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However, the precise mechanism of SUMOylation in SHPT remains unclear. We identified the potential role of SUMOylation in SHPT based on RNA sequencing data obtained from Gene Expression Omnibus (GEO) datasets. Clinical samples were used to verify the expression of SENP1, SUMO1, SUMO2, GRHL2, and vitamin D receptor (VDR) in SHPT cells and tissues. Primary cells were extracted for subsequent experiments. Plasmid transfection and small interfering RNA (siRNA) were used to modulate SENP1 expression in SHPT primary cells. VDR relative expression was detected by Western blot (WB) and immunofluorescence. The effects of SENP1 on SHPT cell apoptosis and anti\u2010proliferation were analyzed by flow cytometry and WB. Co\u2010immunoprecipitation (Co\u2010IP), chromatin immunoprecipitation (ChIP), and ChIP\u2010quantitative polymerase chain reaction (ChIP\u2010qPCR) were employed to explore the regulatory mechanisms of SENP1 in SHPT. We found that SUMOylation was significantly upregulated in SHPT and was closely related to calcitriol resistance. SENP1 and GRHL2 were downregulated. SENP1 was found to upregulate VDR and downregulate the SUMOylation of VDR, which mediates SENP1's regulation of SHPT cell apoptosis and anti\u2010proliferation. Mechanistically Co\u2010IP assays revealed binding between VDR, SENP1, SUMO1, and SUMO2. ChIP assays indicated that transcription of SENP1 was regulated by GRHL2, with binding sites identified by ChIP\u2010qPCR. Additionally, we identified the potential binding pocket of SENP1 and screened 10 candidate small\u2010molecule drugs approved by the US Food and Drug Administration (FDA). Our findings indicate a distinct mechanism of SENP1\u2010mediated VDR SUMOylation and establish the critical role of the GRHL2\/SENP1\/VDR signaling axis in SHPT development.<\/jats:p>","DOI":"10.1002\/biof.70086","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T17:56:06Z","timestamp":1772992566000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>GRHL2<\/scp>\n                    \/\n                    <scp>SENP1<\/scp>\n                    \/\n                    <scp>VDR<\/scp>\n                    Signaling Axis: A Key Regulator of\n                    <scp>SUMOylation<\/scp>\n                    and Calcitriol Resistance in\n                    <scp>SHPT<\/scp>"],"prefix":"10.1002","volume":"52","author":[{"given":"Yucan","family":"Miao","sequence":"first","affiliation":[{"name":"Department of Breast Thyroid Surgery, The Third Xiangya Hospital Central South University  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