2. Academic Validation
  3. UCHL1 promotes temozolomide resistance in glioblastoma by inhibiting the ubiquitination-mediated degradation of keratin 8

UCHL1 promotes temozolomide resistance in glioblastoma by inhibiting the ubiquitination-mediated degradation of keratin 8

  • Transl Oncol. 2026 May:67:102728. doi: 10.1016/j.tranon.2026.102728.
Rujuan Zheng 1,  Xi Chen 1,  Guangjuan Xu 2,  Qian Liu 2,  Sha Hu 1,  Hui Shi 1,  Zengyan Zhu 1,  Xinyuan Ding 3,  Huiling Zhang 4,  Wenjuan Wang 5
Affiliations

Affiliations

  • 1 Department of Pharmacy, Children's Hospital of Soochow University, Suzhou 215025, China; College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • 2 Department of Pharmacy, Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou 215001, China.
  • 3 Department of Pharmacy, Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou 215001, China. Electronic address: [email protected].
  • 4 College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China. Electronic address: [email protected].
  • 5 Department of Pharmacy, Children's Hospital of Soochow University, Suzhou 215025, China; College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China. Electronic address: [email protected].
PMID: 41861659 DOI: 10.1016/j.tranon.2026.102728
Abstract

Background: Resistance to temozolomide (TMZ)-based chemotherapy is a major cause of progression and recurrence in patients with glioblastoma. Although the deubiquitinating enzyme ubiquitin C-terminal hydrolase L1 (UCHL1) has been implicated in tumor chemoresistance, its roles and underlying mechanisms in TMZ resistance remain unclear.

Methods: Bioinformatics analyses and immunohistochemistry were used to assess the prognostic significance and the levels of UCHL1 in glioma specimens. Co-immunoprecipitation assays and mass spectrometry were performed to identify protein interactors of UCHL1. The impact of the UCHL1-Keratin 8 (KRT8) axis on TMZ resistance was evaluated using the cell counting kit-8 (CCK-8) assay and western blotting.

Results: We found that UCHL1 induced resistance of glioblastoma cells to TMZ. Moreover, UCHL1 expression was significantly upregulated in patients with TMZ-resistant glioma and correlated with poor prognosis. As a Deubiquitinase belonging to the UCH enzyme family, UCHL1 utilizes its deubiquitination activity to remove K27-linked polyubiquitin chains from KRT8, thereby preventing KRT8 degradation by the Proteasome and maintaining its stability. In vitro assays further demonstrated that depletion of the UCHL1-KRT8 axis weakened chemoresistance by increasing TMZ-induced Apoptosis.

Conclusion: These findings reveal a novel signaling axis underlying TMZ resistance in glioblastoma and highlight the UCHL1-KRT8 axis as a promising therapeutic target.

Keywords

Chemoresistance; Glioblastoma; Keratin 8; Temozolomide; Ubiquitin C-terminal hydrolase L1.

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