment of potential off-target effects and challenges in specificity, which must be addressed to optimize its clinical application.

    Keywords: Smurf2, HIF1α, Tumor Microenvironment, metabolic reprogramming, ferroptosis, ubiquitin-proteasome system, Cellular adaptation

    Received: 22 Aug 2024; Accepted: 14 Nov 2024.

    Copyright: © 2024 Youssef, Zhao, Purcell, Olson and El-Deiry. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Emile Youssef, Smurf-Therapeutics, Providence, United States
    Wafik El-Deiry, Warren Alpert Medical School, Brown University, Providence, 02912, Rhode Island, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.