Tu, Xinyi

Abstract Cholesterol has long been viewed as a structural component of cellular membranes, yet its role in DNA damage response remains poorly defined. Here, we show that ionizing radiation (IR) induces broad transcriptional upregulation of cholesterol biosynthesis, transport, and storage pathways, leading to sustained intracellular accumulation of cholesterol. BODIPY-cholesterol imaging, Filipin III staining, and quantitative subcellular fractionation confirmed selective nuclear enrichment of cholesterol following IR, coinciding with extensive chromatin remodeling. Proteomic profiling of cholesterol-interacting proteins revealed a strong enrichment of chromatin-associated factors, suggesting a previously unrecognized lipid-chromatin interface in irradiated cells. Functionally, cholesterol accumulation promoted chromatin compaction and repressive histone modification patterns, impairing DNA damage sensing and checkpoint activation despite increased underlying DNA lesions. These alterations facilitated aberrant mitotic entry, formation of cytoplasmic chromatin fragments (CCFs), and activation of cGAS-STING-NF-κB signaling. Cholesterol exposure ultimately diverted damaged cells toward a senescent fate, marked by Lamin B1 loss, p21 induction, and a robust senescence-associated secretory phenotype (SASP) enriched for IL-1 and TNF family cytokines. In vivo, dietary cholesterol exacerbated radiation-induced inflammation and weakened systemic anti-tumor immunity. Transcriptomic analyses of immunotherapy-treated patients revealed that tumors enriched for cholesterol import and senescence signatures were associated with poor response to PD-L1 blockade and worse survival. Together, these findings identify a cholesterol-chromatin-senescence axis that links metabolic remodeling to defective DNA damage signaling and immune suppression after radiation, highlighting cholesterol metabolism as a potential therapeutic vulnerability in cancer therapy. Citation Format: Yiqun Han, Yaobin Ouyang, Shouhai Zhu, Hangcheng Xu, Bin Chen, Ping Yin, Qin Zhou, Jinzhou Huang, Kuntian Luo, Zheming Wu, Huaping Xiao, Xinyi Tu, Jake A. Kloeber, Jiajun Jing, Xiaofeng Huang, Meng Xu Welliver, Zhenkun Lou, Robert Mutter. Cholesterol triggers chromatin stress to drive senescence and inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 539.

Zinc Finger Protein 161 (ZFP161) is a key regulator of Ataxia Telangiectasia and Rad3-related (ATR) signaling, playing a crucial role in maintaining genomic stability. Human ZFP161 activates c-MYC , whereas its murine ortholog, ZF5, serves as a putative transcriptional repressor of c-MYC . In this study, we identified ZFP161 as a direct regulator of c-MYC. We show that ZFP161 binds to the promoter region of c-MYC , modulating its expression and downstream signaling pathways. Additionally, ZFP161 promotes cell proliferation and tumorigenesis through c-MYC regulation and contributes to the malignant transformation of non-cancerous retinal pigment epithelial (RPE-1) cells. Furthermore, high ZFP161 expression is associated with poor survival in patients with mixed colon adenocarcinoma. These findings suggest that the regulation of c-MYC by ZFP161 may represent a potential therapeutic target in c-MYC -driven cancers.