1,25D3 reprograms mitochondrial quality control via sirtuin and sensitizes glioblastoma to chemotherapy

Karrie M Kiang; Yixiong Shen; Yogesh K H Wong; Bo Chen; Junbo Liao; Anza Mnahal; Wanjun Tang; Zhiyuan Zhu; Shuhan Cao; Carmen S C Lo; Sang Jin Lee; Hongbo Guo; Liyang Zhang; Gilberto Ka-Kit Leung

doi:10.1016/j.ymthe.2026.03.006

1,25D3 reprograms mitochondrial quality control via sirtuin and sensitizes glioblastoma to chemotherapy

Mol Ther. 2026 Mar 6:S1525-0016(26)00191-7. doi: 10.1016/j.ymthe.2026.03.006. Online ahead of print.

Authors

Affiliations

¹ Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR. Electronic address: mykiang@hku.hk.
² Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR; Department of Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
³ Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR.
⁴ Department of Functional Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
⁵ Biofunctional Materials, Division of Applied Oral Sciences and Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR.
⁶ Department of Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
⁷ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁸ Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR; Queen Mary Hospital, Hospital Authority, Hong Kong SAR; Clinical Neuroscience Consortium, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR. Electronic address: gilberto@hku.hk.

PMID: 41792999
DOI: 10.1016/j.ymthe.2026.03.006

Abstract

Tumor cells adapt to therapeutic stress by preserving mitochondrial integrity through mitophagy, but excessive mitophagy can overwhelm this adaptative mechanism and precipitate mitochondrial collapse. Here, we demonstrate that 1,25-dihydroxyvitamin D3 (1,25D3) reduces glioblastoma resistance to the standard chemotherapeutic temozolomide by driving mitophagic overload and mitochondrial dysfunction. We identified mitochondrial sirtuin SIRT4 as a key downstream effector of mitochondrial metabolism and quality control triggered by 1,25D3-induced mitochondrial stress. Pharmacological levels of 1,25D3 activate mitophagy by transcriptionally upregulating SIRT4 through vitamin D receptor (VDR) signaling. SIRT4, which is frequently downregulated in glioblastoma, suppresses glioblastoma glutamine metabolism by inhibiting glutamate dehydrogenase activity and limiting α-ketoglutarate availability, thereby integrating metabolic stress with enhanced mitophagy. This VDR-SIRT4 axis shifts mitophagy from a cytoprotective process to a lethal pathway, selectively sensitizing tumor cells while sparing normal astrocytes and brain tissue. By exploiting mitochondrial quality control as a metabolic vulnerability, 1,25D3 enhances chemotherapeutic efficacy and provides a translational rationale for repurposing 1,25D3 in resistant glioblastoma.

Keywords: cancer metabolism; chemoresistance; glioblastoma; metabolic vulnerability; mitochondrial quality control; mitophagy; sirtuin; vitamin D.