A patient-centric therapeutic paradigm uncouples prostate cancer suppression from systemic metabolic collapse
Year: 2026
Type: preprint
Abstract: The clinical benefits of cancer therapies are often compromised by the ‘tolerable’ adverse effects that impair systemic organismal health and may evolve into latent life threats. Here, we identified profound abiraterone-induced but androgen-independent metabolic perturbations in prostate cancer patients and developed Lifehug-9892 to balance tumor therapy with systemic metabolic homeostasis. By integrating population cohorts with high-resolution metabolomics, we demonstrate that abiraterone induces profound systemic lipidomic dysregulation, characterized by the massive, pathological accumulation of desmosterol. Abiraterone inhibits but stabilizes DHCR24, leading to a metabolic trap in patients showing elevated levels of both desmosterol and cholesterol. Desmosterol accumulation is highly lipotoxic, potently triggering endothelial cell senescence and necrosis, macrophage foam cell formation, murine atherosclerosis, and hepatic senescence. To mechanistically uncouple and therapeutically rescue this systemic metabolic collapse, Lifehug-9892 was rationally designed to selectively retain on-target CYP17A1 inhibition while completely sparing DHCR24 function. Lifehug-9892 maintains potent tumor-suppressive activity while fully preserving the desmosterol-cholesterol metabolic axis and preventing systemic cardiovascular and hepatic damage. Our study uncovers a critical mechanistic link between drug-induced metabolic dysregulation and organismal health in cancer patients, providing a biochemical framework for developing patient-centric targeted therapies that preserve host homeostasis. One Sentence Summary Abiraterone inhibits DHCR24 to induce systemic metabolic dysregulation in prostate cancer patients.
Authors: Ziqun Liu, Hanchu Ye, Haoran Hu, Wuhong Chen, Chen Wang, Yongfeng Yang, Xinran Yan, Nathan longlong Chen, Yang Wang, Yumeng Yang, Chunqiao Sun, Yaqing Bai, Haiyang Hou, Xinan Wang, Jun Cao, Qinsheng Chen, Qi Wang, Yuting Xiao, Yuanyuan Cai, Jiahui Chen, Feifei Lin, Yushi Li, Yuanhao Dang, Yuxin Su, Xiaofei Wang, Zheng Tian, Yidong Shen, Linfeng Sun, Jia Liu, Denglong Wu, Chengchao Ruan, Ruobing Ren, Youhong Hu, Huiru Tang, Shengsong Huang, Zhenfei Li
Institutions: Chinese Academy of Sciences, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Tongji University, Fudan University, Zhongshan Hospital, Shanghai Institute of Materia Medica, State Key Laboratory of Drug Research, Shanghai Medical College of Fudan University, University of Science and Technology of China, Shanghai Jiao Tong University, Shanghai Chest Hospital, Shanghai Xuhui Central Hospital
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Award: G5665361705
OpenAlex ID: W7207578490
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