A patient-centric therapeutic paradigm uncouples prostate cancer suppression from systemic metabolic collapse
- 1Shanghai institute of Biochemistry and Cell Biology
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.
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BibTeX
@misc{liu2026patientcentric,
title = {{A patient-centric therapeutic paradigm uncouples prostate cancer suppression from systemic metabolic collapse}},
author = {Z. Liu and H. Ye and H. Hu and W. Chen and C. Wang and Y. Yang and X. Yan and L. Chen and Y. Wang and Y. Yang and C. Sun and Y. Bai and H. Hou and X. Wang and J. Cao and Q. Chen and Q. Wang and Y. Xiao and Y. Cai and J. Chen and F. Lin and Y. Li and Y. Dang and Y. Sun and X. Wang and T. Zheng and Y. Shen and L. Sun and J. Liu and D. Wu and C. Ruan and R. REN and Y. Hu and H. Tang and S. Huang and Z. Li},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.30.748180},
url = {https://www.biorxiv.org/content/10.64898/2026.08.30.748180v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - A patient-centric therapeutic paradigm uncouples prostate cancer suppression from systemic metabolic collapse
AU - Z. Liu
AU - H. Ye
AU - H. Hu
AU - W. Chen
AU - C. Wang
AU - Y. Yang
AU - X. Yan
AU - L. Chen
AU - Y. Wang
AU - Y. Yang
AU - C. Sun
AU - Y. Bai
AU - H. Hou
AU - X. Wang
AU - J. Cao
AU - Q. Chen
AU - Q. Wang
AU - Y. Xiao
AU - Y. Cai
AU - J. Chen
AU - F. Lin
AU - Y. Li
AU - Y. Dang
AU - Y. Sun
AU - X. Wang
AU - T. Zheng
AU - Y. Shen
AU - L. Sun
AU - J. Liu
AU - D. Wu
AU - C. Ruan
AU - R. REN
AU - Y. Hu
AU - H. Tang
AU - S. Huang
AU - Z. Li
PY - 2026
DA - 2026/08/30
PB - bioRxiv
DO - 10.64898/2026.08.30.748180
UR - https://www.biorxiv.org/content/10.64898/2026.08.30.748180v1
AB - 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.
ER -