{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:03:28Z","timestamp":1790701408383,"version":"4.1.0"},"reference-count":34,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Zhejiang Provincial Natural Science Foundation of China","award":["LY22H160044"],"award-info":[{"award-number":["LY22H160044"]}],"id":[{"id":"https:\/\/ror.org\/04aqat463","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Protein inhibitor of activated STAT 2 (PIAS2) is highly expressed in various solid tumors. Its precise function as a ferroptosis regulator in hepatocellular carcinoma (HCC) is still unknown. The purpose of this work was to determine whether PIAS2 overexpression attenuates erastin-induced ferroptotic changes and, in turn, is associated with the development of HCC in a manner that correlates with changes in Glutathione Peroxidase 4 (GPX4) protein levels and small ubiquitin-like modifier 3 (SUMO3) modification signals. Methods: Erastin (Era) was used to induce ferroptosis in HepG-2 and H22 cells, while Ferrostatin-1 (Fer-1) was employed for validation. Western blotting, qPCR, and co-immunoprecipitation (Co-IP) were used to examine the expression and interaction of PIAS2 and GPX4. Ferroptosis markers (lipid-reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), Fe2+), cell viability, migration, and invasion were all analyzed. Functional rescue experiments were performed using PIAS2 overexpression (oe-PIAS2) and GPX4 knockdown (sh-GPX4). In addition, a murine model of H22 cells in the right groin\/lateral abdomen was established for in vivo validation. Tumor weight and volume were measured in these animals. Additionally, tumor tissues were collected and subjected to immunohistochemical staining for Ki-67 expression, as well as biochemical analysis of ferroptosis-related markers (GSH, MDA, Fe2+). Results: In HCC cells, Era-induced ferroptosis resulted in a significant downregulation of PIAS2 and GPX4 expression, as well as elevated levels of lipid ROS, MDA, and Fe2+, decreased GSH content, and decreased cell viability, migration, and invasion. Under Era-treated conditions, overexpression of PIAS2 effectively reversed these changes, suppressing ferroptosis and partially restoring malignant phenotypes within the context of Era challenge. Co-treatment with Fer-1 significantly reversed Era-induced ferroptotic changes and rescued cell viability, migration, and invasion, without affecting PIAS2 expression, while also restoring GPX4 levels. Mechanistic studies revealed that PIAS2 and GPX4 co-immunoprecipitate in HCC cells, and PIAS2 overexpression was associated with increased SUMO3 modification signals and higher remaining GPX4 protein levels at the examined 12- and 24-h CHX time points. GPX4 knockdown attenuated the phenotypes observed under PIAS2 overexpression, suggesting possible involvement of GPX4 in the effects of PIAS2. In Era-treated tumor-bearing mice, PIAS2 overexpression was associated with increased tumor growth, elevated Ki-67 and GPX4 levels, and reduced ferroptosis indicators. Conclusion: PIAS2 overexpression was associated with increased GPX4 SUMO3 modification signals and higher GPX4 protein levels at the examined CHX time points, together with reduced ferroptotic changes under Era-treated conditions.<\/jats:p>","DOI":"10.31083\/fbl53367","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:21:51Z","timestamp":1790698911000},"source":"Crossref","is-referenced-by-count":0,"title":["PIAS2 Overexpression Attenuates Erastin-Induced Ferroptotic Changes and Is Associated With Increased GPX4 Protein and Enhanced GPX4-Related SUMO3 Signaling in Hepatocellular Carcinoma Cells"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9908-9870","authenticated-orcid":true,"given":"Xiang","family":"Cai","sequence":"first","affiliation":[{"name":"Department of General Surgery, Sanmen People\u2019s Hospital, 317100 Sanmen, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0589-5099","authenticated-orcid":true,"given":"Jiangwei","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Sanmen People\u2019s Hospital, 317100 Sanmen, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5697-7622","authenticated-orcid":true,"given":"Linfu","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Sanmen People\u2019s Hospital, 317100 Sanmen, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5870-3099","authenticated-orcid":true,"given":"Xiaokun","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Sanmen People\u2019s Hospital, 317100 Sanmen, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4454-956X","authenticated-orcid":true,"given":"Zejun","family":"Fang","sequence":"additional","affiliation":[{"name":"Central Laboratory, Sanmen People\u2019s Hospital, 317100 Sanmen, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6328-2082","authenticated-orcid":true,"given":"Ming","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Sanmen People\u2019s Hospital, 317100 Sanmen, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Zhan Z, Chen B, Huang R, Lin W, Lan S, Yao X, et al. 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