Skin photoaging, main causes of skin aging, is induced by chronic UV irradiation. LncSPRY4-IT1, a broadly expressed lncRNA, takes part in various biological functions by combining with functional protein molecules. However, the role of LncSPRY4-IT1 in skin photoaging process has not been characterized. This study is to investigate the interacting proteins of LncSPRY4-IT1 by combining RNA pull-down, high-throughput, and bioinformatic analysis. Human skin fibroblasts (HDFs) were exposed to 10J/cm2 UVA irradiation, once a day for 14days. LncSPRY4-IT1 expression was qualified via RT-PCR. In vitro RNA pull-down assays and liquid chromatography-mass spectrometry analysis were used to identify the LncSPRY4-IT1-related proteins. Functional annotation analysis and pathway enrichment were preformed via Gene Ontology and KEGG. LncSPRY4-IT1 expression in photoaging fibroblasts was increased 1.66±0.23 folds. 181 LncSPRY4-IT1-interacting proteins in UVA-induced photoaging skin fibroblast irradiation were identified, of which 56 proteins with two or more unique peptides, 73 proteins related to RNA processing, and 5 proteins related to DNA processing. High-throughput and bioinformatic analysis showed that LncSPRY4-IT1-targeting proteins were involved in cellular process, metabolic process, biological regulation, and cell part in skin photoaging process. The KEGG revealed that LncSPRY4-IT1-targeting proteins were mainly enriched in metabolic pathways. The results of our studies illuminate how LncSPRY4-IT1 formed a LncRNA-protein regulatory network in skin photoaging mechanisms and suggest that LncSPRY4-IT1 may serve as a novel upstream intervention target for the prevention and treatment of photoaging and related skin diseases.