What question did this study set out to answer?

This research aims to explore the role of UCHL1 in osteosarcoma progression and evaluate cryptochlorogenic acid as a therapeutic inhibitor.

April 20, 2026Open Access

UCHL1 promotes osteosarcoma progression via deubiquitination and stabilization of LDHB

Key Points

This research aims to explore the role of UCHL1 in osteosarcoma progression and evaluate cryptochlorogenic acid as a therapeutic inhibitor.
Conducted bioinformatics analysis of GEO datasets to identify UCHL1 overexpression in osteosarcoma.
Performed in vitro experiments using Saos2 cells for UCHL1 knockdown and CCA treatment.
Assessed proliferation, migration, and apoptosis through various assays including CCK-8, EdU, and Western blot.
Utilized co-immunoprecipitation and ubiquitination assays to examine UCHL1-LDHB interaction.
Implemented in vivo xenograft models to evaluate CCA treatment effects.
UCHL1 was significantly overexpressed in osteosarcoma tissues and Saos2 cells.
Knockdown of UCHL1 led to decreased proliferation and migration while increasing apoptosis markers.
UCHL1 deubiquitinated and stabilized LDHB, which was crucial for oncogenic processes.
CCA treatment inhibited Saos2 cell proliferation, migration, and reduced tumor growth in vivo.
Xenograft models showed lower PCNA levels and higher Bax expression with CCA treatment.

Abstract

Osteosarcoma is an aggressive bone malignancy with limited treatment options. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is implicated in tumor progression, but its role in osteosarcoma remains unclear. This study investigates UCHL1's function and explores cryptochlorogenic acid (CCA) as a potential inhibitor. Bioinformatics analysis of GEO datasets (GSE19276, GSE152048) identified UCHL1 overexpression in osteosarcoma. In vitro experiments used Saos2 cells for UCHL1 knockdown (shRNA) and CCA treatment, assessing proliferation (CCK-8, EdU), migration (Transwell, wound healing), and apoptosis (Western blot). Co-immunoprecipitation and ubiquitination assays evaluated UCHL1-LDHB interaction. In vivo, subcutaneous xenograft models tested CCA and UCHL1-LDHB efficacy in mice. UCHL1 was overexpressed in osteosarcoma tissues and Saos2 cells. UCHL1 knockdown suppressed proliferation, migration, and upregulated apoptosis markers (Bax, caspase-8/9). Mechanistically, UCHL1 bound and deubiquitinated LDHB, stabilizing this metabolic enzyme. LDHB knockdown reversed UCHL1-driven oncogenesis. Virtual screening identified CCA as a UCHL1 inhibitor, forming hydrogen bonds with Cys90/Phe160. CCA treatment inhibited Saos2 proliferation, migration, and tumor growth in vivo. Xenografts showed reduced PCNA and elevated Bax expression with CCA. UCHL1 promotes osteosarcoma progression by stabilizing LDHB via deubiquitination. CCA, a natural UCHL1 inhibitor, demonstrates significant anti-tumor efficacy, offering a novel therapeutic strategy for osteosarcoma.

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