SPSB1 Promotes Subcutaneous Adipose Hyperplasia in Facial Port‐Wine Stains by Controlling HDAC1 Degradation and Stability Through Two Distinct Proteolytic Pathways

ABSTRACT Facial port‐wine stains (PWS) are often complicated by subcutaneous adipose hyperplasia, yet the underlying cellular and molecular mechanisms remain unclear. Here, using single‐cell RNA sequencing of facial adipose tissues, we identified a distinct subpopulation of adipose stem and progenitor cells that expressed high levels of SPSB1 in hypertrophic PWS. SPSB1 expression was transcriptionally upregulated by FOSL1. Functional assays revealed that SPSB1 potently promoted adipogenesis both in vitro and in vivo. Mechanistically, SPSB1, acting as an adapter for the Cullin‐RING E3 ligase complex, directly interacted with HDAC1. It specifically mediated K48‐ and K29‐linked polyubiquitination of HDAC1 at lysine residues 89 and 361, respectively, thereby targeting HDAC1 for degradation via both the ubiquitin‐proteasome and autophagy‐lysosome pathways. The degradation of HDAC1 increased chromatin accessibility of key adipogenic genes and promoted their expression. Furthermore, HDAC1 downregulation relieved its transcriptional repression on the SPSB1 promoter, establishing a positive feedback loop that perpetuated the pro‐adipogenic signal. Collectively, our findings delineated a novel SPSB1‐HDAC1 regulatory axis that drove pathological adipose hyperplasia in facial PWS, highlighting SPSB1 and HDAC1 as potential therapeutic targets for this condition.