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HIF1A, a central regulator of the hypoxic response, is known to be regulated by several metabolites. This study aims to elucidate whether L-2-HG regulates the function of HIF1A through histone lactylation modification, thereby contributing to brain metastasis in renal cell carcinoma (RCC). A mouse model of RCC brain metastasis was constructed, and high-throughput metabolomics, transcriptomics, and proteomics sequencing analyses were conducted. Bioinformatics analysis revealed that L-2-HG enhanced HIF1A expression by promoting histone lactylation modification, which suppressed ferroptosis and facilitated RCC brain metastasis. In vitro cellular experiments were conducted, including cell treatment, transfection, chromatin immunoprecipitation (ChIP), malignant phenotype detection assays, Western blotting, and RT-qPCR. The results showed that L-2-HG increased the lactylation modification of HIF1A and enhanced the resistance of renal cancer cells to ferroptosis, thereby increasing cell proliferation, migration, and invasion. In vivo experiments using a nude mouse lung metastasis model demonstrated the mechanism through which L-2-HG promoted RCC brain metastasis.<\/jats:p>","DOI":"10.1038\/s41419-025-08068-z","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T15:21:43Z","timestamp":1762442503000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Novel role of L-2-HG in regulating HIF1A signaling pathway and iron death resistance in renal cancer brain metastasis"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9952-7235","authenticated-orcid":false,"given":"Guangxiang","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixiang","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuiqiang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renjie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4042-2526","authenticated-orcid":false,"given":"Hongqian","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"8068_CR1","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1158\/0008-5472.CAN-22-2224","volume":"83","author":"Z Yu","year":"2023","unstructured":"Yu Z, Lv Y, Su C, Lu W, Zhang R, Li J, et al. 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