# Glycolytic Reprogramming in Uterine Fibroids: Genetic, Transcriptomic, Proteomic, and Metabolomic Insights

## TL;DR

This review explores how changes in metabolism, particularly glycolysis, contribute to the development of uterine fibroids and suggests new pathways for research and treatment.

## Contribution

The paper introduces glycolytic reprogramming as a novel metabolic mechanism in uterine fibroid development.

## Key findings

- Genetic and metabolic studies link fumarate hydratase (FH) deficiency and MED12 mutations to uterine fibroid biology.
- Glycolytic reprogramming is connected to ECM production and fibrosis via TGF-β and Wnt/β-catenin signaling.
- Metabolic regulators like HIF-1α, mTOR, and PI3K/Akt may sustain fibrotic phenotypes in uterine fibroids.

## Abstract

Uterine leiomyomas or fibroids are a common but pernicious benign tumor impacting between 70–80% of women of reproductive age. Despite their high prevalence, the etiology of uterine fibroids is not fully understood. This review aims to highlight the distinct metabolic features that uterine fibroids adopt to meet biosynthetic demands, support proliferation, extracellular matrix production, survival, and fibrosis. Specifically, we posit the role of glycolytic reprogramming—an adaptation in fibrosis across organs (lung, kidney, heart, and liver) as a major contributor to uterine fibroid development. Previous genetic, transcriptomic, proteomic, and metabolic studies have drawn strong links between metabolism and uterine fibroid biology and identified genotype-specific metabolic alterations such as fumarate hydratase (FH) deficiency and mediator of RNA polymerase II transcription (MED12) gene mutations. Studies in non-uterine models have linked glycolysis to ECM production and fibrosis through activation of transforming growth factor-beta (TGF-β) and the canonical Wnt pathway (Wnt/β-catenin) signaling, supporting them as potential key pathways in uterine fibroid pathogenesis via glycolytic reprogramming. Other metabolic regulators, such as hypoxia-inducible factor 1-alpha (HIF-1α), mammalian target of rapamycin (mTOR), and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), may also sustain the fibrotic phenotype through coupling signaling that drives ECM production to metabolic programming. Overall, the proposed metabolic perspective of uterine fibroid pathogenesis invites further exploration of mechanistic investigation in uterine-specific models and therapeutic targeting through larger cohort studies.