Metabolic Targeting of SREBP1 Reprograms the Obesity-Driven Ascites Immune Microenvironment and Enhances Chemotherapy Response in Obesity-Associated Ovarian Cancer.

Authors

Jing Yang, Tyvette S Hilliard, Yueying Liu, Emily Richardson, Sophia Santoso, Viktoriia Khomenko, Molly Conroy, Brandon Martin, Emily Cronberger, Gena Dominique, Zhikun Wang, Jeffrey Johnson, Wanrui Wang, Ijeoma Asilebo, Mary Sharon Stack

Published in

bioRxiv : the preprint server for biology. Sep 16, 2026. Epub Sep 16, 2026.

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.

PMID:
42779959
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

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