Multiorgan metabolic reprogramming induced by chiglitazar in a letrozole-induced PMOS mouse model: Insights from integrated omics analyses

Abstract

BACKGROUND: Polyendocrine metabolic ovarian syndrome (PMOS), formerly named polycystic ovary syndrome (PCOS), is a common endocrine-metabolic disorder with limited treatments. Chiglitazar, a novel pan-PPAR agonist, shows multitarget potential, but its systemic mechanisms in PMOS remain unclear. OBJECTIVE: To compare chiglitazar with metformin and pioglitazone in a PMOS-like mouse model and elucidate its multiorgan mechanisms via integrated omics. METHODS: A letrozole-induced PMOS-like mouse model was established. Mice were divided into five groups: normal control, PMOS model, and PMOS treated with metformin, pioglitazone, or chiglitazar. Phenotypic assessments included glucose tolerance, hormone levels, ovarian morphology, and estrous cycle. Multiomics analyses comprised DIA proteomics of liver, skeletal muscle, and visceral adipose tissue (VAT); ovarian transcriptomics; and 16S rRNA gut microbiota sequencing. RESULTS: Chiglitazar significantly improved insulin resistance (IR), reduced testosterone, restored estrous cyclicity, and ameliorated polycystic ovarian morphology. Proteomics revealed tissue-specific remodeling, with the VAT showing the most extensive proteomic remodeling. In the liver, chiglitazar downregulated mitochondrial OXPHOS proteins (Uqcrb, Ndufs4, Cox6a1) and upregulated insulin-degrading enzymes (Ide, Apeh). In adipose tissue, it inhibited OXPHOS pathways. In skeletal muscle, it modulated ubiquitin-mediated proteolysis. Ovarian transcriptomics indicated regulation of MAPK/GnRH signaling. Gut microbiota diversity was restored with enriched metabolic pathways. CONCLUSIONS: Chiglitazar induces metabolic reprogramming across multiple organs in PMOS-like mice, targeting IR, hyperandrogenism, ovarian dysfunction, and gut dysbiosis through distinct yet convergent pathways. These integrated mechanisms support its potential as a novel multitarget therapy for PMOS.