2. Academic Validation
  3. Inhibition of replication factor C4-induced DNA damage repair reverses the chemoresistance of glioblastoma to temozolomide and reveals the synthetic lethal effect of combined targeting of checkpoint kinase 1

Inhibition of replication factor C4-induced DNA damage repair reverses the chemoresistance of glioblastoma to temozolomide and reveals the synthetic lethal effect of combined targeting of checkpoint kinase 1

  • Int J Biol Macromol. 2026 Mar:351:151067. doi: 10.1016/j.ijbiomac.2026.151067.
Ning Li 1,  Duanyi Cheng 2,  Xinzhe Huang 3,  Shenghua Zhuo 3,  Dayuan Liu 4,  Zezhou Zheng 5,  Rong Sun 5,  Yansong Fu 5,  Jianpeng Lei 3,  Jian Dai 3,  Jigao Feng 6,  Kai Wang 7,  Jiannong Zhao 8
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570105, China; Department of Neurosurgery, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou, Hainan, 570311, China; International Center for Aging and Cancer (ICAC), Hainan Medical University, Hainan Academy of Medical Sciences, Haikou, Hainan, 571199, China; Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, 571199, China.
  • 2 Department of Neurosurgery, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou, Hainan, 570311, China; Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, 571199, China.
  • 3 International Center for Aging and Cancer (ICAC), Hainan Medical University, Hainan Academy of Medical Sciences, Haikou, Hainan, 571199, China.
  • 4 Department of Neurosurgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570105, China.
  • 5 Department of Neurosurgery, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou, Hainan, 570311, China.
  • 6 Department of Neurosurgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570105, China; Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, 571199, China. Electronic address: [email protected].
  • 7 International Center for Aging and Cancer (ICAC), Hainan Medical University, Hainan Academy of Medical Sciences, Haikou, Hainan, 571199, China. Electronic address: [email protected].
  • 8 Department of Neurosurgery, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou, Hainan, 570311, China. Electronic address: [email protected].
PMID: 41747987 DOI: 10.1016/j.ijbiomac.2026.151067
Abstract

Glioblastoma (GBM) is a highly aggressive malignant tumor of the central nervous system, and resistance to temozolomide (TMZ) remains a major cause of treatment failure and tumor recurrence. DNA damage repair (DDR) serves as a critical mechanism underlying chemoresistance, with replication factor C4 (RFC4) emerging as a key mediator. We aimed to investigate the mechanism by which RFC4 induces TMZ resistance in GBM through DDR activation. Analysis of clinical specimens revealed that RFC4 is overexpressed in glioma tissues and correlates with poor prognosis in patients with GBM. Functional assays in vitro and in vivo demonstrated that RFC4 knockdown significantly inhibits GBM cell proliferation, invasion, and migration, while concurrently enhancing TMZ sensitivity. Bioinformatic analysis identified checkpoint kinase 1 (Chk1) as a key downstream effector of RFC4. Mechanistic studies further showed that RFC4 promotes DDR activation through a synergistic interaction with Chk1, thereby diminishing cellular sensitivity to TMZ. Notably, Chk1 inhibition effectively reversed RFC4-mediated TMZ resistance. Collectively, these findings indicate that RFC4 functions as an oncogenic driver in GBM by stabilizing Chk1 and enhancing DNA repair. Targeting RFC4 to modulate DDR may therefore represent a promising therapeutic strategy to overcome TMZ resistance and improve outcomes for patients with GBM.

Keywords

DNA damage repair; Glioblastoma; Resistance; Temozolomide.

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