SUMO2 inhibits ACSL3 protein degradation to antagonize erastin-induced ferroptosis in hepatocellular carcinoma
Abstract Hepatocellular carcinoma (HCC) is the prevalent form of primary liver cancer with a high rate of morbidity and death. Ferroptosis is a kind of regulatory cell death mode that depends on iron. Small ubiquitin-like modifier 2 (SUMO2) is linked to HCC progression; however, its role in ferropto...
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Springer
2025-06-01
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| Series: | Discover Oncology |
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| Online Access: | https://doi.org/10.1007/s12672-025-02921-5 |
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| author | Yanxi Shen Bin Ye Chuanfei Li |
| author_facet | Yanxi Shen Bin Ye Chuanfei Li |
| author_sort | Yanxi Shen |
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| description | Abstract Hepatocellular carcinoma (HCC) is the prevalent form of primary liver cancer with a high rate of morbidity and death. Ferroptosis is a kind of regulatory cell death mode that depends on iron. Small ubiquitin-like modifier 2 (SUMO2) is linked to HCC progression; however, its role in ferroptosis within HCC remains unclear. Our goal was to evaluate the regulatory effects and molecular mechanisms of SUMO2 in HCC ferroptosis. SUMO2 was screened by bioinformatics analysis, and its expression was verified in HCC tissues. Stable SUMO2 knockdown and overexpression cell lines were created. The downstream target protein acyl-CoA synthetase long-chain family member 3 (ACSL3) of SUMO2 was screened to assessed the mechanism of SUMO2 regulating ferroptosis in HCC cells. In HCC tissues, SUMO2 expression was higher and linked to a worse prognosis for patients. SUMO2 overexpression reduced malondialdehyde content, prevented mitochondrial crest loss, and increased glutathione level under ferroptotic stimuli. Meanwhile, overexpression of SUMO2 lowered the expression of molecules that promote ferroptosis and raised the expression of molecules that prevent it. SUMO2 knockdown produced the opposite effects. Mechanistically, SUMO2 elevated ACSL3 protein level by inhibiting its entry into the ubiquitin–proteasome degradation pathway and enhanced its protein stability. The inhibitory effects of SUMO2 on ferroptosis in HCC cells were reversed by ACSL3 knockdown in SUMO2-overexpressing cells. In summary, SUMO2 binds to ACSL3, preventing its protein degradation, thereby increasing its protein stability and level, which in turn negatively regulates ferroptosis in HCC cells. These results point to interesting targets and therapeutic approaches for HCC. |
| format | Article |
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| institution | OA Journals |
| issn | 2730-6011 |
| language | English |
| publishDate | 2025-06-01 |
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| spelling | doaj-art-c1b413c9286e47efaf3a023fab51990e2025-08-20T02:37:14ZengSpringerDiscover Oncology2730-60112025-06-0116111410.1007/s12672-025-02921-5SUMO2 inhibits ACSL3 protein degradation to antagonize erastin-induced ferroptosis in hepatocellular carcinomaYanxi Shen0Bin Ye1Chuanfei Li2Department of Pathogen Biology, College of Basic Medicine, Chongqing Medical UniversityDepartment of Pathogen Biology, College of Basic Medicine, Chongqing Medical UniversityDepartment of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical UniversityAbstract Hepatocellular carcinoma (HCC) is the prevalent form of primary liver cancer with a high rate of morbidity and death. Ferroptosis is a kind of regulatory cell death mode that depends on iron. Small ubiquitin-like modifier 2 (SUMO2) is linked to HCC progression; however, its role in ferroptosis within HCC remains unclear. Our goal was to evaluate the regulatory effects and molecular mechanisms of SUMO2 in HCC ferroptosis. SUMO2 was screened by bioinformatics analysis, and its expression was verified in HCC tissues. Stable SUMO2 knockdown and overexpression cell lines were created. The downstream target protein acyl-CoA synthetase long-chain family member 3 (ACSL3) of SUMO2 was screened to assessed the mechanism of SUMO2 regulating ferroptosis in HCC cells. In HCC tissues, SUMO2 expression was higher and linked to a worse prognosis for patients. SUMO2 overexpression reduced malondialdehyde content, prevented mitochondrial crest loss, and increased glutathione level under ferroptotic stimuli. Meanwhile, overexpression of SUMO2 lowered the expression of molecules that promote ferroptosis and raised the expression of molecules that prevent it. SUMO2 knockdown produced the opposite effects. Mechanistically, SUMO2 elevated ACSL3 protein level by inhibiting its entry into the ubiquitin–proteasome degradation pathway and enhanced its protein stability. The inhibitory effects of SUMO2 on ferroptosis in HCC cells were reversed by ACSL3 knockdown in SUMO2-overexpressing cells. In summary, SUMO2 binds to ACSL3, preventing its protein degradation, thereby increasing its protein stability and level, which in turn negatively regulates ferroptosis in HCC cells. These results point to interesting targets and therapeutic approaches for HCC.https://doi.org/10.1007/s12672-025-02921-5Hepatocellular carcinomaFerroptosisSUMO2ACSL3Protein degradationErastin |
| spellingShingle | Yanxi Shen Bin Ye Chuanfei Li SUMO2 inhibits ACSL3 protein degradation to antagonize erastin-induced ferroptosis in hepatocellular carcinoma Discover Oncology Hepatocellular carcinoma Ferroptosis SUMO2 ACSL3 Protein degradation Erastin |
| title | SUMO2 inhibits ACSL3 protein degradation to antagonize erastin-induced ferroptosis in hepatocellular carcinoma |
| title_full | SUMO2 inhibits ACSL3 protein degradation to antagonize erastin-induced ferroptosis in hepatocellular carcinoma |
| title_fullStr | SUMO2 inhibits ACSL3 protein degradation to antagonize erastin-induced ferroptosis in hepatocellular carcinoma |
| title_full_unstemmed | SUMO2 inhibits ACSL3 protein degradation to antagonize erastin-induced ferroptosis in hepatocellular carcinoma |
| title_short | SUMO2 inhibits ACSL3 protein degradation to antagonize erastin-induced ferroptosis in hepatocellular carcinoma |
| title_sort | sumo2 inhibits acsl3 protein degradation to antagonize erastin induced ferroptosis in hepatocellular carcinoma |
| topic | Hepatocellular carcinoma Ferroptosis SUMO2 ACSL3 Protein degradation Erastin |
| url | https://doi.org/10.1007/s12672-025-02921-5 |
| work_keys_str_mv | AT yanxishen sumo2inhibitsacsl3proteindegradationtoantagonizeerastininducedferroptosisinhepatocellularcarcinoma AT binye sumo2inhibitsacsl3proteindegradationtoantagonizeerastininducedferroptosisinhepatocellularcarcinoma AT chuanfeili sumo2inhibitsacsl3proteindegradationtoantagonizeerastininducedferroptosisinhepatocellularcarcinoma |