{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T21:41:25Z","timestamp":1792618885023,"version":"4.5.0"},"reference-count":25,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Innovation Project of Guangxi Graduate Education","award":["YCSW2026651"],"award-info":[{"award-number":["YCSW2026651"]}]},{"name":"the 2025 National Undergraduate Training Program on Innovation and Entrepreneurship of Youjiang Medical University for Nationalities","award":["S202510599120"],"award-info":[{"award-number":["S202510599120"]}]},{"name":"High-Level Talent Research Launch Fund of Xinjiang Institute of Technology","award":["XJLG2023G001"],"award-info":[{"award-number":["XJLG2023G001"]}]},{"name":"Second batch of Tianchi Talent Cultivation Plan for Young PHD Support Project","award":["2023TCQN01"],"award-info":[{"award-number":["2023TCQN01"]}]},{"name":"Xinjiang Undergraduate Innovation Training Program","award":["S202513558010"],"award-info":[{"award-number":["S202513558010"]}]},{"name":"Guangxi Young Elite Scientist Sponsorship Program","award":["GXYESS2025011"],"award-info":[{"award-number":["GXYESS2025011"]}]},{"name":"General Support Policy for Young Talent (the First Batch) of Guangxi Zhuang Autonomous Region"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) remains a malignancy with poor prognosis and limited therapeutic targets. Emerging evidence suggests a critical role for iron metabolism and ferroptosis in tumor progression. However, the involvement of hematopoietic lineage cell-specific protein 1 (HAX1) in HCC, particularly its regulatory role in ferroptosis, remains largely unknown. Here, we report that HAX1 is significantly upregulated in HCC tissues and correlates with advanced pathological stages and poor patient survival, suggesting its potential as an oncogene. Functionally, HAX1 overexpression promotes the proliferation and migration of HCC cells, while its knockdown inhibits these malignant phenotypes. Mechanistically, we demonstrate that HAX1 acts as a negative regulator of ferroptosis. Silencing HAX1 sensitizes HCC cells to the ferroptosis inducer IKE, leading to abnormal accumulation of intracellular ferrous iron (Fe2+) and increased lipid reactive oxygen species (ROS). Conversely, HAX1 overexpression suppresses iron overload and lipid peroxidation. Furthermore, we reveal that HAX1 maintains redox homeostasis by regulating the GSH\/GPX4 antioxidant pathway. Knockdown of HAX1 depletes reduced glutathione (GSH), reduces glutathione peroxidase activity, and downregulates key ferroptosis defense proteins, including GPX4, FSP1, and SLC7A11. Our findings identify HAX1 as a critical promoter of HCC progression that functions by inhibiting ferroptosis through the modulation of iron homeostasis and the GSH\/GPX4 pathway. Targeting the HAX1-mediated anti-ferroptotic mechanism may represent a promising therapeutic strategy for HCC treatment.<\/jats:p>","DOI":"10.3390\/ijms27135935","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T12:41:38Z","timestamp":1782909698000},"page":"5935","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["HAX1 Promotes Hepatocellular Carcinoma Progression by Inhibiting Ferroptosis Through Modulation of Iron Homeostasis and the GSH\/GPX4 Pathway"],"prefix":"10.3390","volume":"27","author":[{"given":"Yueyue","family":"Guo","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Zhou","sequence":"additional","affiliation":[{"name":"Food Safety and Nutrition Experimental Teaching Demonstration Center, Department of Food Science and Engineering, Xinjiang Institute of Technology, Aksu 843000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jizhe","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaomiao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Food Safety and Nutrition Experimental Teaching Demonstration Center, Department of Food Science and Engineering, Xinjiang Institute of Technology, Aksu 843000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delong","family":"Xie","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangui","family":"Yi","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongling","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cld.2022.08.004","article-title":"Hepatocellular Carcinoma: New Developments","volume":"27","author":"Ganesan","year":"2023","journal-title":"Clin. Liver Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Saqib, H.W., Khan, M.I., Hayat, T., Haider, S.S.E., Shah, M.I., Nabi, R., Wijdan, S.A., Bashir, R., and Khan, T. (2026). Safety and Efficacy of Radiotherapy Plus Immunotherapy in Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Asia-Pac. J. Clin. Oncol.","DOI":"10.1111\/ajco.70116"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.31557\/APJCP.2026.27.4.1377","article-title":"A Network Meta-Analysis Comparing the Efficacy of Lenvatinib, Atezolizumab plus Bevacizumab, and Sorafenib in the Treatment of Unresectable Hepatocellular Carcinoma","volume":"27","author":"Remitha","year":"2026","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/s41580-024-00703-5","article-title":"The cell biology of