Year: 2026
Type: preprint
Abstract: Chemobrain, characterized by cognitive dysfunction, has emerged as a significant health concern following cancer treatment. Doxorubicin, an FDA-approved chemotherapeutic agent, is widely used to treat various cancers. However, its adverse effects raise concerns regarding toxicity in non-cancerous cell types. Microglia, the resident immune cells of the brain, play a central role in maintaining neural homeostasis. Despite this, the mechanisms by which microglia become dysfunctional following doxorubicin exposure remain poorly understood. Understanding the transcriptomic alterations induced by doxorubicin in microglia could provide critical insights into mechanisms underlying its neurotoxic effects. In this study, the transcriptomic response of human microglia to doxorubicin using mRNA sequencing combined with bioinformatic analysis was investigated. Exposure to doxorubicin significantly altered microglial morphology, promoting a shift toward a process-bearing phenotype in human HMC3 cells. This phenotypic change was accompanied by elevated levels of DNA damage and was associated with the induction of cellular senescence. At the gene regulation level, the Illumina-based transcriptomic analysis provided 25,834 gene expression profiling in which 5,669 were differentially expressed. The future analyses revealed that 3,431 (upregulated) and 2,238 (downregulated) were differentially expressed under the treatment of doxorubicin. Genes associated with the p53 signaling pathway and inflammatory responses were upregulated, whereas genes involved in translation, DNA replication, and cell-cycle progression were downregulated. This transcriptional dysregulation was accompanied by differential expression of key transcription factors. This study provides transcriptomic evidence elucidating the genotoxic response to doxorubicin in microglial cells, offering mechanistic insights into chemobrain and highlighting key molecular pathways as potential targets for therapeutic intervention. Highlights Doxorubicin induces persistent DNA damage and senescence-associated phenotypic changes in human HMC3 microglial cells. Unbiased Illumina-based transcriptomic profiling identified 25,834 expressed genes, including 5,669 differentially expressed genes following doxorubicin treatment. Genes involved in p53 signaling and inflammatory responses were upregulated, whereas genes associated with translation, DNA replication, and cell -cycle progression were downregulated. Transcriptomic dysregulation was accompanied by altered expression of key transcription factors, including interferon regulatory factor 4 (IRF4). These findings provide a transcriptomic framework for investigating the potential contribution of microglial dysfunction to chemotherapy-associated neurotoxicity.
Author: Ekkaphot Khongkla
Institution: Mahidol University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7221466517