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<p>Papillary thyroid carcinoma (PTC) is prone to metastasis, and patients with metastatic PTC have a poor prognosis. This study aimed to investigate the function of GLOD4 in PTC. Cancerous and paracancerous tissues were collected from patients with PTC. CO-IP was performed to detect the level of GLOD4 or ubiquitination modification, as well as to verify protein interactions of GLOD4 with UCHL1 or GLO1. Cell proliferation was detected by CCK-8 or EdU staining, cell migration and invasion by transwell assay, GLO1 enzyme activity by ELISA, total and mitochondrial methylglyoxal levels by commercial kits, mitochondrial ROS levels by flow cytometry, and oxygen consumption rate and ATP levels by seahorse energy metabolism analyzer. GLOD4 knockdown subcutaneous xenograft model was constructed in nude mice, HE staining was used to detect the histopathological condition of the tumor, and IHC was used to detect Ki67 and GLOD4 expression. GLOD4 levels were significantly upregulated in PTC tissues and cells, and overexpression of GLOD4 enhanced PTC cell proliferation, migration, and invasion. Mechanistically, UCHL1 could directly bind to GLOD4 and enhance its protein stability by promoting K48-linked deubiquitination, whereas the ability of GLOD4 to promote invasion and migration in PTC cells depends on this regulatory function of UCHL1. Furthermore, GLOD4 regulated GLO1 to detoxify methylglyoxal, a toxic by-product of glycolysis, to maintain mitochondrial homeostasis. GLOD4 knockdown inhibited PTC tumor growth in vivo. UCHL1 enhances the protein stability of GLOD4 through deubiquitination, promoting its interaction with GLO1 to cooperatively detoxify methylglyoxal, maintain mitochondrial homeostasis, and ultimately drive PTC progression.</p>

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UCHL1-mediated deubiquitination of GLOD4 regulates mitochondrial homeostasis and PTC malignant progression via GLO1

  • 期刊论文

  • 发表日期：

    2026年5月21日

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  • Lei Cai,
  • Li-Yuan Qian,
  • Wei Wu,
  • Bo-Ni Ding,
  • Zi-Run Luo,
  • Juan Du

摘要

Papillary thyroid carcinoma (PTC) is prone to metastasis, and patients with metastatic PTC have a poor prognosis. This study aimed to investigate the function of GLOD4 in PTC. Cancerous and paracancerous tissues were collected from patients with PTC. CO-IP was performed to detect the level of GLOD4 or ubiquitination modification, as well as to verify protein interactions of GLOD4 with UCHL1 or GLO1. Cell proliferation was detected by CCK-8 or EdU staining, cell migration and invasion by transwell assay, GLO1 enzyme activity by ELISA, total and mitochondrial methylglyoxal levels by commercial kits, mitochondrial ROS levels by flow cytometry, and oxygen consumption rate and ATP levels by seahorse energy metabolism analyzer. GLOD4 knockdown subcutaneous xenograft model was constructed in nude mice, HE staining was used to detect the histopathological condition of the tumor, and IHC was used to detect Ki67 and GLOD4 expression. GLOD4 levels were significantly upregulated in PTC tissues and cells, and overexpression of GLOD4 enhanced PTC cell proliferation, migration, and invasion. Mechanistically, UCHL1 could directly bind to GLOD4 and enhance its protein stability by promoting K48-linked deubiquitination, whereas the ability of GLOD4 to promote invasion and migration in PTC cells depends on this regulatory function of UCHL1. Furthermore, GLOD4 regulated GLO1 to detoxify methylglyoxal, a toxic by-product of glycolysis, to maintain mitochondrial homeostasis. GLOD4 knockdown inhibited PTC tumor growth in vivo. UCHL1 enhances the protein stability of GLOD4 through deubiquitination, promoting its interaction with GLO1 to cooperatively detoxify methylglyoxal, maintain mitochondrial homeostasis, and ultimately drive PTC progression.