KDM3B regulates hair follicle stem cell differentiation by activating the mTOR-dependent translation program

Hair follicle (HF) development and regeneration rely on the precise differentiation of hair follicle stem cells (HFSCs), a process governed by epigenetic regulation. While nutrient-sensing mTOR signaling is known to be pivotal, the upstream epigenetic triggers and the downstream events orchestrating this pathway remain poorly defined. The histone H3K9me2 demethylase KDM3B has recently emerged as a key player in stem cell fate decisions. By integrating recent high-throughput sequencing data and employing a conditional knockout mouse model, we demonstrated that KDM3B was essential for HFSC differentiation, as its loss led to severe defects in postnatal HF development and HFSC differentiation. Mechanistically, we identified the mTOR signaling pathway and its downstream protein translation machinery as the primary effectors of KDM3B. KDM3B activated mTOR complex 1 (mTORC1) signaling, which subsequently upregulated the TOP mRNA-binding protein LARP1 to drive ribosome biogenesis and global protein synthesis. Our work delineated a complete 'KDM3B-mTORC1-LARP1-ribosome' axis that functionally integrates epigenetic control with translational regulation to direct HFSC differentiation. These findings not only establish KDM3B as a novel key regulator in skin epithelia but also provide the first comprehensive mechanistic link from an epigenetic modifier through the mTOR pathway to the ribosomal translation program within the HF model.