Hepatocellular carcinoma (HCC) is a common malignant tumor with a high recurrence rate and a poor prognosis. Long intergenic nonprotein coding RNA 942 (LINC00942) is reported to be related to ferroptosis and the immune response in HCC and serves as an oncogene in various cancers. This research aimed to explore the contribution of LINC00942 in HCC progression. Functional assays were used to evaluate the functional role of LINC00942 in vitro and in vivo. Mechanistic assays were conducted to assess the association of LINC00942 with insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) and solute carrier family 7 member 11 (SLC7A11) and the regulatory pattern of LINC00942 in HCC cells. LINC00942 was found to exhibit upregulation in HCC tissue and cells. LINC00942 facilitated HCC cell proliferation, suppressed ferroptosis, and converted naive CD4⁺ T cells to inducible Treg (iTreg) cells by regulating SLC7A11. Furthermore, SLC7A11 expression was positively modulated by LINC00942 in HCC cells. IGF2BP3 was a shared RNA-binding protein (RBP) for LINC00942 and SLC7A11. The binding between the SLC7A11 3′ untranslated region and IGF2BP3 was verified, and LINC00942 was found to recruit IGF2BP3 to promote SLC7A11 mRNA stability in an m6A-dependent manner. Moreover, mouse tumor growth and proliferation were inhibited, and the number of FOXP3⁺CD25⁺ T cells was increased, while ferroptosis was enhanced after LINC00942 knockdown in vivo. LINC00942 suppresses ferroptosis and induces Treg immunosuppression in HCC by recruiting IGF2BP3 to enhance SLC7A11 mRNA stability, which may provide novel therapeutic targets for HCC.

肝细胞癌（HCC）是常见的恶性肿瘤，复发率高，预后差。据报道，长基因间非蛋白编码 RNA 942 (LINC00942) 与 HCC 中的铁死亡和免疫反应有关，并在多种癌症中充当癌基因。本研究旨在探讨 LINC00942 在 HCC 进展中的贡献。使用功能测定来评估 LINC00942 的体外和体内功能作用。进行机制测定以评估 LINC00942 与胰岛素样生长因子 2 mRNA 结合蛋白 3 (IGF2BP3) 和溶质载体家族 7 成员 11 (SLC7A11) 的关联以及 LINC00942 在 HCC 细胞中的调节模式。 LINC00942 被发现在 HCC 组织和细胞中表现出上调。 LINC00942 通过调节 SLC7A11 促进 HCC 细胞增殖，抑制铁死亡，并将初始 CD4 ⁺ T 细胞转化为诱导性 Treg (iTreg) 细胞。此外，HCC 细胞中的 SLC7A11 表达受到 LINC00942 的正向调节。 IGF2BP3 是 LINC00942 和 SLC7A11 共享的 RNA 结合蛋白 (RBP)。验证了SLC7A11 3'非翻译区与IGF2BP3之间的结合，发现LINC00942招募IGF2BP3以m6A依赖性方式促进SLC7A11 mRNA稳定性。此外，在体内敲除LINC00942后，小鼠肿瘤生长和增殖受到抑制，FOXP3 ⁺ CD25 ⁺ T细胞数量增加，而铁死亡增强。 LINC00942通过招募IGF2BP3增强SLC7A11 mRNA稳定性来抑制HCC中的铁死亡并诱导Treg免疫抑制，这可能为HCC提供新的治疗靶点。