ST6GAL1 Is a Functional Regulator of UVA-Induced Photoaging in Human Dermal Fibroblasts

Skin photoaging, primarily driven by UVA radiation, is characterized by the accumulation of senescent fibroblasts and the degradation of the extracellular matrix (ECM). While the roles of reactive oxygen species (ROS) and matrix metalloproteinases (MMPs) are well-documented, the regulatory impact of post-translational glycosylation in this process remains poorly understood. We established a UVA-induced photoaging model in human dermal fibroblasts (HDFs) and employed bulk mRNA-seq and high-throughput lectin microarrays to profile glycomic alterations. The functional role of the sialyltransferase ST6GAL1 was investigated through pharmacological inhibition of cellular sialylation (3Fax-Neu5Ac), siRNA-mediated knockdown, and gain-of-function overexpression. Mechanistic insights were gained via RAS-ERK pathway analysis and validated in a 3D reconstructed human full-thickness skin model (T-Skin™). Glycomic profiling revealed that UVA irradiation triggers a broad increase in α2,6-sialylation in HDFs. We identified ST6GAL1 as the primary enzymatic driver of this remodeling, with its expression upregulated in both photoaged HDFs and 3D skin models. Functional assays demonstrated that ST6GAL1 overexpression induces hallmark features of photoaging, including p16, MMP and γ-H2AX upregulation, G0/G1 cell cycle arrest and increased SA-β-gal activity. Conversely, pharmacological or genetic inhibition of ST6GAL1 effectively mitigated the photoaged phenotype. Mechanistically, ST6GAL1 regulates the expression of p16 via the activation of the RAS-ERK signaling cascade. Our study identifies ST6GAL1-mediated α2,6-sialylation as a novel functional hallmark of skin photoaging, highlighting the association of ST6GAL1 with the RAS-ERK-p16 axis as a potential regulator for targeting UVA-induced skin photoaging and dermal senescence.