Mammary gland-specific deletion of MTA1 causes abrupt involution through activation of STAT3 signaling in lactating mice.

AIMS: Mammary gland involution is a tightly coordinated post-lactational remodeling program that restores tissue homeostasis and preserves the capacity of the gland for subsequent lactation. Although this process requires extensive epithelial regression, stromal remodeling, and immune cell recruitment, the mechanisms that prevent premature or excessive involution remain incompletely understood. Here, we examined the role of metastasis-associated protein 1 (MTA1) in regulating mammary gland involution. MATERIALS AND METHODS: Mammary epithelial-specific MTA1 deletion was used to assess lactational function and mammary gland remodeling. Histological and molecular analyses were performed to evaluate epithelial regression, apoptosis, macrophage accumulation, and STAT3 signaling. MTA1 regulation of STAT3 was further investigated in mammary epithelial cells and by promoter occupancy analysis. Mouse and human single-cell RNA-sequencing datasets were analyzed to support the relationship between MTA1 expression and involution-related transcriptional programs. KEY FINDINGS: Mammary-gland specific MTA1 deletion reduced milk ejection and impaired pup growth during subsequent lactation, indicating a functional defect in lactational capacity. MTA1-deficient mammary glands underwent accelerated post-lactational regression, characterized by reduced alveolar structures, increased epithelial apoptosis, and enhanced accumulation of M2-like macrophages. Loss of MTA1 increased STAT3 and phosphorylated STAT3 expression in mammary tissues and epithelial cells. Mechanistically, MTA1 directly occupied the STAT3 promoter and recruited the Nucleosome Remodeling and Deacetylase (NuRD) component histone deacetylase 1 (HDAC1), thereby suppressing STAT3 transcription. Low MTA1 expression was associated with enhanced STAT3- and involution-related transcriptional signatures in mouse and human datasets. SIGNIFICANCE: MTA1 restrains STAT3-driven involution to maintain mammary epithelial homeostasis and preserve functional competence across successive lactation cycles.