ferroptosis","volume":"25","author":"Dixon","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/s41392-024-01769-5","article-title":"Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies","volume":"9","author":"Zhou","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e2203973","DOI":"10.1002\/advs.202203973","article-title":"Targeted xCT-mediated Ferroptosis and Protumoral Polarization of Macrophages Is Effective against HCC and Enhances the Efficacy of the Anti-PD-1\/L1 Response","volume":"10","author":"Tang","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e2301928","DOI":"10.1002\/advs.202301928","article-title":"PGAM1 Inhibition Promotes HCC Ferroptosis and Synergizes with Anti-PD-1 Immunotherapy","volume":"10","author":"Zheng","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s13045-024-01599-6","article-title":"METTL16-SENP3-LTF axis confers ferroptosis resistance and facilitates tumorigenesis in hepatocellular carcinoma","volume":"17","author":"Wang","year":"2024","journal-title":"J. Hematol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.jhep.2023.03.016","article-title":"ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis","volume":"79","author":"He","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3155","DOI":"10.1111\/1759-7714.13634","article-title":"HAX1 enhances the survival and metastasis of non-small cell lung cancer through the AKT\/mTOR and MDM2\/p53 signaling pathway","volume":"11","author":"Liang","year":"2020","journal-title":"Thorac. Cancer"},{"key":"ref_11","first-page":"6375025","article-title":"Cytoplasmic HAX1 Is an Independent Risk Factor for Breast Cancer Metastasis","volume":"2019","author":"Szafron","year":"2019","journal-title":"J. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11170","DOI":"10.1111\/jcmm.17038","article-title":"HAX1 maintains the glioma progression in hypoxia through promoting mitochondrial fission","volume":"25","author":"Lin","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1186\/s12964-025-02353-2","article-title":"HAX1 inhibits apoptosis and promotes maturation of neutrophils","volume":"23","author":"Yue","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.yexcr.2019.04.030","article-title":"HAX-1 promotes the migration and invasion of hepatocellular carcinoma cells through the induction of epithelial-mesenchymal transition via the NF-\u03baB pathway","volume":"381","author":"Hu","year":"2019","journal-title":"Exp. Cell Res."},{"key":"ref_15","first-page":"8099","article-title":"HAX-1 is overexpressed in hepatocellular carcinoma and promotes cell proliferation","volume":"8","author":"Wang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"116512","DOI":"10.1016\/j.biopha.2024.116512","article-title":"GPX4, ferroptosis, and diseases","volume":"174","author":"Zhang","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.62347\/SIGP9279","article-title":"Potential therapies for HCC involving targeting the ferroptosis pathway","volume":"14","author":"Li","year":"2024","journal-title":"Am. J. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1517\/14728222.2011.561787","article-title":"Hax-1: A regulator of calcium signaling and apoptosis progression with multiple roles in human disease","volume":"15","author":"Simmen","year":"2011","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tice.2018.07.001","article-title":"HAX1 is associated with neuronal apoptosis and astrocyte proliferation after spinal cord injury","volume":"54","author":"Lu","year":"2018","journal-title":"Tissue Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/s41419-022-04748-2","article-title":"Anti-apoptotic HAX-1 suppresses cell apoptosis by promoting c-Abl kinase-involved ROS clearance","volume":"13","author":"Dong","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"E6466","DOI":"10.1073\/pnas.1508760112","article-title":"HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart","volume":"112","author":"Lam","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4631","DOI":"10.1074\/jbc.RA119.012361","article-title":"Hepatic HAX-1 inactivation prevents metabolic diseases by enhancing mitochondrial activity and bile salt export","volume":"295","author":"Alogaili","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.cell.2005.07.013","article-title":"Efficient transposition of the piggyBac (PB) transposon in mammalian cells and mice","volume":"122","author":"Ding","year":"2005","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Xie, D., Zhou, J., Guo, Y., Wan, G., Lu, F., Guo, Y., Yi, S., and Liu, Z. (2026). miR-135a-5p exerts tumor-suppressive effects in 769P renal carcinoma cells through the TFAP2A\/KRT8 signaling axis. Vitro Cell. Dev. Biol.\u2013Anim.","DOI":"10.1007\/s11626-026-01188-6"},{"key":"ref_25","first-page":"71","article-title":"An improvement of the 2\u02c6(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis","volume":"3","author":"Rao","year":"2013","journal-title":"Biostat. Bioinform. Biomath."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5935\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T12:46:26Z","timestamp":1782909986000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5935"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":25,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135935"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135935","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]}}}