{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:58:31Z","timestamp":1790521111677,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,16]]},"group-title":"Cancer Biology","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["IRG126-762"],"award-info":[{"award-number":["IRG126-762"]}],"id":[{"id":"https:\/\/ror.org\/02e463172","id-type":"ROR","asserted-by":"publisher"}]},{"award":["IRG-17-182-04"],"award-info":[{"award-number":["IRG-17-182-04"]}],"id":[{"id":"https:\/\/ror.org\/02e463172","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RO1CA109545"],"award-info":[{"award-number":["RO1CA109545"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["KO1CA218305"],"award-info":[{"award-number":["KO1CA218305"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"DEPARTMENT OF DEFENSE OVARIAN CANCER RESEARCH PROGRAM","award":["OC22025"],"award-info":[{"award-number":["OC22025"]}]},{"award":["579937"],"award-info":[{"award-number":["579937"]}],"id":[{"id":"https:\/\/ror.org\/03b3akj74","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,16]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>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&gt;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.<\/jats:p>","DOI":"10.64898\/2026.09.14.751517","type":"posted-content","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T20:35:16Z","timestamp":1789590916000},"source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Targeting of SREBP1 Reprograms the Obesity-Driven Ascites Immune Microenvironment and Enhances Chemotherapy Response in Obesity-Associated Ovarian Cancer"],"prefix":"10.64898","author":[{"given":"Jing","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of Notre Dame, South Bend, IN, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyvette S.","family":"Hilliard","sequence":"additional","affiliation":[{"name":"Department of Biology, Tuskegee University, Tuskegee, AL, USA"},{"name":"Center for Biomedical Research, Tuskegee University, Tuskegee, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueying","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of Notre Dame, South Bend, IN, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Richardson","sequence":"additional","affiliation":[{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Santoso","sequence":"additional","affiliation":[{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoriia","family":"Khomenko","sequence":"additional","affiliation":[{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly","family":"Conroy","sequence":"additional","affiliation":[{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Martin","sequence":"additional","affiliation":[{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Cronberger","sequence":"additional","affiliation":[{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gena","family":"Dominique","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of Notre Dame, South Bend, IN, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhikun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of Notre Dame, South Bend, IN, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of Notre Dame, South Bend, IN, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanrui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of Notre Dame, South Bend, IN, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ijeoma","family":"Asilebo","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of Notre Dame, South Bend, IN, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4563-7390","authenticated-orcid":false,"given":"M. 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