Mechanisms of postpartum metabolic dysfunction-associated steatotic liver disease in women with a history of gestational diabetes mellitus.

Abstract: Gestational diabetes mellitus (GDM) is a rapidly increasing global health challenge that is closely linked to the rising rates of obesity and type 2 diabetes mellitus. Similarly, metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a leading cause of chronic liver disease. Emerging evidence indicates that a history of GDM is associated with a significantly elevated risk of postpartum MASLD that may persist for decades. This review synthesizes the shared and distinct pathophysiological mechanisms linking GDM to postpartum MASLD, with a particular focus on the enduring metabolic memory effect induced by GDM. While sharing common features with MASLD, the synergistic effects of amplified insulin resistance, chronic low-grade inflammation, and oxidative stress during GDM profoundly impact hepatic lipid metabolism. Critically, this programmed vulnerability persists postpartum, causing persistent mitochondrial dysfunction, endoplasmic reticulum stress, and reprogramming of the adipose-liver and gut-liver axes. These enduring alterations, extending beyond transient hyperglycemia, impair hepatic lipid metabolism and trigger MASLD. Further exploration into emerging mechanisms, including metabolomic profiles, genetic susceptibility, and gut microbiota dysbiosis, reveals a complex association network and highlights potential avenues for early detection and targeted intervention. Understanding these intricate mechanisms is crucial for developing effective intervention strategies. Future research focusing on gut microbiota modulation, precision epigenetic profiling, and multi-omics integration holds promise for dual prevention and management of both GDM and postpartum MASLD. Highlights: This review synthesizes shared and distinct pathophysiological mechanisms linking GDM to postpartum MASLD. It highlights the critical and unique role of the metabolic memory effect of GDM, where persistent organelle dysfunction, inflammation, and epigenetic reprogramming predispose women with prior GDM to postpartum MASLD. This review provides a comprehensive framework for understanding the GDM-MASLD transition, identifying key targets for dual prevention and management, with potential future strategies including gut microbiota modulation, precision epigenetic interventions, and multi-omics integration.