Abstract
Mammary gland involution is a highly coordinated, reversible-to-irreversible process that transitions the lactating gland back to a non-lactating state. This regression involves cell death, immune activation, extracellular matrix (ECM) remodeling, and stromal reorganization. A growing body of evidence demonstrates that epigenetic modifications, transcriptional networks, and chromatin-restructuring events govern the pace and architecture of involution. Using a multi-omics lens—integrating transcriptomics, epigenomics, proteomics, and single-cell sequencing—this paper reviews core regulators of involution, including STAT3, NF-κB, C/EBP family members, HDACs, DNMTs, histone methyltransferases, and long non-coding RNAs (lncRNAs). We highlight the temporal two-phase model of involution, define epigenetic signatures of epithelial cell fate, and explore links between aberrant involution and postpartum breast cancer risk. Additionally, we propose an integrated systems biology roadmap for future translational research.
