Dysregulation of the ubiquitin-proteasome system in von Hippel-Lindau syndrome - molecular insights and clinical perspectives

Sep 30, 2026

Upload by Aurelia

von Hippel-Lindau (VHL) syndrome is an autosomal dominant tumor susceptibility disorder in which dysfunction of the ubiquitin-proteasome system (UPS) disrupts intracellular protein homeostasis, driving tumorigenesis. When key UPS components, including E1, E2 and E3 enzymes as well as the proteasome, malfunction, the resulting imbalance provides new therapeutic opportunities. This review analyzes mechanisms underlying abnormal UPS enzyme expression in VHL and evaluates progress in strategies targeting distinct UPS components to support precision treatment development.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Abstract

Preface

Introduction

Clinical and Experimental Medicine (2026) 26:90 [https://doi.org/10.1007/s10238-025-01978-4](https://doi.org/10.1007/s10238-025-01978-4) RESEARCH Dysregulation of the ubiquitin-proteasome system in von HippelLindau syndrome: molecular insights and clinical perspectives Yege Bi1,2,3,4 · Rui Wang1,2,3,4 · Lu Li1,2,3,4 · Lili Wang1,6 · Xingwang Chen1,2,3,4 · Xiaomei Nie1,5 · Jia Meng1,2,3,4 · Shanjun Cai1,2,3,4,7 Received: 21 July 2025 / Accepted: 14 November 2025 © The Author(s) 2025 Abstract von Hippel-Lindau (VHL) syndrome is an autosomal dominant tumor susceptibility syndrome whose pathogenesis is closely associated with dysfunction of the ubiquitin-proteasome system (UPS) . When core UPS components—E1, E2, E3 enzymes, and the proteasome—malfunction, the intracellular protein homeostasis network becomes severely disrupted, thereby driving tumorigenesis. This discovery also opens a novel perspective for addressing the therapeutic challenges of VHL syndrome. This review systematically analyzes the mechanisms of abnormally expressed enzymes within the UPS in VHL syndrome and thoroughly examines the progress in therapeutic strategies targeting various UPS components. It aims to provide a theoretical foundation for understanding the molecular mechanisms of this disease and developing precision treatment approaches. Keywords VHL syndrome · The ubiquitin-proteasome system · E3 ubiquitination ligase · Deubiquitinating enzyme · Drug therapy Preface von Hippel-Lindau (VHL) syndrome is a hereditary cancer syndrome caused by germline mutations in the VHL tumor suppressor gene. The core molecular event of this disease is the loss of VHL protein function. The VHL protein, a crucial ‘substrate recognition module’ within the 􀀍 Shanjun Cai [caishanjun@163.com](caishanjun@163.com) 1 Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi 563000, China 2 Department of Ophthalmology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China 3 Guizhou Eye Hospital, Zunyi 563000, China 4 Guizhou Provincial Branch of National Eye Disease Clinical Research Center, Zunyi 563000, China 5 Department of Ophthalmology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China 6 Department of Ophthalmology, Zunyi First People’s Hospital, The Third Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China 7 Aier Eye Hospital of Guizhou Province, Guiyang, China ubiquitin-proteasome system, is not an ordinary cellular component. It is the core of the E3 ubiquitin ligase complex, performing the key function of ‘molecular tagging’by attaching ubiquitin molecules to specific proteins, marking them for degradation. The ubiquitin-proteasome system (UPS) is the most important pathway for selective protein degradation within cells. It precisely regulates cellular life processes by ubiquitinating target proteins and directing them to the proteasome for degradation. In VHL syndrome, the inactivation of the VHL protein prevents the normal ubiquitination and degradation of its most important substrate—the hypoxiainducible factor (HIF) . This leads to the abnormal activation of a series of oncogenes, a critical factor driving tumorigenesis. Therefore, a deep understanding of UPS function is fundamental to unraveling the pathogenesis and urgent therapeutic strategies for VHL syndrome. This review systematically elucidates the UPS’s intricate regulation and functional dysregulation in VHL syndrome, starting from the core components of the ubiquitin-mediated degradation system. First, we focus on dissecting the structure, function, and molecular mechanisms of substrate recognition within the VHL-E3 ubiquitin ligase complex. Subsequently, we explore how deubiquitinating enzymes 1 3 (DUBs) exert reverse regulation on this process and their potential roles in VHL-associated tumors. Finally, we will focus on the promising research advances in drugs t

FAQs

What role does the ubiquitin-proteasome system (UPS) play in VHL syndrome?

VHL pathogenesis is closely linked to dysfunction of the UPS. Core UPS malfunction disrupts protein homeostasis and contributes to tumor development by affecting degradation of key substrates, including HIF.

How does loss of VHL protein function contribute to tumorigenesis?

Loss of VHL protein function prevents normal ubiquitination and degradation of its important substrate, hypoxia-inducible factor (HIF). This abnormal activation promotes oncogenic signaling that drives tumorigenesis.

What does the review focus on regarding UPS components and therapies?

The review analyzes UPS regulation and functional dysregulation in VHL, starting with substrate recognition in the VHL-E3 ubiquitin ligase complex. It also examines roles of deubiquitinating enzymes (DUBs) and discusses therapeutic advances targeting the ubiquitin-proteasome pathway, including PROTAC.

Sep 30, 2026

Upload by Aurelia