Latency-Associated Nuclear Antigen (LANA) Promotes Ferroptosis by Suppressing Nrf2/GPX4 and Upregulating MDM2
Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is regulated by key mediators including glutathione peroxidase 4 (GPX4) and nuclear factor erythroid 2-related factor 2 (Nrf2). Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes latency-associated nuclear antigen (LANA), a...
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2025-06-01
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| author | Yuejia Cao Shihan Shao Yingying Zhang Dandan Song Fei Gui Xinyi Chen Yu Hong Rong Chen Yang Song Dongmei Li Xiaohua Tan Chunhong Di |
| author_facet | Yuejia Cao Shihan Shao Yingying Zhang Dandan Song Fei Gui Xinyi Chen Yu Hong Rong Chen Yang Song Dongmei Li Xiaohua Tan Chunhong Di |
| author_sort | Yuejia Cao |
| collection | DOAJ |
| description | Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is regulated by key mediators including glutathione peroxidase 4 (GPX4) and nuclear factor erythroid 2-related factor 2 (Nrf2). Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes latency-associated nuclear antigen (LANA), a multifunctional protein critical for viral persistence. Although studies reported that KSHV infection enhanced cellular resistance to ferroptosis, the specific role of LANA in this process remains unexplored. Here, we demonstrate that LANA unexpectedly promotes ferroptosis. In KSHV-positive iSLK.219 cells, LANA knockdown significantly attenuated RSL-3-induced ferroptosis, whereas LANA overexpression sensitized HeLa cells to ferroptotic death. Quantitative analysis revealed that LANA-depleted cells exhibited significantly elevated ROS accumulation (<i>p</i> < 0.01), whereas LANA-overexpressing cells maintained reduced ROS levels during challenge with the ferroptosis inducer RSl-3. Mechanistically, LANA suppressed glutathione peroxidase 4 (GPX4) expression, reduced nuclear factor erythroid 2-related factor 2 (Nrf2) expression and impaired its nuclear translocation, and upregulated mouse double minute 2 homolog (MDM2) expression. Pharmacological inhibition of Nrf2 (ML385) or MDM2 (nutlin3a) reversed the ferroptotic effects of LANA knockdown or overexpression, respectively. These findings reveal a pro-ferroptotic role of LANA via Nrf2/GPX4 suppression and MDM2 activation. |
| format | Article |
| id | doaj-art-db5f0dff402d4030930728287fc43e05 |
| institution | OA Journals |
| issn | 2076-0817 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| series | Pathogens |
| spelling | doaj-art-db5f0dff402d4030930728287fc43e052025-08-20T02:21:49ZengMDPI AGPathogens2076-08172025-06-0114659010.3390/pathogens14060590Latency-Associated Nuclear Antigen (LANA) Promotes Ferroptosis by Suppressing Nrf2/GPX4 and Upregulating MDM2Yuejia Cao0Shihan Shao1Yingying Zhang2Dandan Song3Fei Gui4Xinyi Chen5Yu Hong6Rong Chen7Yang Song8Dongmei Li9Xiaohua Tan10Chunhong Di11School of Public Health, Hangzhou Normal University, Hangzhou 311121, ChinaSchool of Public Health, Hangzhou Normal University, Hangzhou 311121, ChinaSchool of Public Health, Hangzhou Normal University, Hangzhou 311121, ChinaSchool of Public Health, Hangzhou Normal University, Hangzhou 311121, ChinaSchool of Public Health, Hangzhou Normal University, Hangzhou 311121, ChinaSchool of Public Health, Hangzhou Normal University, Hangzhou 311121, ChinaSchool of Public Health, Hangzhou Normal University, Hangzhou 311121, ChinaSchool of Public Health, Hangzhou Normal University, Hangzhou 311121, ChinaSchool of Public Health, Hangzhou Normal University, Hangzhou 311121, ChinaSchool of Medicine, Shihezi University, Shihezi 832002, ChinaSchool of Public Health, Hangzhou Normal University, Hangzhou 311121, ChinaSchool of Public Health, Hangzhou Normal University, Hangzhou 311121, ChinaFerroptosis, an iron-dependent cell death driven by lipid peroxidation, is regulated by key mediators including glutathione peroxidase 4 (GPX4) and nuclear factor erythroid 2-related factor 2 (Nrf2). Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes latency-associated nuclear antigen (LANA), a multifunctional protein critical for viral persistence. Although studies reported that KSHV infection enhanced cellular resistance to ferroptosis, the specific role of LANA in this process remains unexplored. Here, we demonstrate that LANA unexpectedly promotes ferroptosis. In KSHV-positive iSLK.219 cells, LANA knockdown significantly attenuated RSL-3-induced ferroptosis, whereas LANA overexpression sensitized HeLa cells to ferroptotic death. Quantitative analysis revealed that LANA-depleted cells exhibited significantly elevated ROS accumulation (<i>p</i> < 0.01), whereas LANA-overexpressing cells maintained reduced ROS levels during challenge with the ferroptosis inducer RSl-3. Mechanistically, LANA suppressed glutathione peroxidase 4 (GPX4) expression, reduced nuclear factor erythroid 2-related factor 2 (Nrf2) expression and impaired its nuclear translocation, and upregulated mouse double minute 2 homolog (MDM2) expression. Pharmacological inhibition of Nrf2 (ML385) or MDM2 (nutlin3a) reversed the ferroptotic effects of LANA knockdown or overexpression, respectively. These findings reveal a pro-ferroptotic role of LANA via Nrf2/GPX4 suppression and MDM2 activation.https://www.mdpi.com/2076-0817/14/6/590Kaposi’s sarcoma-associated herpesvirus (KSHV)latency-associated nuclear antigen (LANA)ferroptosisnuclear factor erythroid 2-related factor 2 (Nrf2)mouse-double minute 2 (MDM2) |
| spellingShingle | Yuejia Cao Shihan Shao Yingying Zhang Dandan Song Fei Gui Xinyi Chen Yu Hong Rong Chen Yang Song Dongmei Li Xiaohua Tan Chunhong Di Latency-Associated Nuclear Antigen (LANA) Promotes Ferroptosis by Suppressing Nrf2/GPX4 and Upregulating MDM2 Pathogens Kaposi’s sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) ferroptosis nuclear factor erythroid 2-related factor 2 (Nrf2) mouse-double minute 2 (MDM2) |
| title | Latency-Associated Nuclear Antigen (LANA) Promotes Ferroptosis by Suppressing Nrf2/GPX4 and Upregulating MDM2 |
| title_full | Latency-Associated Nuclear Antigen (LANA) Promotes Ferroptosis by Suppressing Nrf2/GPX4 and Upregulating MDM2 |
| title_fullStr | Latency-Associated Nuclear Antigen (LANA) Promotes Ferroptosis by Suppressing Nrf2/GPX4 and Upregulating MDM2 |
| title_full_unstemmed | Latency-Associated Nuclear Antigen (LANA) Promotes Ferroptosis by Suppressing Nrf2/GPX4 and Upregulating MDM2 |
| title_short | Latency-Associated Nuclear Antigen (LANA) Promotes Ferroptosis by Suppressing Nrf2/GPX4 and Upregulating MDM2 |
| title_sort | latency associated nuclear antigen lana promotes ferroptosis by suppressing nrf2 gpx4 and upregulating mdm2 |
| topic | Kaposi’s sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) ferroptosis nuclear factor erythroid 2-related factor 2 (Nrf2) mouse-double minute 2 (MDM2) |
| url | https://www.mdpi.com/2076-0817/14/6/590 |
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