Fibrinolysis plays a crucial role in maintaining coagulation homeostasis, but its functions in hepatocellular carcinoma (HCC) remain poorly understood. This study aimed to develop a fibrinolysis-based molecular classification and prognostic signature for HCC and to identify a key regulatory gene. Using non-negative matrix factorization (NMF), we identified distinct fibrinolysis-related HCC subtypes with specific clinical outcomes and tumor microenvironment characteristics. A six-gene prognostic signature comprisingACAT1,GRHPR,HPX,PCK2,IYD, andPON1was established through weighted gene co-expression network analysis (WGCNA) and LASSO-Cox regression, which effectively stratified patients into different risk groups across multiple cohorts. Hemopexin (HPX) was identified as the top candidate and functionally validated: HPX overexpression suppressed clonogenicity and migration, promoted apoptosis, and inhibited xenograft tumor growth. RNA sequencing analysis suggested associations between HPX and apoptosis as well as TNF-α signaling pathways, which were confirmed through flow cytometry apoptosis assays, mitochondrial membrane potential measurements, and TUNEL staining. Western blot and immunohistochemical analyses further demonstrated that HPX upregulates the Bax/Bcl-2 ratio via the TNF-α signaling pathway. This study defines novel molecular subtypes of HCC and reveals that HPX exerts anti-tumor effects through TNF-α-mediated mitochondrial apoptosis, characterized by an increased Bax/Bcl-2 ratio.
纤维蛋白溶解在维持凝血稳态中发挥关键作用，但其在肝细胞癌（HCC）中的功能尚不明确。本研究旨在建立基于纤维蛋白溶解的HCC分子分型及预后标志物，并识别关键调控基因。通过非负矩阵分解（NMF）方法，我们识别出具有特定临床结局和肿瘤微环境特征的纤维蛋白溶解相关HCC亚型。利用加权基因共表达网络分析（WGCNA）和LASSO-Cox回归，构建了包含ACAT1、GRHPR、HPX、PCK2、IYD和PON1的六基因预后标志物，该标志物能在多个队列中有效将患者分层至不同风险组。血红素结合蛋白（HPX）被确定为最优候选基因，并通过功能实验验证：HPX过表达能抑制克隆形成与迁移能力，促进细胞凋亡，并抑制异种移植瘤生长。RNA测序分析提示HPX与细胞凋亡及TNF-α信号通路存在关联，该结果通过流式细胞术凋亡检测、线粒体膜电位测定及TUNEL染色得到证实。Western blot和免疫组化分析进一步表明，HPX通过TNF-α信号通路上调Bax/Bcl-2比值。本研究定义了新型HCC分子亚型，并揭示HPX通过TNF-α介导的线粒体凋亡途径发挥抗肿瘤作用，其特征表现为Bax/Bcl-2比值升高。
Hemopexin Suppresses Hepatocellular Carcinoma via TNF-α-Mediated Mitochondrial Apoptosis
肿瘤(癌症)患者之家