Reproductive Endocrinology

ORF17-05 - Ovarian RNA Splicing Regulates Systemic Hormonal and Metabolic Homeostasis in Polycystic Ovary Syndrome

Saturday, June 13, 2026

4:00 PM - 4:15 PM CT

Location: Room W187

Oral Abstract Presenter(s)

Christy M. Nguyen (she/her/hers)

PhD Candidate
UNIVERSITY OF CA - IRVINE
Irvine, CA, United States

Co-Author(s)

LV

Leandro M. Velez, PhD

University of California, Irvine
Irvine, California, United States
YC

Youngseo Cheon, PhD

University of California, Irvine
Irvine, California, United States
CJ

Casey D. Johnson, n/a

University of California, Irvine
Irvine, United States
ML

Marie Li, n/a

University of California, Irvine
Irvine, California, United States
TG

Tvisha Gujjarlapudi, n/a

University of California, Irvine
Irvine, California, United States
KO

Kaitlene Ofilan, n/a

University of California, Irvine
Irvine, California, United States
IT

Ian Tamburini, n/a

University of California, Irvine
Irvine, United States
MZ

Mingqi Zhou, n/a

University of California - Irvine
Irvine, United States
NM

Neha Mishra, PhD

University of California, Irvine
Irvine, United States
NU

Naveena Ujagar, n/a

University of California, Irvine
Irvine, United States
CV

Carlos H. Viesi, PhD

University of California, Irvine
Irvine, United States

Senior Author/Primary Investigator(s)

IM

Ivan Marazzi, PhD

University of California, Irvine
Irvine, United States
Dequina A. Nicholas, PhD (she/her/hers)

Assistant Professor
University of California Irvine
Irvine, CA, United States
MS

Marcus Seldin, PhD

University of California, Irvine
Irvine, United States

Disclosure(s):

Christy M. Nguyen: No financial relationships to disclose

Dequina A. Nicholas, PhD: No financial relationships to disclose

Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders in women and a major risk factor for infertility and cardiometabolic disease. Although ovarian dysfunction is central to PCOS diagnosis, individuals with PCOS exhibit wide variability in systemic hormonal and metabolic outcomes. The mechanisms underlying this heterogeneity remain incompletely understood. We hypothesized that genetically driven differences in ovarian molecular function contribute to variation in systemic hormonal and metabolic phenotypes in PCOS. To test this, we generated letrozole-induced PCOS models across a panel of 27 genetically distinct mouse strains to capture inter-individual variation in disease response. This approach produced diverse ovarian, hormonal, and metabolic responses across strains, reflecting the heterogeneity observed in women. Integrative analyses of these phenotypes with ovarian transcriptomics identified RNA splicing, mediated by the spliceosome factor SF3B1, as a key ovarian regulator of PCOS hormonal and metabolic traits. We next tested this mechanism by treating letrozole-induced PCOS mice from diverse genetic backgrounds with the SF3B1 inhibitor H3B-8800. This resulted in improvements in key hormonal and metabolic measures, including reductions in circulating testosterone and insulin, body weight, and fat mass, with the extent of the effects varying across strains. Notably, pan-tissue transcriptomic profiling revealed that the ovary exhibited the most pronounced transcriptional response to SF3B1 inhibition relative to peripheral metabolic tissues. Integration of ovarian single-cell datasets localized PCOS-associated transcriptional programs primarily to granulosa cells; therefore, we tested the effects of SF3B1 inhibition in human KGN granulosa cells. Under androgen excess conditions, H3B-8800 treatment altered the expression of key steroidogenic genes. Together, these findings demonstrate that ovarian RNA splicing contributes to PCOS phenotypic heterogeneity and systemic dysfunction, identifying the ovary as a genetically informed therapeutic target with potential for PCOS and related endocrine disorders.