Targeting Long Noncoding RNA LUCAT1 Alleviates Insulin Resistance of Ovarian Granulosa Cells in Polycystic Ovary Syndrome by Blocking HMGB1-Mediated Autophagy

Abstract

Problem

Dysfunctional autophagy in ovarian granulosa cells (GCs) represents a key pathological feature of insulin resistance (IR) in polycystic ovary syndrome (PCOS), though regulatory roles of autophagy-associated lncRNAs remain poorly characterized.

Method of Study

Comparing GCs from IR-PCOS patients, non-IR PCOS patients, and non-PCOS controls revealed significantly elevated LUCAT1 expression in IR-PCOS. Functional validation via LUCAT1 knockdown in primary IR-PCOS GCs assessed cell viability, apoptosis, autophagy markers, and insulin sensitivity. Mechanistic studies employed Ago2-RIP, dual-luciferase reporter assays, and rescue experiments with miR-19a-3p mimic or HMGB1 overexpression.

Results

LUCAT1 knockdown promoted cell viability, reduced cell apoptosis, suppressed autophagy (decreased LC3B puncta, reduced LC3II/LC3I ratio, elevated p62), enhanced insulin sensitivity (upregulated IRS1, promoted GLUT4 membrane translocation, increased glucose uptake), and restored the secretion of steroid hormones (estradiol and progesterone) in GCs. Mechanistically, LUCAT1 functioned as a molecular sponge for miR-19a-3p, thereby increasing HMGB1 expression. MiR-19a-3p mimic replicated LUCAT1 knockdown effects, while HMGB1 overexpression abolished these phenotypes.

Conclusion

Altogether, LUCAT1 knockdown reduces autophagy, apoptosis, dysfunction, and IR of GCs from PCOS-IR patients through modulating the miR-19a-3p/HMGB1 axis.

Trial Registration

This study is a retrospective observational clinical study. No prospective study-designed interventions, additional clinical treatments, or randomized controlled trials were performed in this work. In accordance with the recommendations of the International Committee of Medical Journal Editors (ICMJE), formal clinical trial registration is not mandatory for retrospective observational studies without trial intervention. Thus, no trial registration number is available for this study.