Metabolic Targeting of SREBP1 Reprograms the Obesity-Driven Ascites Immune Microenvironment and Enhances Chemotherapy Response in Obesity-Associated Ovarian Cancer
- 1UNIVERSITY OF NOTRE DAME
Abstract
Obesity has an adverse effect on survival of women with ovarian cancer (OC), supporting a link between obesity, metastatic progression, and therapeutic response, but comprehensive mechanistic insight is lacking. In pre-clinical models of diet-induced obesity and OC, mice fed a high fat diet (HFD) exhibit substantially increased tumor burden relative to low fat diet (LFD) mice and respond poorly to standard-of-care (SOC) chemotherapy. Both HFD murine tumors and tumors from women with BMI>30 show increased expression and nuclear localization of sterol regulatory element binding protein 1 (SREBP1), a master regulator of lipogenesis and lipid transport. The objective of this study was to assess whether inhibition of SREBP1 processing could improve SOC chemotherapy response in obesity-associated OC. We evaluated the FDA-approved drug Nelfinavir (NFV), a pharmacologic inhibitor of site-2 protease that blocks SREBP1 processing, in combination with SOC (paclitaxel+carboplatin) chemotherapy in preclinical models of diet-induced obesity and OC. Our results demonstrate significantly improved therapeutic response, corresponding changes in intra-tumoral adipocytes, and reprogramming of the obesity-driven ascites immune microenvironment. These findings support a model in which NFV-mediated inhibition of SREBP1 processing disrupts obesity-associated metabolic pathways linked to immune suppression and therapeutic resistance, thereby enhancing response to SOC chemotherapy in obesity-associated OC. Collectively, these results highlight metabolic targeting as a strategy to improve therapeutic outcomes in obesity-associated ovarian cancer.
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BibTeX
@misc{yang2026metabolic,
title = {{Metabolic Targeting of SREBP1 Reprograms the Obesity-Driven Ascites Immune Microenvironment and Enhances Chemotherapy Response in Obesity-Associated Ovarian Cancer}},
author = {J. Yang and T. S. HILLIARD and Y. LIU and E. RICHARDSON and S. SANTOSO and V. KHOMENKO and M. CONROY and B. MARTIN and E. CRONBERGER and G. DOMINIQUE and Z. WANG and J. JOHNSON and W. WANG and I. ASILEBO and M. S. Stack},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.14.751517},
url = {https://www.biorxiv.org/content/10.64898/2026.09.14.751517v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Metabolic Targeting of SREBP1 Reprograms the Obesity-Driven Ascites Immune Microenvironment and Enhances Chemotherapy Response in Obesity-Associated Ovarian Cancer
AU - J. Yang
AU - T. S. HILLIARD
AU - Y. LIU
AU - E. RICHARDSON
AU - S. SANTOSO
AU - V. KHOMENKO
AU - M. CONROY
AU - B. MARTIN
AU - E. CRONBERGER
AU - G. DOMINIQUE
AU - Z. WANG
AU - J. JOHNSON
AU - W. WANG
AU - I. ASILEBO
AU - M. S. Stack
PY - 2026
DA - 2026/09/14
PB - bioRxiv
DO - 10.64898/2026.09.14.751517
UR - https://www.biorxiv.org/content/10.64898/2026.09.14.751517v1
AB - Obesity has an adverse effect on survival of women with ovarian cancer (OC), supporting a link between obesity, metastatic progression, and therapeutic response, but comprehensive mechanistic insight is lacking. In pre-clinical models of diet-induced obesity and OC, mice fed a high fat diet (HFD) exhibit substantially increased tumor burden relative to low fat diet (LFD) mice and respond poorly to standard-of-care (SOC) chemotherapy. Both HFD murine tumors and tumors from women with BMI>30 show increased expression and nuclear localization of sterol regulatory element binding protein 1 (SREBP1), a master regulator of lipogenesis and lipid transport. The objective of this study was to assess whether inhibition of SREBP1 processing could improve SOC chemotherapy response in obesity-associated OC. We evaluated the FDA-approved drug Nelfinavir (NFV), a pharmacologic inhibitor of site-2 protease that blocks SREBP1 processing, in combination with SOC (paclitaxel+carboplatin) chemotherapy in preclinical models of diet-induced obesity and OC. Our results demonstrate significantly improved therapeutic response, corresponding changes in intra-tumoral adipocytes, and reprogramming of the obesity-driven ascites immune microenvironment. These findings support a model in which NFV-mediated inhibition of SREBP1 processing disrupts obesity-associated metabolic pathways linked to immune suppression and therapeutic resistance, thereby enhancing response to SOC chemotherapy in obesity-associated OC. Collectively, these results highlight metabolic targeting as a strategy to improve therapeutic outcomes in obesity-associated ovarian cancer.
ER -